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Volume 8 Issue 1

Peer Reviewed International Pharmaceutical Industry

Supporting the industry through communication

Applications of CRISPR Contribution of Circulating Tumor Cells In Drug Development Parenteral Manufacturing And Industry 4.0 Tackling Global Counterfeiting

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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 Marline Symmonds 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 June 2016. ISSN No. International Pharmaceutical Industry ISSN 1755-4578. The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright. 2016 PHARMA PUBLICATIONS Volume 8 issue 1 - Spring - 2016

08 Exploring the Opportunities and Challenges in Repurposing a Master Dossier It is known that developing an innovative healthcare product from bench to market is a very expensive and complex effort, as the pharmaceutical industry is highly regulated to protect the consumer. Global spend on medicines is forecast to reach nearly $1.4 trillion by 2020, an increase of about 32% over 2015. This is driven by population growth and improved access to emerging markets. Interestingly, the revenue driver at many leading companies remains the innovative medicines portfolio, despite some companies diversifying into generics, consumer medicines, diagnostics and other related healthcare products. Bindu Narang, Director of Scientific Writing Regulatory Affairs, with Dr Rajendra Wable, Regulatory Writing Coach, Scientific Writing and Regulatory Affairs at Sciformix Corporation, explore the opportunities and challenges in repurposing a master dossier. 14 The Total IDMP Effort – an Insight into the Data Volume of an ISO IDMP Submission It has, since 2012, been a well-established fact that pharmaceutical companies which have medicinal products or are conducting clinical trials in the European Union (EU) will have to adhere to the ISO standards mandated in EU Regulation 520/2012. With the aim of improving overall pharmacovigilance signal detection and oversight, the European Medicines Agency (EMA) will rely on these standards (11615, 11616, 11238, 11239 & 11240) to achieve this goal. Niels Grønning and Rune Ringsholm Bergendorff at NNIT give us an insight into the data volume of an ISO IDMP submission. 18 Why Agility Holds the Key to Transformation in Life Sciences The priority that will unite all life sciences companies in 2016 is the pursuit of greater agility. As long as organisations keep taking a short-term view, investing in standalone information management systems for each new business requirement, the only thing they’ll successfully grow is cost, warns Mark Evenepoel, Group CEO at Amplexor Life Sciences. The real focus should be flexibility and responsiveness to whatever the market demands next. 22 How to Protect your IP Rights Abroad Many life sciences companies which protect their inventions, brands or product designs through patents, trademarks or registered designs in their home country, do not realise that this does not give them automatic protection in other countries. Intellectual property rights are territorial rights, meaning that the protection afforded by a granted patent or a registered trade mark is geographically limited. Jim Robertson at Wynne-Jones IP submits his white paper on IP rights abroad. DRUG DISCOVERY, DEVELOPMENT & DELIVERY 26 Applications of CRISPR Scientific interest in Clustered Regularly Interspaced Palindromic Repeats (CRISPR) systems exploded in 2012/2013 when focus shifted from their natural function as a component of adaptive bacterial immunity to their use as a toolkit to find, cut and replace DNA at a specific location in eukaryotes. Widely considered to be a breakthrough technology, the speed of adoption of this technology has been phenomenal. Catherine Coombes, Senior Patent Attorney at HGF Limited concentrates on applications of CRISPR. 30 Contribution of Circulating Tumour Cells in Drug Development Circulating tumour cells (CTCs) are becoming very welcome in the field of oncology, and they are also promising in the clinical field, in the area of drug development. Proof of concept that CTCs may correlate with the prognosis of cancer has been completed for many types already. Also, the CTCs may carry information that is relevant to the disease progression and behaviour and this data cannot be obtained from the primary tumour. Hence they are becoming

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Contents extremely valuable in the field of drug development and evaluation of candidate medications in pharmaceutical research and industry. Dr Ioannis Papasotiriou, MD at RGCC, discovers the contribution of circulating tumour cells in drug development. 34 Where are the Gaps in your Data? In drug discovery, data is king. Gathering the right information makes it easier to design better compounds, faster. How can you be sure that you are getting the most out of your SAR data? And how easy is it to see where the gaps are in your data? A typical lead optimisation phase of a drug discovery project will gather many thousands of data points. Hundreds, or even thousands, of compounds will be synthesised over the course of the project, and each of these compounds has an associated wealth of potency, selectivity and ADMET information. Katriona Scoffin and Giovanna Tedesco answers the question asked; where are the gaps in your data? 38 Engineering of Enzymes for Industrial Biocatalysis Enzymes are important biocatalysts with many applications in medicine, food technology and the chemical industry. To further expand their reaction scope and to meet the demands of industrial processes, the enzymes’ properties are routinely optimised by protein engineering. Due to a rapidly increasing number of protein sequences and structures and powerful computational tools, rational approaches are nowadays complementing random approaches. However, in most cases combined approaches prove to be most successful. Dr Kerstin Steiner, Project Manager and Senior Researcher at the Austrian Center of Industrial Biotechnolgy (ACIB) submits a white paper on enzyme engineering for industrial biocatalysis. CLINICAL RESEARCH 42 Systemic Epigenetic Biomarkers for ALS Improve Early Diagnosis, Treatment, and Trials Amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease is a devastating, rapidly progressive and invariably fatal neurological disease that attacks the nerve cells responsible for controlling voluntary muscles and for which there is no diagnostic or prognostic test. The disease belongs to a group of disorders known as motor neuron diseases (MNDs), characterised by the gradual degeneration and death of motor neurons. ALS is one of the most common neuromuscular diseases worldwide, affecting around 2 in 100,000 people each year. Magdalena Jeznach, BSc MSc, ALS Project Manager at Oxford Biodynamics Ltd, focuses on systemic epigenetic biomarkers for ALS. 46 Genomics and Precision Medicine: Marketing Challenges and Opportunities In an age of big data, companies now have more power to respond to their customers as individuals. Ever since the first internet shops discovered that tracking users’ buying habits could help them to predict what other products users might be interested in, a personalised and tailored service is something companies strive to deliver and consumers increasingly expect. Within this editorial, Jan Van den Burg at Veeva Systems shares his thoughts on genomics and precision medicine, reflecting on marketing challenges and opportunities. LABS AND LOGISTICS 50 Temperature-controlled Packaging: More Than Just an Insulated Box The demand to frequently transport temperature-sensitive products with greater compliance and often in more difficult conditions is increasing. This places temperature-controlled packaging manufacturers under immense pressure to achieve temperature stability in more efficient and robust ways. This has resulted in a marked shift in the temperature-controlled packaging sector, as manufacturers are having to provide increasingly sophisticated

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packaging solutions, to ensure that the high-value payloads reach their destination on time and intact. Neil Sherman, Technical Services Manager at Intelsius, explains why temperature-controlled packaging is more than just an insulated box. TECHNOLOGY 54 Reinventing Data Management, with R&D at the Centre R&D generates a wealth of vital data, which is pivotal to everything else a life sciences organisation does. Yet there is often great diversity in the way this is collected, retained and accessed. This lack of consistency compromises the ability to track products effectively, both within the business and out in the market. The new ISO Identification of Medicinal Products (IDMP) standards couldn’t have come at a better time then, says Steve Scribner, life sciences advisor to AMPLEXOR Group. 58 The Digital Age: Tackling the Challenges and Embracing the Opportunity The life sciences industry has always been incredibly innovative in its R&D and bringing new life-saving and -changing medicines, devices, diagnostic tools and products to market. However, it has often been a late adopter of new communication technologies, platforms, and channels – perhaps understandably, given the highly-regulated life sciences operating environment. In this digital age, with information instantly available with a few keyboard strokes or taps on the latest smartphone or wearable, our world is changing exponentially, and with it, the needs, wants, and demands of patients, carers, healthcare providers, and payers across the globe. Susan Macdonald, Founder and Director at Macdonald Lewis Associates (MLA) guides us to the digital age, by focusing on the challenges and opportunities. 62 Digital Health: Increasing the Quality and Efficiency of Care New technologies allow for direct patient care and necessitate an overhaul in the focus of healthcare industry business models. It is becoming clear that in order to stay relevant in the future healthcare ecosystem, pharma companies must look to business models that foster much more direct patient engagement than previously. New methods offer significant potential in increasing the quality and efficiency of care. Digital health solutions could therefore solve the major long-term issues of pharma’s most important client groups – patients, providers and payers – all at the same time. Ulrica Sehlstedt, Nils Bohlin, Fredrik de Maré and Richard Beetz at Arthur D. Little describe how digital is reshaping the pharma arena. MANUFACTURING 64 Comparison of Good Manufacturing Practice Compliance Requirements – European Union, United States and India The intentions of the current study are to expedite the compliance requirements to support the regulatory approval for selected pharmaceuticals in the United States, the European Union and India. The literature search is done using different resources like regulatory authority websites, pharmaceutical review articles, journals and public domain. To ensure the quality, all pharmaceutical manufacturers are required to establish and implement effective quality management systems. B. Naga Vamsi, Balamuralidhara V., Shenaz Z Khaleeli and Srinath S from JSS College of Pharmacy compare the GMP compliance requirements in Europe, the US and India. 68 Parenteral Manufacturing and Industry 4.0 Industry 4.0 will be a game changer in how the patient will interact with all the partners who are involved in all aspects of the wellbeing of the end-user. Real-time data on the status of the health situation of the individual will have the possibility of flowing seamlessly to an array of partners. Morten Munk and Gert Moelgaard at NNE Pharmaplan submit an overview of parenteral manufacturing.

Spring 2016 Volume 8 Issue 1


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Contents 72 Designing for Quality Over the past several years, there has been a steady rise in new biologic drugs coming onto the market for the treatment of chronic conditions such as multiple sclerosis, rheumatoid arthritis and autoimmune diseases. This trend is likely to continue in the future, with the IMS Institute for Healthcare Informatics predicting that the market for biologics will grow to $221 billion by 2017. Along with this new class of drugs comes a corresponding increase in selfadministration systems, which offer patients who must repeatedly self-dose the freedom to do so outside of the doctor’s office or clinic. The following article by Mike Schäfers, Vice President of Global Product Management and Marketing Operations at West Pharmaceutical Services, highlights the quality of design in pharmaceutical manufacturing. PACKAGING 76 Cold Chain Outsourcing: A Simple Answer to a Complex Question? Pharmaceutical manufacturers are facing a new challenge. The recent patent cliff and the exponential growth in the development of high-value pharmaceutical products, biologically developed therapies and live vaccines in the last ten years, has resulted in a greater need for temperature-assured handling of drug product, from active ingredients to finished dosage form. This can be demonstrated by the fact that in 2013, seven of the top ten highest-selling pharma products were biologics, with global sales contribution from biologic drugs forecasted to jump from 23% in 2014 to 27% in 2020. Fiona Withey, Chief Executive Officer at PCI, shares her thoughts on cold chain outsourcing. 80 Improving Adherence: Packaging’s Synergistic Role in Delivery, Communication and Education On 9 February 2016, the European Parliament and Council published the amended version of the Falsified Medicines Directive (FMD), detailing the characteristics of the security features that will be required on packaging for medicinal products for human use. It stated that both a unique identifier and an anti-tampering device will be mandatory, helping to address the current ever-growing threat of counterfeit medicines. Ian Lemon at Essentra reviews global counterfeiting. 84 Automating the De-blistering Process This article, by Luke Beedle, Sales Support Manager at Sharp Clinical Services, provides an overview of why de-blistering is required, what issues this creates, and how automated de-blistering technology can be implemented to improve run rates, increase efficiency, lower costs and help reduce risks to staff. Blister-packs are a very common means of packaging pharmaceutical tablets, capsules and soft gels. Such packs generally comprise a sheet of initially flat plastic or aluminium base material, in which is formed a series of wells. A tablet is inserted into each of the wells, the open ends of which are sealed by means of a sheet of aluminium foil which is attached to the base material sheet. Each tablet is thus sealed in its own well until use, when the base material well is depressed by finger pressure and the tablet is forced out through the foil backing. 88 Why Do Pharmaceutical Glass Containers Break: The Underestimated Power of Strength Testing and Fractography Most times in our life we use products with little understanding of how and why the packaging was selected. We usually don’t think about the design specifications of the container and its crucial role in delivering the contents safely. It is only when a problem occurs that we dig deeper into the selection criteria and science that were used to specify the packaging system. In the pharmaceutical industry, glass is by far the dominant material used for the packaging of liquid and lyophilised drugs due to its impermeability and chemical inertness for drug product stability, transparency for ease of inspection, thermal stability for flexible use and processing, low extractables and leachables, and cost. The main focus of this paper is the reason for pharmaceutical glass containers fracture by Dan Haines, Florian Maurer and Uwe Rothhaar at Schott. 4 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Spring 2016 Volume 8 Issue 1


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Editor's Letter Quality-by-design (QbD) is now a well-established and commonly employed approach to the development and commercialisation of products in the pharmaceutical industry. According to a 2012 survey conducted by Kourti and Davis, eleven of the twelve pharmaceutical companies surveyed indicated they use QbD to some capacity in the development process. The benefits were clearly articulated and companies agreed that QbD was the right philosophy for better product and process understanding. QbD is, by definition, a data-driven process with the goals of achieving maximum process understanding and control focused on science and quality risk management. Several rounds of design of experiments (DoEs), criticality and risk assessments are needed in order to establish the overall control strategy and the ongoing process verification and improvement approach. Therefore, good documentation and knowledge transfer practices are critical to success, particularly for commercialising products throughout a network of external suppliers.

quality systems. The key to a successful relationship, one built to endure through the lifetime of the product, is to move as many items as possible into the shared ownership realm while minimising the competing obstacles. In this issue of IPI, Mike Schäfers, Vice President, Global Product Management and Marketing Operations, West Pharmaceutical Services, highlights the quality of design in pharmaceutical manufacturing.

digital age, by focusing on the challenges and opportunities. The Manufacturing section starts off with a comparison of good manufacturing practice compliance requirements in the European Union, United States and India, by our esteemed colleagues at JSS College of Pharmacy, followed by parenteral manufacturing and Industry 4.0, which is explained by Morten Munk and Gert Moelgaard at NNE Pharmaplan.

Scientific interest in Clustered Regularly Interspaced Palindromic Repeats (CRISPR) systems exploded in 2012/2013, when focus shifted from their natural function as a component of adaptive bacterial immunity to their use as a toolkit to find, cut and replace DNA at a specific location in eukaryotes. Widely considered to be a breakthrough technology, the speed of adoption of this technology has been phenomenal. In the Drug Discovery section, Catherine Coombes, Senior Patent Attorney at HGF Limited, concentrates on the applications of CRISPR.

In the Packaging section, Fiona Withey, Chief Executive Officer at PCI, shares her thoughts on cold chain outsourcing, and Ian Lemon at Essentra reviews global counterfeiting. Dan Haines, Florian Maurer and Uwe Rothhaar at Schott explain why pharmaceutical glass containers break and the solution to that problem.

The new ISO Identification of Medicinal Products (IDMP) standards couldn’t have come at a better time. In the Technology section, Steve Scribner, Life Sciences Advisor to AMPLEXOR Group, discusses reinventing data management with R&D at the centre, and Susan Macdonald, Founder and Director at Macdonald Lewis Associates (MLA), guides us to the

IPI has now launched its social media channels. Please visit www. ipimediaworld.com, and follow us on Twitter, Facebook, Google Plus and Tumblr.

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

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

There is still a high degree of variability in the documentation needed for QbD implementation (including knowledge transfer) among different clients, which might present challenges for the CMO’s

I hope you all enjoy the first IPI issue of 2016. We look forward to bringing you more interesting features in the summer issue.

Orsolya Balogh Editor

Editorial Advisory Board

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

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

Spring 2016 Volume 8 Issue 1


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Regulatory & Marketplace

Exploring the Opportunities and Challenges in Repurposing a Master Dossier It is known that developing an innovative healthcare product from bench to market is a very expensive and complex effort, as the pharmaceutical industry is highly regulated to protect the consumer. Global spend on medicines is forecast to reach nearly $1.4 trillion by 2020, an increase of about 32% over 2015. This is driven by population growth and improved access to emerging markets.1 Interestingly, the revenue driver at many leading companies remains the innovative medicines portfolio, despite some companies’ diversification into generics, consumer medicines, diagnostics and other related healthcare products. To save time and money in bringing products to market, product development activities should be conducted in accordance with predefined global and region-specific regulatory requirements.

proving that the drug has quality, efficacy and safety properties suitable for the intended use, additional administrative documents, samples of finished product or related substances and reagents necessary to perform analyses of finished product as described in that dossier. The content and format of the dossier must follow rules as defined by the competent authorities. For example, since 2003, the authorities in the US, the European Union and Japan ask for the common technical document (CTD) format, and more recently, its electronic version – the electronic common technical document (eCTD). The application is filed with the competent drug regulatory authority in the concerned country, which can be either an independent regulatory body or a specialised department in the ministry of health.

For any biopharmaceutical, submitting a new drug application (NDA) is the ultimate goal and a mandatory step for commercialisation. As biopharmaceutical companies plan to put their product out in multiple markets, they have to consider a global regulatory strategy for registration in the developed countries as well as in several emerging market countries. However, differing registration requirements across markets are a burden. Knowledge of the drug registration processes and submission content is key for effective planning and execution of global regulatory strategy. A step-by-step approach is essential to make any global submission successful.

In accordance with local legislation, the resulting document allowing the applicant to market the product may be more detailed (in addition to data identifying the product and its holder, it may contain addresses of all manufacturing sites, appended labelling, artwork of packaging components, etc.) to a one-page document called the certificate of registration (containing

minimal data identifying the product and its source). Harmonisation of Technical Requirements for Registration of Pharmaceuticals Given the major resources needed to assemble registration dossiers in multiple countries, there has always been an incentive to promote as much similarity as possible in the regulatory requirements and content of registration applications. Through the International Conference on Harmonization (ICH) process, considerable harmonisation has been achieved among the US, Europe and Japan in the technical requirements for the registration of pharmaceuticals. However, until now, there has been no harmonisation of the organisation of the registration documents. To avoid the need to generate and compile different registration dossiers, the agreement to assemble all the quality, safety and efficacy information in a CTD (Figure 1) has revolutionised the regulatory review processes. For industries, it has eliminated the need to reformat the information for submission to the different ICH regulatory authorities. Non-ICH countries have also expressed the need to ensure harmonisation, which

This article will discuss regulatory requirements for product registration in different geographic regions, key similarities and differences in the regulatory requirements and the opportunities and challenges in repurposing or reformatting an existing market dossier for registration in new markets worldwide. Background The application dossier for marketing authorisation is called an NDA in the US or marketing authorisation application (MAA) in the European Union and other countries, or simply registration dossier. It consists of a dossier with data 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 1: The CTD is organised into five modules. Module 1 is region-specific and modules 2, 3, 4 and 5 are common for all regions. Spring 2016 Volume 8 Issue 1


Corporate Profile How does it work?

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The Vision of Dr.Heinrich Handel-Mazzetti and Esther van der Graaf We have decades-long experience in the healthcare industry. In our daily business we often deal with the challenge of finding suitable business partners for various corporations who want to expand their markets or product ranges in a particular region, or even worldwide. It was through this continued challenge that a determination arose to solve this problem, and make finding the right business partners a lot more efficient and convenient. A leading design philosophy was to stay true to the primary goal of bringing together business partners based on mutual demands. Therefore we committed ourselves to provide an independent, accessible, easy to use site with a low priced membership so every interested company can afford to become a member.

The business model is based on a Membership Fee. With Full Membership companies can; • be found and automatically matched connect with business partners • search for business partners in a certain region with common business interests • start business development in an easy and efficient way • search through the system for a reliable contact • introduce their company • introduce their products • visit their My Matches page to see which companies matched including the matching specifications • visit their My Alerts page to see which companies “found” their company incl. the alert specification • directly follow up with the potential business partner through the my matches or my alerts page In addition full members can directly search the site, filter information to customize a search and save the search for future reference. If a member chooses to contact a potential business partner then this happens outside of the site through the regular e-mail, phone or other means which guarantees that communications are private and between members only. www.ipimedia.com www.animalhealthmedia.com

As such, we believe we have created the greatest independent international platform for reliable business partners, truly bringing the medical world together in an easy and efficient way! After two years in development gomed2med.com was launched in April 2015. • •

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We have exhibited at CPHI/Madrid and Medica Düsseldorf, and got very positive reactions from our members getting matched 365 days/7 days a week! This is how to develop business in the future!

INTERNATIONAL PHARMACEUTICAL INDUSTRY 9 International Animal Health Journal 69


Regulatory & Marketplace has resulted in regional initiatives. In Asia and the South Pacific, the Association of South-East Asian Nations (ASEAN) countries has agreed to a common approach to medicines regulation, and established an ASEAN CTD to harmonise pharmaceutical product dossiers, much like has been done with ICH. In Latin America the Pan American Health Organization (PAHO) via the Pan American Network for Drug Regulatory Harmonization (PANDRH) is aiming to establish a regional drug regulatory harmonisation network and now has a working group on drug registration.

account for 52% of the projected increase in total medicines spending of $305$335 billion.3 With the slowing growth in developed markets, biopharmaceutical companies have made substantial investments into emerging markets, striving for rapid, simultaneous global launches. Aligning regulatory strategy across countries saves time and cost for drug developers, and results in quicker access by patients. Hence, it is a logical approach to reuse and reformat the core dossier submitted in regulated countries to meet

Table 1. Difference between ASEAN CTD and ICH CTD Despite the harmonisation initiatives, the structure and content of the product dossier today differs from region to region and country to country. From the industry perspective, harmonisation would increase the registration and marketing chances of a particular molecule in several countries in a short time. Reduced development time, less cumbersome approval processes across countries, and increased speed-to-market are important business drivers. In addition, harmonisation would give patients faster access to new medicines and might lower the costs of drug development, which could lower the price, making new drugs more affordable in many more markets. The Demand to Repurpose Dossiers New product introductions are on the rise, with 86 new drugs being approved across the US and EU in 2014.2 In the past years, the rate of new drug approvals by the US Food and Drug Administration (FDA) was greater than 80%. Despite unmet therapeutic need, these players can no longer depend only on their innovation engine and pricing to drive profits. As the focus of global healthcare shifts from value to volume, generics and biosimilars have become an integral part of the strategy. Generics are the largest contributors to growth in both regulated and emerging markets; many companies are monitoring patent expiries and developing generics of small molecules as well as biologics (i.e. biosimilars). On a global basis, generics are forecast to 10 INTERNATIONAL PHARMACEUTICAL INDUSTRY

region- or country-specific registration requirements. Development of and regulatory approval for ‘new uses’ of alreadyapproved drugs is an important source of innovation. One study that analysed the number of supplemental-indication approvals by US FDA found over 1000 new-use approvals during 19982011.4 Additionally, the number of new paediatric indications rose substantially over this period due to a legislated market incentive to study already-approved drugs in paediatric populations.4 This provides an opportunity to reuse the sections or data from the alreadysubmitted dossiers to support the new application with its specific requirements. Approach to Repurposing of a Master Dossier Preparing one core dossier and adapting it to the regional specificities can optimise resources and may lead to a faster global registration. Similarly, a sequential approach can allow the applicant to obtain feedback from the first agency and make adjustments to the second dossier prior to its submission. For many biopharmaceuticals, the core or master dossier generally contains the most comprehensive CMC, nonclinical and clinical information available on the product from a regulatory point of view. This master dossier forms the basis of the international master dossier

for the non-ICH countries. Generally, the master dossier is kept up-to-date with all new information requested by health authorities from the time of initial approval and through the product’s life cycle. These updated core dossiers are tailored to suit other country-specific submission formats and requirements. From this core dossier, the CMC sections are shortened for confidentiality and intellectual property issues. For a generic, a company develops a dossier that contains data primarily about the pharmaceutical chemistry of the product and some limited clinical data. In some instances, a product can be registered on the basis of chemical and manufacturing data only, describing the method of synthesis and quality control for the product. The requirements for generic product registration do vary from country to country, and within a country there are variations in the data required, depending on the type of generic product. Issues can arise, for example, if an applicant just deletes some sections of the ICH dossier and submits an “incomplete” dossier, there is a risk of refusal to file. Therefore it is strongly recommended that only the content in some sections should be reduced to fulfil the regulatory requirement. One possibility to make these changes within the dossier is the creation of a master dossier with a high granularity for documents in order to be able to exchange parts quite easily for the emerging countries. This approach helps limit the highly confidential information and reduces the workload in writing and reformatting. Generally, for any successful submission, creating and managing global submission templates is of paramount importance. Selection of the correct ‘submission template’ for a specific country and submission type is a critical step for successful submission. The primary purpose to develop and use the standard template is to ensure compliance with the regulatory norms of that particular region. Regulatory agencies have provided granularity guidelines and these guidelines vary based on product, agency and submission type. The template needs to be versatile such that it can be used for submissions in CTD in paper format, non-eCTD electronic submissions (NeeS) and for eCTD. Additionally, the template should be user-friendly, and ensure that Spring 2016 Volume 8 Issue 1


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Regulatory & Marketplace regulatory professionals can perform the reformatting with minimal training. Increasing Market Access Through Regulatory Strategy The number of regulatory requirements has grown exponentially as biopharmaceutical companies enter new and disparate markets, but efforts in global regulatory harmonisation have stalled. To support the global growth imperative, regulatory functions must meet the local needs of a greater number of countries, while supporting an expanding list of products and aggressive project timelines. Altering regulatory strategies to meet new business models will generate faster approvals and help propel growth in emerging markets. Biopharmaceutical companies have honed their regulatory submission operating models to facilitate the introduction of new products in the US, Europe, and Japan. But those models are not always transferable to emerging markets. To achieve simultaneous global approvals, companies need to focus on the strategy, capabilities, and processes. An effective global regulatory strategy must address both the differences and the similarities across markets. Companies should maximise common elements of the global dossier while ensuring that each submission for market authorisation can be tailored to meet local regulatory requirements. Standards of care, clinical trial requirements, distribution needs, and local regulations vary greatly across countries and regions. Emerging countries often make product approval contingent upon regulatory approval in a reference country, where the product undergoes a more advanced and rigorous health authority review. To limit approval delays in emerging countries, biopharmaceutical companies can generate the emerging-market filing in parallel with the primary filing and completing pre-reviews with those health authorities so that the filing can be submitted as soon as approval has been granted in the reference country. Companies’ global regulatory strategies should outline the type and sequence of such submissions, taking into account the unique requirements of each country involved in a development plan. Companies must not only evolve their commercial, R&D, and supply chain organisations to meet the needs of the www.ipimedia.com

global marketplace, but they also must adapt their regulatory organisations. It is important for companies to focus on optimising their global footprint with internal resources and strategic partners. The challenge is to develop a sourcing and organisational model that builds global capabilities without increasing cost and infrastructure. Collaboration among global and local resources, both within a company and involving its strategic partners, is essential for delivering products that meet the needs of local markets. Summary In order to protect consumers, the pharmaceutical industry is highly regulated, with rules enforced by the health agencies. These requirements are growing all the time as companies enter new markets. However, regulatory functions must meet the local needs of a greater number of countries, while supporting an expanding list of products and aggressive project timelines. Preparing one core dossier and adapting it to the regional specificities can allow for optimising resources and lead to a faster global registration. Harmonisation would give patients faster access to new medicines and could lower drug costs, making them more affordable in many more markets. By redefining regulatory operating models, companies will be better positioned to achieve nearsimultaneous global market approvals and reach populations in need of their products, wherever those patients may be. References 1. IMS Health, November 2015. Global Medicines Use in 2020. Outlook and Implication. (Internet) http:// www.imshealth.com/en/thoughtleadership/ims-institute/reports/ global-medicines-use-in-2020 [Accessed 20/11/2015] 2. Olga BjĂśrklund, 2015. Europe Vs USA: new drug product approvals in 2014 (Internet) http://www.ndareg. com/new-article-europe-vs-usa-newdrug-product-approvals-in-2014/ [Accessed 04/11/2015] 3. The Pharma Letter, 2014. Global medicines spending to rise 30% by 2018 to $1.3 trillion, says IMS (Internet) http://www.thepharmaletter.com/ article/global-medicines-spending-torise-30-by-2018-to-1-3-trillion-saysims [Accessed 04/11/2015] 4. DiMasi JA. Innovating by developing

Chapter Title new uses of already-approved drugs: trends in the marketing approval of supplemental indications. Clin Ther. 2013;35(6):808-18.

Bindu Narang is a seasoned pharmaceutical professional, and has over 25 years of experience working both with pharmaceutical companies and CROs. She has set up regulatory, medical communications and regulatory operations teams and has worked closely with teams in labelling, medical information services and safety and risk management. Prior to Sciformix, Bindu set up a matrix regulatory writing organisation for Pfizer Global RnD. Bindu holds a Masters degree in pharmaceutical sciences (medicinal chemistry). Bindu currently heads Scientific Writing and Regulatory Affairs at Sciformix Corporation, an SPO incorporated in Massachusetts, in the US; the company also has offices in Manila, Manchester in the UK, and India. Email: bindu.narang@sciformix.com

Dr Rajendra Wable, Subject Matter Expert SWRA, is a post graduate in veterinary science [B.V. Sc. & A. H and M.V. Sc (Veterinary Pathology)]. He is currently managing several regulatory writing projects (preclinical and clinical) and providing support to the global pharmaceuticals for product registration in international markets. He has handson experience in authoring a variety of regulatory submission documents including protocols, clinical study reports, investigator’s brochure, CTD summaries and overviews required for marketing applications. He is also experienced in developing strategies for regulatory submission, responding to health authority queries, biowaiver applications, and biological characterisation of pharmaceutical impurities. He has worked as a study director/study pathologist for various regulatory toxicity studies and managed several PK, PD and toxicology projects. Emai: rajendra.wable@sciformix.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 12


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Regulatory & Marketplace

The Total IDMP Effort – an insight into the data volume of an ISO IDMP submission It has, since 2012, been a wellestablished fact that pharmaceutical companies that have medicinal products or are conducting clinical trials in the European Union (EU) will have to adhere to the ISO standards mandated in EU Regulation 520/2012. With the aim of improving overall pharmacovigilance signal detection and oversight, the European Medicines Agency (EMA) will rely on these standards (11615, 11616, 11238, 11239 & 11240) to achieve this goal. Pharmaceutical companies that are faced with this regulatory requirement must in turn brace themselves for the implications (e.g. financially, organisationally, process, etc.) and the structural changes required to achieve compliance. A natural starting-point to further understand the impact of ISO IDMP is to analyse the data volume required for submission and, even more important, the uniqueness of the data required. But how do you evaluate this while taking into consideration the complexity of the ISO IDMP data models (ISO 11615 & ISO 11238)? Some publications have exemplified the potential data volume and complexity associated with IDMP submission to further support the establishment of a corporate business case. These publications have, however, neglected to take into consideration the data uniqueness across registrations which may significantly implicate the workload and solution scenario chosen to support IDMP compliance. To further qualify this notion, we have analysed the ISO 11615 data model (authorised products) with regard to data uniqueness and areas for potential overlap between registrations. Our initial approach involved the analysis of the ISO 11615 data model with emphasis on the data domains that potentially could be candidates for datasharing across registrations. The marketing authorisation and medicinal product domain both represent 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

domains that we found exhibited the highest degree of data uniqueness across registrations. The data required to fulfil these data domains may be found at a national level (e.g. medicinal product name) and is furthermore tightly linked with the regulatory approval procedure (e.g. approval date, registration number, etc.) which largely is unique. The marketing authorisation class is also one of the predominant classes when it comes to transactional data (e.g. date attributes) which, due to the nature of these data, are considered highly unique. Of notable interest for this article were the areas where we potentially would find data overlaps across registrations. The manufacturer establishment (organisation), packaged medicinal product, pharmaceutical product, clinical particulars and substance IDMP domains were all speculated to represent areas where companies may benefit from data overlap (i.e. data that may be shared across IDMP submissions). Using two fictive products (A & B) and their respective regulatory data, we calculated the individual data volume to further represent the expected data overlap between IDMP submissions. Our calculation was based on a pre-analysis where we had identified areas where we would expect to find potential data overlaps due to the nature of the IDMP attribute. Please refer to Table 1 for a breakdown of the data used to prepare this article. Note that both products were intentionally very homologous in terms of the respective IDMP data. This was deliberate, to investigate the expected data overlap between two seemingly similar products (except for strength). Our calculation showed that 2.595

data fields would be required for the submission of Product A according to the ISO 11615 information model. Due to the data overlap exhibited between the two products (1663 fields) we would expect to be able to re-use approximately 64% of the data generated as part of the initial registration of Product A. We have prepared an illustration to visualise the

data uniqueness (and overlap) across the various IDMP domains (see Figure 1). In our example, both products were manufactured at the same manufacturers and similar operation types were stated in the regulatory dossier. We found that companies with a limited number of manufacturers may benefit from datasharing across registrations, since the same manufacturer may be used across multiple registrations. It is not uncommon that pharmaceutical companies aspire to have a limited number of manufacturers and our observations illustrate that this strategy may positively impact the initial IDMP submission and the subsequent maintenance of data. The same holds true for the packaged medicinal product area where a oneto-many relationship may exist between select packaging material and the respective registrations. This in turn offers the possibility to type data in once and associate all relevant registrations with the applicable packaging material. Pharmaceutical companies with a very broad packaging material landscape will, however, be forced to type in multiple Spring 2016 Volume 8 Issue 1


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Product A Powder and solution for Injection 20 mg

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and pharmaceutical companies may benefit from starting an evaluation of the consistency across national SmPCs early to factor this into the project timeline.

Within the substance domain, we again Manufacturer Establishement (Organization) would expect that pharmaceutical Packaged Medicinal Product companies may benefit from the utilisation of data Pharmaceutical Product across registrations. It is expected that the implementation of ISO Clinical Particulars 11238 will significantly change the manner Substance in which substances are registered and identified. The Figure 1: Representation of data uniqueness and overlap individual substance across IDMP domains IDs (substance ID & specified substance unique data attributes and associate ID I-III) which are a natural outcome of these with the applicable registrations the implementation of ISO 11238 may, to support IDMP compliance. This however, be used across products and further complicates the subsequent would again offer the possibility for maintenance of data and an analysis of replication across registrations. G-SRS the packaging material landscape within (GInAS) is proposed as a repository for the organisation may be beneficial to this information and we would expect that further qualify the complexity related to all submission and maintenance activities IDMP compliance in this area. would be performed in this system. In relation to ISO 11615, this standard In the clinical particulars domain, we would merely rely on the IDs generated would also expect that some degree of in the G-SRS (GInAS) system and since data overlap would be prevalent across some of these IDs are generated based registrations. It is our experience that on manufacturers, grade, physical state, this, however, is one of the more complex etc., we can only speculate as to the areas to definitively determine the data overlap between registrations for this volume, since this greatly depends on data. the uniformity of the respective SmPCs and the alignment between these and For small and mid-size pharmaceutical the company core data sheet (CCDS). companies with a limited regulatory In principle, the greater the alignment application landscape and potentially between the CCDS and the respective a homologous product and registration SmPCs, the greater the data overlap. In portfolio, the above observations are our example, we assume a significant important to take into consideration since data overlap since we assume the it may directly impact the business case products exhibit similar adverse event associated with manual data entry of profile, contraindications, indications etc. IDMP-relevant data elements. It is, however, not unfamiliar that there is significant variance between SmPCs in Furthermore, since it has been the respective EU countries and caution communicated by the European should be exercised when attempting Medicines Agency that data from EVWeb to calculate the true data volume. will be migrated as part of the ISO IDMP This national variance furthermore implementation, these fields will serve complicates coding of relevant sections as the base for IDMP and focus may be in the SmPC against controlled placed on the EVWeb vs. ISO IDMP gap. reference terminologies (e.g. MedDRA) 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Conclusion: Based on two fictive products, we have demonstrated the percentage of IDMPrelevant data overlap as well as the respective IDMP domains where data overlap may be expected. We have also included some silent observations which may be worthwhile considering when analysing the impact of ISO IDMP within your organisation. The findings are intended to start a discussion about the order of magnitude for IDMP projects and the associated factors that should be taken into consideration when scoping and estimating the internal IDMP efforts. The objective of the article is also to present observations from the analysis that may help pharmaceutical companies that are currently compiling business cases related to ISO IDMP compliance.

Niels Groenning. In his role as Managing Consultant and IDMP SME Niels Groenning has led and supported a number of projects in the regulatory affairs domain. Within ISO IDMP Niels is leading a number of ISO IDMP projects that span from early impact assessment to IT implementation. This experience ensures a broad perspective on IDMP and the many strategic considerations and roadmaps that companies are evaluating to support IDMP compliance. Within NNIT Niels is part of the ISO IDMP SME working group that actively monitors and comments on ISO IDMP implementation guides and standards.

Rune Ringsholm Bergendorff is responsible for NNIT’s ISO IDMP services. He has conducted numerous ISO IDMP assessments, is a member of the EU IDMP Task Force and ISO/TC215 WG6 and participates in this group’s ballots and reviews of ISO IDMP standards and implementation guidelines. Bergendorff has worked with xEVMPD since 2011, advising on issues from requirements to the submission of data. He has written several articles and heads an ISO IDMP networking group for Danish pharma companies. He can be contacted at rrb@nnit.com.

Spring 2016 Volume 8 Issue 1


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Regulatory & Marketplace

Why Agility Holds the Key to Transformation in Life Sciences The priority that will unite all life sciences companies in 2016 is the pursuit of greater agility. As long as organisations keep taking a short-term view, investing in standalone information management systems for each new business requirement, the only thing they’ll successfully grow is cost, warns Mark Evenepoel, Group CEO at AMPLEXOR Life Sciences. The real focus should be flexibility and responsiveness to whatever the market demands next. The fact that life sciences organisations continue to feel stretched in all directions should be a clue that something is fundamentally wrong in the way they are organised. Not necessarily in logistical terms, but in the way they manage their information. Traditionally, systems have been built up to serve specific applications in defined parts of the business. This singlepurpose approach is now preventing them from adapting at the speed and to the degree required to meet today’s business needs – including regulatory compliance in an environment where the goalposts keep changing. Running an international life sciences business is challenging enough in an intensely competitive global playing field. But as new pressures mount – to enter new markets, position products differently, develop new business models, and meet a raft of strict new regulatory demands - the best that companies can hope for is that they are agile enough to respond quickly, efficiently and while the opportunity is still ripe. Tackling each new requirement as a project in its own right this can be counteractive to efforts to move the business forward, because each set of standalone task forces, processes and supporting administration – creates a new bureaucratic dead-end, which goes against any plan to become more adaptable and agile. Breaking this habit of disparate, ad-hoc, single-application projects needs to be a primary goal this year. Unless they do this, companies will continue to build new barriers and fence themselves in. 18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The healthier alternative is to take a higher view – identifying and exploiting the common, underlying facilitator linking all of these ventures. Simply put, that’s data – in all of its rich and varied forms. Whether the immediate priority is to create new transparency and more detailed and consistent reporting for regulators, or to make inspired new decisions about customer/product alignment, it is simplified access to reliable, complete supporting information that holds the key to moving forward.

is both efficient and adaptable – as new regulatory requirements will continue to appear, and not all of these can be predicted in advance.

One Data Source, Multiple Applications The more that the entire discipline of information management can be consolidated, centralised and automated, the lighter the associated workload and the shorter the time to task completion.

Other forms of transformation and realignment are high on the business agenda too. The last year has seen a lot of strategic change in the life sciences industry, as organisations have sought to re-imagine their value propositions in line with specific customer groups, for example hospitals versus over-thecounter pharmacies. Selling customer solutions rather than product features is not only more appealing to customers, it also presents additional cross-selling opportunities. Yet behind the scenes, operations aren’t currently conducive to enabling this readily – due to the numerous different information systems and processes, dispersed across multiple geographies. This fragmentation inhibits progress, preventing new types of collaboration, for example. Mergers and acquisitions further add to the complexity. This situation is detrimental to the organisation’s strategic goals. The aim now must be to simplify and streamline processes, and lower operating costs and administrative barriers, so that companies can seize opportunities and extract value.

Over the year ahead, the life sciences industry faces increasingly complex regulatory challenges and operational risks: the result of technology advances, clinician and patient expectations, and a globally-connected healthcare market. One of the biggest preoccupations for data managers over the coming months is emerging EU legislation requiring the implementation of new data standards (Identification of Medicinal Products or IDMP). This will enable the unique identification of medicinal products at an international level, improving patient and consumer safety. To comply, life sciences organisations must develop a method and process for generating global product identifiers, which can then be used for product reconciliation and linking across the entire product supply chain. The specifics of IDMP compliance requirements will continue to evolve over the next two years, a reminder of why an agile approach to data management is so important. Significant investment will be required not only to align key product data across a wide range of functions – from research and development (R&D) and manufacturing to the supply chain – but also to pursue operational excellence in R&D and customer safety: the ultimate goal of the new requirements. From a regulatory and risk perspective, these requirements absolutely must be met. But companies need to do this in a way that

Commercial Priorities There are commercial implications too. If laborious internal processes are needed to collate and file detailed product lifecycle data in the mandated format, this could cost companies dearly in time to market – a serious consideration in today’s aggressively global playing field.

Without Agility, Businesses Can’t Evolve Put all of this together, and it’s not hard to see why agility is becoming more important now than ever before. For a whole host of reasons, life sciences businesses now need to be better positioned to adapt and take advantage of emerging situations and opportunities. As part of the transformation that is required, new strategies need to be set out which promote greater collaboration and information-sharing – both among internal functions and with external partners. This is necessary Spring 2016 Volume 8 Issue 1


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 19


Regulatory & Marketplace to create a global supply ecosystem which is more closely integrated, more responsive, and more focused on the patient. All of this must begin with a single, centralised approach to product lifecycle data management. Each time companies approach a new information management project as a distinct entity, to meet a specific new need, they are creating a new data and process silo that adds to, rather than alleviates, their current challenges – and limiting the return on investment in new systems, processes and training. This might sound like a tall order for organisations with the scale and structural complexity of a large international pharma brand. But it is achievable – if companies commit themselves to a new approach to content management which looks beyond a single set of current needs, and which is capable of meeting not only current requirements, but also those that will emerge in the future. This cannot be achieved overnight, but it should be the overarching aim. By this time next year, pharma organisations should aim to have a clear roadmap for transformation, and be ready to get stuck in. Formulating a Plan Even where there are long-established legacy systems to be taken into consideration, it is important to establish some kind of centralised strategy for master data and product lifecycle information management as a first step. This doesn’t have to involve a lot of physical upheaval: it could be achieved virtually. Tools such as integration ‘middleware’ can help in the interconnection of disparate and ostensibly incompatible systems, but companies can leave this kind of detail to external experts. The great positive in all of this is that life sciences organisations typically already have most of the data they will need to become more agile, thanks to the rigorous demands of regulatory compliance which have imposed the need for comprehensive record-taking over the years. The catch is that much of this information exists in an unstructured format. One of the first priorities, then, must be to address this so that information can be more readily consolidated, accessed and shared to serve the broader needs of the organisation. Appropriate actions are proposed in the adjacent boxes. 2016 will be a pivotal year in life 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

sciences, with the multitude of challenges and new opportunities now on the horizon. Provided companies don’t ignore the call to be more agile, adaptable and responsive; it could be the start of a bright new future as a consolidated approach to data management allows several things to fall into place at once. Box copy 1: As the life sciences industry adapts to modern business challenges, companies need a reliable way to manage a wide range of content – from what is submitted to regulators, to what goes out on and in their product packaging and on their website, and what’s distributed across digital and social media – in every region and every country. Research by Gens and Associates in 2015 found that the majority of life sciences companies aspire to adopt an enterprise-wide approach to content management governance between now and the end of the decade. Aims include improving operational efficiency as well as information exchange with regional and local affiliate offices, for example as they prepare input for regulators. Where a pan-organisation view of content is lacking, Gens has found evidence that as much as 40% of affiliate time is taken up by coordinating and managing regulatory information – much of it on very basic tasks such as data re-entry. Even so, firms were found to typically lack confidence in the quality of information maintained in their global systems.vWhere life sciences organisations are managing content more holistically across the business, the payback on systems is significantly higher, Gens and Associates has found. Box copy 2: The Roadmap to Greater Agility Practical Steps to More Holistic Information Management •

Formulate an overarching transformation plan for the way information is managed across the organisation and its various operations • Aim to turn product and other everyday business data and content assets into a panorganisation master content resource • Think beyond single applications towards building a centralised

• •

pool of (business, product, operational, financial) knowledge – even if this is achieved virtually Standardise and streamline the way data is captured, stored and managed, to enable easier integration, and deeper analysis and cross-comparison Consider how you will plan and handle system design, integration, migration, reformatting Drawing on external experts could pay dividends by relieving alreadyoverstretched internal IT teams of complex work that may exceed their expertise and capacity and distract them from day-to-day tasks Improve content accuracy, completeness and currency, ensuring regulatory compliance and patient safety • Address data duplication • Aim to create a ‘single version of the truth’ – i.e. the fuller picture of a situation as a whole, based on complete and up-to-date detail Make information easy to share, and quick to access – aiding transparency and paving the way for new innovation as new potential is identified Reduce reliance on static, periodend reports, empowering business users to find the insight they need on demand Automate workflow where possible • Reduce the administrative workload associated with delivering regulatory information, or providing the business with the latest operational and commercial insight Don't delay • Competitive and regulatory pressures will continue to mount, and each project that takes place outside of the context of improved agility will increase costs and slow overall business progress

Mark Evenepoel is Group CEO at AMPLEXOR Life Sciences, a digital solutions company offering global compliance, digital experience and content solutions. Mark is charged with group strategy and development and has overall responsibility for global communications & marketing, HR and sourcing and solutions development. Email: mark.evenepoel@amplexor.com Spring 2016 Volume 8 Issue 1


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Regulatory & Marketplace

How to Protect Your IP Rights Abroad Many life sciences companies which protect their inventions, brands or product designs through patents, trade marks or registered designs in their home country, do not realise that this does not give them automatic protection in other countries. Intellectual property rights are territorial rights, meaning that the protection afforded by a granted patent or a registered trade mark is geographically limited. Unfortunately, this means that for many businesses, they will not be able to stop infringing or counterfeit products from hitting the market in other countries unless they have corresponding protection in those countries. Intellectual property is particularly important in the life sciences industry. This is due to the disproportionately large capital investment required for research and development. Therefore, ensuring your inventions are protected is vital to guaranteeing a return on your investment. If companies wish to seek patent protection for their inventions, potentially the most important thing to be aware of is that they must keep their invention confidential until a patent application is filed. This is because any public disclosure (e.g. in a journal article, advertising material, product brochure, at a conference etc.) can be used to invalidate a subsequently filed patent application. Jim Robertson, Partner and Patent Attorney specialising in life sciences at Wynne-Jones IP, one of the UK’s leading IP specialists, has put together some key considerations for how to protect your IP rights abroad. 1. Seek Advice If you have decided to launch a new life sciences product in another country, it is vital that you speak to an IP expert to find out what you need to do to ensure that you, your products and brand are all protected. Make sure you choose a firm which has patent attorneys with sector expertise 22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

in life sciences as they will have greater understanding of the protection you will require. Depending on whether you are interested in seeking patent protection for a new invention, trade mark protection for a product name/logo or registered design protection for the appearance of a product, an IP specialist should ensure that the relevant patent and/or trade mark attorneys are present to discuss your objectives in order to develop a comprehensive IP strategy to achieve these goals. 2. Research the Market Whilst you may have IP rights in one country, in other countries there may be brands or products which have registered IP that could be used to stop you from trading there. Perform a novelty search to ensure that no one has come up with your invention before you. The majority of territories apply an absolute novelty requirement, meaning that if your invention has been disclosed anywhere in the world prior to the date of first filing of an application for a patent for that invention, it will not be considered patentable. If you have already filed a patent application in one territory, such as the UK, check the deadline by which you must file the patent application in other territories. This is one year from the date of first filing and whilst there are extensions available in some countries, these should not be relied upon. In other countries there may be registered IP that could be used to stop you from trading there. This applies to patents but it also applies to other IP rights such as trade marks and designs. To avoid a costly lawsuit, make sure you research the market and its IP registers to ensure your brands and products will not infringe on other companies’ rights. 3. Protect your Product Companies should ensure that they apply for patent protection for their inventions in all territories which will be commercially

relevant to them. The potential monopoly provided by patent protection is the only effective way to prevent others from exploiting your inventions and to receive a good return on the initial investment. Equally, it is extremely important for life sciences companies to protect their brands with registered trade marks. When a granted patent expires, brand names are crucial in maintaining a competitive edge over generic manufacturers when the market may become diluted. For example, the patent application for ibuprofen (GB971700) was filed in 1961, and the resulting granted patents expired back in the 1980s. However, Boots developed (and protected) the NurofenÂŽ brand name and that has provided significant income in the face of competition from generic manufacturers and other brands. If you do not take action to protect your rights, it can be the case that unscrupulous third parties will apply to register it themselves. You also need to remember that as your business develops and grows, your IP requirements may change as a result. You should regularly review your IP protection to ensure it fits in with your ongoing business goals and strategy. 4. Understand the Cultures and Patent Rules of the Countries you will be Operating in A common pitfall for businesses entering a new market overseas is not researching whether the brand is right for the language and culture. It is important to check that your product names do not mean anything offensive or have any undesirable connotations when translated. If you are going to be operating in a country with a different alphabet, such as China or the Middle East, it is advisable to control the translation or transliteration of your brand and marketing collateral. If you fail to do this, the local market will most likely translate and adopt Spring 2016 Volume 8 Issue 1


Regulatory & Marketplace an alternative themselves, potentially resulting in the loss of control over your brand and market. Furthermore, it is important to understand the different rules that apply regarding what can be patented. In many countries, there is subject matter relevant to life sciences companies that cannot be patented. For example, in the UK and Europe, methods of treatment of the human or animal body by surgery or therapy are excluded from patentability, as are methods of diagnosis practised on the human or animal body. However, there are often ways around these exclusions; for example, substances for use in such methods are patentable. A number of biotechnological inventions are also excluded from patentability in the UK, including the human body and gene sequences discovered in it, industrial or commercial exploitation of human embryos including stem cells harvested from embryos, and invention relating to individual plant or animal varieties. Recent case law in the USA has made it more difficult to patent

inventions relating to gene sequences as well. The best advice we can give is to speak to a qualified patent attorney who will not only be able to advise you whether or not the subject matter of your invention is patentable but also be able to draft a patent specification providing you with the best scope of protection for your invention. 5. Identify the Key Aspects When it comes to protecting your IP, don’t just concentrate on one element of your product. Many can be protected through a combination of patents, designs and trade marks – these rights are not mutually exclusive and, when combined, can provide a strong fortress of protection around the valuable innovative elements of your product. And don’t delay in seeking protection. Delay can remove the ability to obtain valid patent and design protection, and allows a window of opportunity for would-be infringers to copy. Remember, it is the lack of protection which creates the greater problems, so act quickly to ensure you are protected.

6. Grouping Systems Overseas To help encourage cost-efficiency, many countries have joined group systems, allowing companies to lodge IP rights with a group of countries rather than just one. There are several international grouping systems that have the potential to provide patent protection in a number of different states. The two most common are a European Patent Application filed under the European Patent Convention and an International Patent Application filed under the Patent Cooperation Treaty. These international grouping systems are very commonly used and for good reasons. One very strong reason is that they can provide a very good economy of scale. The European Patent Convention provides inventors with a uniform application procedure in which an applicant can file one application which will go through a single prosecution procedure, resulting in a single granted European Patent. Once granted, the applicant can validate the European Patent in the countries they wish the patent to have effect in. Subject to

Product News SARTOFLOW® Smart: Sartorius Stedim Biotech Presents New Crossflow Filtration System for Process Development Sartorius Stedim Biotech (SSB), a leading international supplier for the biopharmaceutical industry, announces the launch of SARTOFLOW® Smart, the smart and easy benchtop crossflow system for optimised ultra- and diafiltration applications. It is ideal for use in many downstream processes, such as purification of vaccines, monoclonal antibodies and recombinant proteins. The system is suitable

for flexible use in laboratory environments for process development and clinical trials, as well as for cGMP environments.

to automatically run sequences for concentration, diafiltration, rinsing, filling, draining, flushing steps and tare functions.

The brand new system is equipped with a low-shear four-piston membrane pump that enables highest product yields to be achieved. In addition, the pump provides a wide range of flow rates allowing selection between membrane surface areas from 50 cm² to as much as 0.14 m².

An optional peristaltic diafiltration pump is available to load product or buffer as a discrete process step. Furthermore, several options are available to customise the system according to specific requirements. For example, a conductivity, pH or temperature probe can be installed in the recirculation vessel. The system can also be upgraded in the case of changing process requirements.

The crossflow system is supplied with SSB’s intuitive and easy-to-use DCU-4 control unit, which, when combined with the company’s BioPAT® SCADA, MFCS-4 software, provides data logging and export. Its touchscreen offers instant access to all critical process parameters and displays control and alarm functions. A logbook function stores alarms, set points and user logs. The SARTOFLOW® family of crossflow systems shares a unique operation design with a 7” touchscreen that supports the operator with interactive prompts for easy guidance through entire process sequences. Users can select predefined parameters

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“SARTOFLOW® Smart is a milestone development in the landscape of small crossflow systems. It combines outstanding technology with options that are normally only available with process systems. With an exceptionally wide working range of membrane surface areas, the system is the perfect tool for both R&D optimisation trials and cGMP production,” stated Dr Marc Jenke, expert for benchtop crossflow filtration systems at Sartorius Stedim Biotech. Contact: Sartorius Stedim Biotech GmbH Goettingen, Germany Phone: +49.(0)551.308.0 info@sartorius-stedim.com www.sartorius-stedim.com INTERNATIONAL PHARMACEUTICAL INDUSTRY 23


Regulatory & Marketplace

each country’s legal requirements for validation, for example, some countries require a translation of the whole or part of the granted patent specification to be filed, the European patent will have effect and be subject to the same conditions as a national patent granted in that state. Therefore, once the patent has been granted and validated in the European states of interest, the owner is afforded the same rights and obligations as if they owned a bundle of granted national patents in the same states. This means that the post-grant renewal costs are the same and if you are thinking of seeking patent protection in a number of European countries then it could very likely decrease the costs of prosecution. A Unitary Patent system will soon come into force in Europe, allowing a granted European Patent to be brought into force in all EU member states as a single Unitary Patent. This will further help to reduce costs. The Patent Cooperation Treaty is completely different and is not considered a cost-saving exercise. It is often used as a time-buying exercise that provides an applicant with a further 18 to 30 months to decide which countries they wish to file a patent application for their invention in. A single international application is filed and searched, however, the application is not normally examined in the international phase. The applicant 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

still has to file separate applications in each of the countries in which they wish to seek patent protection for their invention, including paying the relevant application fees. 7. Be Aware of Timescales Obtaining a patent can be an altogether more difficult and lengthy process than registering a trade mark or a design. It is difficult to put a number to the duration of the patent application process, as it varies hugely depending on the territory in which you have applied for the patent, and also depending on the subjectmatter of the patent application and the invention disclosed. As an example, assuming that the invention is patentable, the average patent application will tend to take around four to five years from the date of filing to reach grant. Some countries have a deadline by which the patent application must be in order for grant, thereby limiting the duration of the patent application process. For example, in the UK, the period for putting the application in order for grant is known as the compliance period, being four years six months from the date of first filing an application for a patent for that invention. There are exceptions to this rule, however, in general, patent applications in the UK tend to go from filing to grant in around three to five years. Yet, in many other territories, such as Europe,

there is no deadline by which the patent application must be in order for grant, and the application process can take a lot longer, often in the region of around seven years. It is also not unheard of for patent applications to take a lot longer than this to proceed to grant. Conclusion When looking at expanding into new markets abroad, it is essential that you do your research and ensure you’re adequately protected by speaking to an IP expert. They will be able to work with you and develop a strategy to achieve your objectives. IP attorneys will work with legal experts in all countries to ensure relevant requirements are fulfilled and that your business is protected correctly. Without this research and advice, it could be a costly mistake for your business.

Jim Robertson is partner and head of the life sciences team at Wynne-Jones IP. He is a qualified UK and European patent attorney, having worked in the sector for over 20 years and is also a member of the Chartered Institute of Patent Attorneys Life Sciences committee. With an MA in Natural Sciences from Cambridge University, he specialises in the life sciences sector working with companies in the biotechnology, pharmaceuticals, diagnostics and medical devices fields. www.wynne-jones.com Spring 2016 Volume 8 Issue 1


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Drug Discovery, Development & Delivery

Applications of CRISPR Scientific interest in Clustered Regularly Interspaced Palindromic Repeats (CRISPR) systems exploded in 2012/2013 when focus shifted from their natural function as a component of adaptive bacterial immunity to their use as a toolkit to find, cut and replace DNA at a specific location in eukaryotes. Widely considered to be a breakthrough technology, the speed of adoption of this technology has been phenomenal. Since 2013, scientific publications relating to CRISPR have exploded, and the wide-ranging applications of this technology have become evident. Patent wars relating to the rights to the underlying technology do not appear to have impeded progress in applying this technology to broad-ranging applications. Just a few years on, the use of CRISPR/Cas (CRISPR associated protein) as the primary tool to effect genome editing has become routine in many labs. Here, we take a look at applications using CRISPR and, in particular, consider the inventive step issues that may arise in such a fastmoving field. CRISPR Systems To date, utilisation of CRISPR for gene editing has mainly focused on Type II CRISPR systems. Unlike Type I and Type III systems, Type II systems advantageously only need a single Cas protein (Cas9). Typically, a Type II CRISPR composition for gene editing comprises Cas9 and two RNA components, a programmable crRNA (CRISPR RNA) and a fixed tracrRNA (trans-activating crRNA), which may be fused to form a single guide RNA (sgRNA). Typically, the crRNA component of the sgRNA is programmed to comprise a guanine residue at the 5’ end of the crRNA to enable RNA expression when under the control of a U6 RNA polymerase III promoter, a section complementary to the target sequence and a repeat region. The section complementary to the target sequence is designed to immediately proceed a short motif named the protospacer adjacent motif (PAM) on the other strand of target DNA. The tracrRNA component comprises an anti-repeat region (i.e. a portion complementary to 26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the crRNA repeat region) such that the sgRNA can form a duplex required for Cas9 function. Typically, the tracrRNA will have further repeat and antirepeat regions, such that further stem loops are formed.

Venture and Novartis. Further, on 26 October 2015, Vertex Pharmaceuticals announced a large upfront investment of $105 million in CRISPR startup CRISPR Therapeutics, in a much-publicised deal potentially valued at up to $2.6 billion.

On binding, conformational changes resulting from the recognition of the sgRNA and the PAM motif enable the HNH domain of the Cas9 protein to cleave one strand of the DNA, and the RuvC domain of Cas9 to cleave the other, such that a double-stranded break occurs. However, Cas9 can be modified to carry out other functions. For example, inactivating either the RuvC or the HNH domain to prevent cleavage results in a Cas9 nickase, which can be used to create staggered breaks when accompanied by two sgRNAs. When combined with multiple sgRNA various site specific deletions, additions and modifications can be achieved.

Currently published patent applications in this field generally focus on specific therapeutic applications, including HSV1, HSV-2, cystic fibrosis, glaucoma, β-thalassemia, sickle cell diseases, HIV, Leber’s congenital amaurosis 10, Usher syndrome and retinitis pigmentosa. The claims in these patents are directed towards seeking protection for gRNAs for treating such therapeutic applications.

Furthermore, by inhibiting both RuvC and HNH domains, Cas9 can be used to inhibit function of a target (CRISPRi), or provide fusion mediated activation (CRISPRa). The various ways such CRISPR/ Cas compositions can be used; the programmability of crRNA to various desired targets and the capacity of using multiple sgRNAs, enables broad applications of such compositions in various fields. Therapeutic Applications One key area which has seen a lot of investment is the therapeutic applications of CRISPR. Editas medicine has received over $160 million in two rounds of investment from investors including Juno Therapeutics, Google and Bill Gates . They have also since announced further investment from Juno Therapeutics, pursuing programmes utilising Editas’ CRISPR/Cas9 with Juno’s CAR and TCR technologies. Intellia Therapeutics, which was created by Atlas Venture and Caribou Biosciences, announced on 18 November 2014 it has received $15 million in a Series A investment round, led by Atlas

However, many recently published patent applications relating to therapeutic applications have limited experimental data in the patent application as filed. In particular, many often contain no experimental data to show the gRNAs actually work as claimed. In such patent applications, experimental protocols may amount to how to test the gRNAs and identify those having the greatest genetargeting efficiency. In the rush to be first past the post in a first-to-file system, particularly in such a fast-moving area of science, where publications in a similar area pose a threat to the patentability of an invention, filings like these are not surprising. However, this can potentially have implications for patentability. Determination of inventive step before the EPO is based on a problem and solution approach. This approach involves an analysis of a technical contribution achieved by the claimed invention which is not found in the closest prior art. The technical contribution is then considered in formulating the objective technical problem to be solved over the prior art. Where the EPO has acted as the International Search Authority (ISA), a large number of CRISPR filings have had a lack of inventive step arguments raised. In some of these cases, the EPO has raised queries as to whether there is enough data to render it credible that Spring 2016 Volume 8 Issue 1


Drug Discovery, Development & Delivery

the technical problem has been solved. A technical problem put before the EPO may be regarded as being solved only if it is credible that substantially all claimed embodiments exhibit the technical effects upon which the invention is based. As stated in John Hopkins (T1329/04):

EPO as having patentability issues. In some cases, the EPO may require that the claims contain technical features other than claiming “a gRNA comprising a target domain configured to target a mutation in gene X”, particularly where the desired “edit” is known.

“The definition of an invention as being contribution to the art, i.e., as solving a technical problem and not merely putting forward one, requires that it is at least made plausible by the disclosure in the application that its teaching indeed solves the problem it purports to solve.”

Some of the currently published patent applications provide vast arrays of potential target domain sequences together with instructions on how to test and identify which gRNAs have the optimal gene-targeting efficiency. For these applications, the EPO has raised queries as to whether it is plausible that all the gRNAs achieve the desired effect. Patent applications which lack any experimental data to show any of the specific gRNAs as claimed achieve the desired technical effect are more likely to be met with queries from the EPO as to plausibility. If the applicant cannot satisfy the EPO that the claimed patent scope is plausible, this may result in the EPO refusing to allow post-published data to be considered.

It is possible to file post published data, but this is only permitted to confirm that the claimed subject-matter solves the problem where it is already credible from the disclosure in the patent that the problem is indeed solved (see T1329/4 and T415/11). Therefore, a balance needs to be struck between filing early enough in a first-to-file system whilst ensuring that the technical problem is credibly solved. Applications defining a gRNA molecule purely by the result to be achieved are likely to be flagged by the www.ipimedia.com

As the field moves on, establishment of inventive step may require data demonstrating desired technical results in terms of efficiency of cleavage and

reduction of off-target effects. Although many early patent applications provide large lists of potential targeting domains, this may still leave the door open for later “selection inventions” of gRNA constructs found to be particularly effective for the application in hand. Other Applications To date, most patent applications which have published relate either to the underlying technology or therapeutical applications of CRISPR. However, given that patent applications do not usually become available before 18 months after the earliest filing date, it is only applications filed prior to October 2014 which are publicly visible. Nevertheless, the number of published CRISPR patent families are reported to have already multiplied by five in the last 18 months. We foresee that this upward trend will continue such that there is a sharp increase in such filings going forward. Other areas where we expect to see a rise in patent applications are as follows: AgBio There has been a lot of interest in agricultural applications of CRISPR. INTERNATIONAL PHARMACEUTICAL INDUSTRY 27


Drug Discovery, Development & Delivery For example, DuPont has entered into a strategic alliance with Caribou Biosciences and is seeking to be at the forefront of applications of CRISPR technology in improving agricultural productivity. CRISPR/Cas has particular utility in modifying plants to exhibit desired traits, such as to promote drought tolerability, improve crop yields and increase or introduce disease resistance. With world food demand predicted to increase by 50% by 2030, the utilisation of CRISPR technology to increase yields and/or reduce waste has great potential. Advantageously, it is possible to modify agricultural species using CRISPR/ Cas in ways which would not currently render the plant subject to regulation as a genetically modified organism. This means that introducing modifications using CRISPR/Cas can have regulatory advantages. Even at this early stage, some patent applications have published relating to applications of CRISPR in this field. This is in addition to applications seeking protection for general methods of modifying plants and the resultant modified plants. Early applications include those which have filed experimental data to show modification of tomato plants to increase resistance to tomato yellow leaf curl virus. Industrial Biotechnology There is a lot of potential for the use of CRISPR/Cas in industrial biotechnology. Applications could relate to generating better cell factories for the production of chemicals and for the improvement of enzymes for various applications. For example, Caribou Biosciences have an interest in industrial fermentation using CRISPR technology. We can foresee patent applications relating to new or improved methods of producing chemicals and other products by editing the genome of microbes with CRISPR, with further claims to modified bacteria, yeast and enzymes produced by modified organisms. For example, in bacteria, it may be useful to inhibit pathways which result in the production of side-products to increase the yield of the desired product. However, when the pathways are fully characterised, and the way to inhibit the 28 INTERNATIONAL PHARMACEUTICAL INDUSTRY

undesired pathway is known, inventive step issues could potentially arise unless the CRISPR composition used (e.g. the gRNAs) are particularly effective for the claimed purpose. Diagnostics Another aspect which has generated considerable interest is the use of CRISPR to generate diagnostic kits for various conditions. For example, it is now possible to integrate detectable tags, such as fluorescent protein, into the CRISPR composition to identify specific targets which can in turn be used for diagnostic applications. Thus, we can foresee patent applications claiming diagnostic kits and patient population stratification methods for personalised medicines. Claims to diagnostic kits, and methods of determining patient populations susceptible to certain drugs using diagnostics are currently permissible in Europe. However, particular care is required when drafting such claims, particularly for the US. Summary In such a fast-moving area, filing multiple priority documents can be a useful strategy. This allows a group to frequently publish in order to maintain its reputation in the scientific field, whilst optimising commercial protection. However, this needs to be carefully managed. It can be vital to maintain the earliest possible priority date to avoid patentability issues arising from intervening publications. Therefore, publications need to be managed to ensure that all new information is filed in a priority application prior to any disclosures, such as in journal publications and oral presentations at conferences. The applications of CRISPR/Cas are vast and this article has only touched on a few of the applications of this technology. Given the scientific interest in this rapidly evolving field, we expect the floodgates to open and to see a large volume of patent applications filed using the platform technology in various technological areas.

References 1. http://ir.editasmedicine.com/ phoenix.zhtml?c=254265&p=irolnewsArticle&ID=2125221 2. http://ir.editasmedicine.com/ phoenix.zhtml?c=254265&p=irolnewsArticle&ID=2125229 3. h t t p : / / w w w. i n t e l l i a t x . c o m / intellia-therapeutics-announces15-million-in-funding-to-developtherapeutic-products-utilizing-crisprcas9-gene-editing-technology/ 4. http://crisprtx.com/news-events/ press-releases_2015-26-10.php 5. h t t p : / / w w w . i p s t u d i e s . ch/2016/01/10-facts-fromthe-januar y-2016-crispr-patentlandscape/

Catherine Coombes, Senior Patent Attorney. Catherine has considerable experience in handling all patent related matters including: preparing patent applications, prosecuting patent applications before the EPO and UKIPO, managing worldwide patent prosecution, strategic reviews, due diligence, and validity opinions. Additionally, Catherine is very experienced in opposition matters before the EPO Opposition Division. Catherine entered the profession in 2004, after gaining a BSc in Biotechnology at the University of Leeds and an MSc in Management of Intellectual Property Law at QMW, University of London. Cath joined HGF Limited in June 2015. Prior to joining the profession, Catherine’s background was in process development of food ingredients and in the scale-up of active pharmaceuticals. Catherine is an Examiner for the European Qualification Examination, which assesses candidates seeking to qualify as a European Patent Attorney. She sits on the Examination Committee responsible for setting and marking the Opposition paper Email: ccoombes@hgf.com

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Drug Discovery, Development & Delivery

Contribution of Circulating Tumour Cells in Drug Development Abstract Circulating tumour cells (CTCs) are becoming very welcomed in the field of oncology, and they are also promising in the clinical field, in the area of drug development. Proof of concept that CTCs may correlate with the prognosis of cancer has been completed for many types already. Also, the CTCs may carry information that is relevant to the disease progression and behaviour and this data cannot be obtained from the primary tumour. Hence they are becoming extremely valuable in the field of drug development and evaluation of candidate medications in pharmaceutical research and industry. The ability to isolate and analyse them is already known, including the limitations and barriers. The rationale and the concept of utility of CTCs and the relevant cancer stem cell like as a subset, could offer more possible solutions and further targeted therapeutic approaches for treating cancer. Introduction After many decades of endeavour in drug development, today we have concluded a more rational and target-based drug development based on the identification of the proper target, and on the understanding of the precise mechanism of a disease. Especially in the disease of cancer, the progress of molecular biology and the breakthrough achievements in the physiology of cancer progression and metastases lead us to understand the importance of heterogeneity of the disease, and that our interest should focus on the proper entity which determines the disease progression and relapse. Since circulating tumour cells (CTCs) are disseminated from the primary lump and through them the relapses are generated, they become the carrier of the cancer cells population of interest. Therefore, they become very important and popular in our quest for understanding cancer development and progression, in order to point out new therapeutic targets and create new therapeutic molecules. Physiology/Biology of CTCs and CSCs It is well established that the primary tumour mainly starts from a multiple process of carcinogenesis that is composed of an accumulation of 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

aberrations and abnormalities which finally spawn the malignant phenotype of an abnormal malignant cell. Then the cancerous cell, without any control of the cell division mechanism, quickly replicates at the same time as the immune system is reacting against the abnormal cells. This point is called equilibrium1. In contrast, the genetic instability of the cancerous cells generates heterogeneity and pleomorphy of the abnormal cells, and the best fit clones are replicated fast and are no longer detectable from the immune-surveillance. At that stage the cancerous tumour is entering the phase of immune-editing and immune-escape2. Many mechanisms are implicated in this process, like the HLA histocompatibility system or even the interaction between tumour cells and the immune system, through cytokines and receptors like TNF-a, or ligands PD-1, etc. When the bulk of the tumour cells are growing, the hypoxia triggers the mechanisms of neovascularisation. In this phase the tumour cells excrete factors that attract normal endothelial cells and fibroblasts that form abnormal vessels of the lymph or blood circulation towards the position of the tumour, and through them more nutrients and oxygen are supplied to the primary tumour cells. Then the sub-clone of the primary lump is able to invade the circulation and perform the process of epithelial to mesenchymal transition (EMT)3. The cells may circulate to the “depositor” organs, like bone marrow or liver. They may relocate there and remain in dormancy and receive the influence of several triggering factors like bone morphogenic proteins (BMPs), which additionally alter the circulating tumour cells phenotype4. When these disseminated circulating tumour cells arrive at the organ, the cells there have specific markers on their surface and the proteins interact between the disseminated tumour cells and the tissue of the distant organ5, 6. As is obvious from the previous outline of the cancer physiology, the circulating tumour cells are the intermediate entity which may include the clone of cancer cells that may initiate the growth of a tumour in a distant organ. This particular clone of cancer cells is called tumour

initiating cells, or cancer stem cells like. The properties of this clone are that they are able to completely regrow a tumour when they are engrafted. It is also essential to distinguish the entities of CTCs and CSCs, which are not identical although the CTCs can include the CSCs as a subset. This particular feature makes the entity of CTCs favourable as a sample, in order to identify and isolate the CSCs in order to be analysed. At that point it is essential to understand that the present therapeutic strategies are based on data obtained from the primary tumour sample, which may often be different compared to the disseminated tumour cells or the distant metastases. This is the major reason why the therapeutic protocols are generating such poor responses and clinical benefit in advance stages of the disease. There is a need to point out relevant samples and new markers that will determine new therapeutic options or even new molecules that may prove to be beneficial for advanced stages of the disease. Discussions There are several approaches to isolating the CTCs from a blood sample and preserving the viability of the cells. The difficulties exist in two main points: •

One point is the difficulty to identify all CTCs including all the necessary sub-clones without any irrelevant kinds of cell, The other point is to preserve the viability of the CTCs using our technique without interfering with their viability and their phenotype, while at the same time having enough material (number of cells) to perform comprehensive analysis.

In the attempts to resolve the first difficulty, there are two main strategies: one is the positive and the other is the negative selection-based methods. In the positive selection methods, we speculate that one or a few marker/s will be present on the CTCs’ surface and we select the cells based only on that factor. On the negative-based selection method the strategy is to subtract the unwanted and irrelevant cells and the remaining Spring 2016 Volume 8 Issue 1


Drug Discovery, Development & Delivery cells will be all the subsets of CTCs. The first strategy has the disadvantage that there are subsets of CTCs that will not express the expected membrane marker, and this particular subset may have tumour initiative properties. The second strategy is laborious and requires multiparameter standardization, and very few combinations of techniques can achieve such an outcome (Figure 1).

Figure 1. Circulating detection system

tumour

prognostic value in several types of malignancies. Also, there is a strong prior art that supports CTC’s diagnostic and therapeutic value. To be precise it is well known that the number of CTCs is related with the spread of the disease, but also the fingerprinting of the CTCs is related to the primary, but equally with the metastases of the disease. Hence the analysis of the CTCs can be a tool to identify therapeutic options for primary, as well as for metastases or recurrences (Figure 3).

cells

The second difficulty is mainly caused by the fact that CTCs are considered as rare events. The CTCs exist in a ratio of up to 1 CTC per 106 WBC, and this means that there are very few cells of interest from a blood sample to perform a comprehensive analysis (Figure 2). Therefore there are attempts to “amplify” the cells of interest, either by molecular techniques like qPCR or by cell expansion. The first approach causes very easy biases since it affects the actual cell profile by the pre-amplification step and the results are altered compared to the original profile, and the second approach is difficult and requires precision and different approaches on cell expansion methodologies in order to generate repeatable results. Nevertheless, the combination of techniques can today provide possibilities to resolve all aspects of isolation, enumeration and analysis of CTCs.

Figure 3. Circulating tumour cells So the utility in clinical practice can be as follows: • The concentration of CTCs can become a prognostic tool but also a method of responsiveness to a therapy • The detection and enumeration of CTCs can be a diagnostic tool for relapses or recurrences, even before they become macroscopically present • The analysis of CTCs (genomic, epigenetic, proteomic, etc.) can provide information about the efficacy of the proposed therapeutic strategy and the existing endogenous mechanisms of resistance (Figure 4)

Figure 4. Analysis of the efficacy of the therapeutic strategy

Figure 2. Circulating tumour cells The utility of the number of CTCs has already been proven in clinical practice, since there is a strong relationship with www.ipimedia.com

Based on the same principles, the same utilities of CTCs and CSCs in a broader spectrum can be offered to the drug development sector. To be specific, the analysis of CTCs and CSCs on a genomic, as well as epigenetic and proteomic, level may reveal repeatable patterns on specific types of malignancies and in a specific stage of histological type. Since CTCs are the connective link

between the primary and the recurrences they become favourable samples to be analysed in order to identify new “druggable” targets or biomarkers (Figure 5). When the repeatable epigenetic or proteomic patterns are validated, then they may have therapeutic, prognostic or diagnostic value. The main method of target validation is the technique of knocking down. When this methodology is applied and the phenotype is altered, then the target may have therapeutic value and the particular target-protein is used as primary material for drug development. According to the location of the target-protein, the selection for drug development is decided. If the location is on the cancer cell membrane or in the extracellular matrix, then it is more favourable to follow the development of therapeutic monoclonal antibodies. In that case, the protein domains are assessed according to their antigenicity and based on that the process of generation of hybridomas and production of monoclonal antibodies (MoAb)7, 8. If the target-protein is located intracellularly, then it is more rational to apply the process of small molecular weight organic molecule development. In that case, the protein is analysed in order to detect the active site of it and the possible ligand that bonds to that site of the protein. Then a ligand-based drug design is applied in order to generate leading compounds. If there is no ligand available but only the active site is known, then a structure-based drug design or a fragment-based strategy is utilised in order to generate leading compounds. If no active site is known, then a de novo drug design is used, in which the homology of the target protein with other proteins or similar proteins of other species is used, so that a ligand or a possible active site will be determined. When all in silico leading compounds are available, then a combinatorial chemistry is applied for synthesis which is then optimised according to the biochemical or biological assays of assessment. Then the candidate molecules may enter the in vivo studies on animals and then proceed to clinical trials. In the stage of clinical trials, it is well known that in Phase I, the toxicity and the tolerability are assessed, but in Phase II and III the efficacy of the candidate is assessed and many recruits are required. At that point, the CTCs can again become a useful “tool”, either to primarily prove the efficacy of the candidate medication INTERNATIONAL PHARMACEUTICAL INDUSTRY 31


Drug Discovery, Development & Delivery V, Macrina L, Raso C, Amodio N, Aprigliano S, Minniti AM, Russo V, Roveda L, Coluccio ML, Fini M, Voci P, Prati U, Di Fabrizio E, Mollace V. In vitro expansion of tumour cells derived from blood and tumour tissue is useful to redefine personalized treatment in non-small cell lung cancer patients. J Biol Regul Homeost Agents. 28(4), 717-31 (2014 Oct-Dec)

Figure 5. Circulating tumour cells technologies by measuring the concentration of CTCs before and after application, or to be used as an assay to select the subset of patients for which the candidate drug may be beneficial, and exclude the rest9,10. By that approach, the CTCs may avoid unnecessary expense on failed trials. Additionally, by selecting the set of patients that will benefit from a candidate drug, the rate of successful clinical trials is increased. Finally, the candidate drug may also be connected with a diagnostic parameter in order to increase the spectrum of personalised medicine in oncology, since the beneficial subset will be detected. Conclusions All the above support the value of CTCs in clinical practice as well as in drug development. With further assessment and analysis of CTCs, the concept of using them as one of the major tools for a personalised approach in cancer treatment is becoming more and more established. The need for more druggable targets as well as new candidate drugs is forcing the more frequent implementation of CTC analysis in drug development and more widely in cancer treatment. References 1. Bathia A, Kumar Y. Cancer-Immune Equilibrium: Questions unanswered, Cancer Micro-environment. 4, 209217 (2011) 2. Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights into cancer immunoediting and its three component phases — elimination, 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

equilibrium and escape, Curr Opin Immunol. 27, 16–25 (2014) 3. Dhruve SJ, Jared BC, Alex B, Raj M, Meena J-U. Molecular Pathways Mediating Metastases to the Brain via Epithelial-to-Mesenchymal Transition: Genes, Proteins, and Functional Analysis. Anticancer Research. 36, 523-532 (2016) 4. Kobayashi A, Okuda H, Xing F, Pandey PR, Watabe M, Hirota S, et al. Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J Exp Med. 208, 2641–2655, (2011) 5. Lam H-M, Vessella RL, Morrissey C. The Role of the Microenvironment – Dormant Prostate Disseminated Tumor Cells in the Bone Marrow. Drug Discov Today Technol. 11, 41– 47 (2014 Mar) 6. Rahman M, Mohammed S. Breast cancer metastasis and the lymphatic system, Oncol Lett. 10(3), 1233– 1239. (2015 Sep) 7. Dillman RO, Hendrix CS. Unique aspects of supportive care using monoclonal antibodies in cancer treatment. Support Cancer Ther. 1(1), 38-48 (2003 Oct 1) 8. El Miedany Y. MABS: targeted therapy tailored to the patient's need. Br J Nurs. 24(16 Suppl 1). S413 (2015 Sep) 9. Huang SK, Hoon DS. Liquid biopsy utility for the surveillance of cutaneous malignant melanoma patients. Mol Oncol. 10(3), 450-63 (2016 Mar) 10. Malara NM, Givigliano F, Trunzo

Dr Papasotiriou is a medical geneticist who graduated from the Medical School of Thessaloniki University in 1997. He specialised in human genetics in the University of Zurich until 2001. He obtained two Masters degrees, one in molecular biology in medicine from Westminster University and one in oncology from the University of Nottingham. He completed his promotion (MD) in MLU University in the area of TKIs in human cancer cell lines. Between 2001 and 2004 he established Arzt Genetik Zentrum in Thessaloniki, where he was a director. Since May 2004 he has been CEO and medical director of RGCC Ltd in Greece, where his major field of expertise is molecular oncology with a major interest in the entity of cancer stem cell like. Email: papasotiriou.ioannis@rgccgenlab.com Spring 2016 Volume 8 Issue 1


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Drug Discovery, Development & Delivery

Where are the Gaps in Your Data? In drug discovery, data is king. Gathering the right information makes it easier to design better compounds, faster. How can you be sure that you are getting the most out of your SAR data? And how easy is it to see where the gaps are in your data?

she was working with. “Projects were moved and new compounds were being made. You had to get familiar with the SAR really quickly to make sure you were not re-doing experiments or re-exploring hypotheses for which the solution was already known.”

Navigating a Complex Web of Information A typical lead optimisation phase of a drug discovery project will gather many thousands of data points. Hundreds, or even thousands, of compounds will be synthesised over the course of the project and each of these compounds has an associated wealth of potency, selectivity and ADMET information.

Even though such historical information, both in-house and published, is often available in electronic format, exploring the known SAR for a target can be a tedious and time-consuming exercise for the project team because of the volume of data involved.

Structure-activity relationships (SAR) make it possible to extract valuable information from this data, but thousands of data points translates to millions of comparison points. Navigating this complex web of information is a daily challenge for the project team. Their goal is to identify areas of critical activity in order to work out what synthetic decisions to make and to guide the project forward to the next lead candidate. In addition to the data generated by the project, it’s also important for the team to stay up to date by reading, extracting and summarising SAR information from published patent information and literature during the lifespan of a project. This is a time-consuming process, but new patent publications on a project of current interest will have a significant bearing on optimisation decisions on inhouse series. Getting up to Speed on New Projects Whenever a new research project is initiated, or transferred across teams, familiarisation with the prior art for the project must be completed in the shortest possible time. The team must get an overview of the data that has been gathered to date in order to avoid wasting resources investing in directions already explored in the past. This leads to a steep familiarisation curve. Dr Giovanna Tedesco recalls the merger between two companies that 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Creating One Picture from Many SAR Data Points Whether tracking an existing project, or getting to grips with an ongoing project, getting a useful handle on so much project data requires smart analysis solutions. Visualisation is a particularly powerful tool for interpreting large amounts of complex data. The data journalist David McCandless works with big data and talks about the beauty of creating data maps when you are lost in information. His TED talk ‘The beauty of data visualisation’1 is an engaging introduction to the power of data visualisation and to the insights that can come about that might otherwise not be apparent. He describes the process as ‘knowledge compression,’ that is, ‘a way of squeezing an enormous amount of information into a small space.’ SAR data for a discovery project does not enter the realm of big data, but it can still reach far beyond the level at which the human mind can draw useful conclusions from a spreadsheet. The ideal scenario is to be able to condense large data tables into a single picture that summarises structure-activity data into visual 3D maps. These maps can then be used to give an overall snapshot of the data and to inform the design and optimisation of new compounds. For example, a visualisation tool that can show the electrostatic, hydrophobic and shape regions that have been fully explored by the project makes it easy to assess whether new designs are worth

making, on the basis of whether or not they bring new knowledge to the project (Figure 1). This visualisation makes it easy to identify areas where there is little or no SAR data, helping scientists to target future investigations.

Figure 1: These visualisations of the electrostatic, hydrophobic and shape regions that have been fully explored by a project condense SAR data into a form that is easier to understand and interpret. Converting Patent Data into 3D Maps of SAR In this case study, the 3D SAR mapping software Activity Atlas2 was used to explore the SAR of a large data set of orexin 2 receptor ligands taken from the US patent literature. Activity Atlas is a probabilistic method of analysing the SAR of a set of aligned compounds as a function of their electrostatic, hydrophobic and shape properties. The method uses a Bayesian approach to take a global view of the data in a qualitative manner. This is useful for gaining a better understanding of the features which underlie the SAR of a compound series. Crystal Structure of Suvorexant Bound to the Human Orexin 2 Receptor The Orexin system is composed of two widely-expressed G-protein coupled receptors: the orexin 1 (OX1R) and orexin 2 (OX2R) receptors, which respond to the two peptide agonists orexin-A and orexin-B. These receptors work in the central nervous system to regulate sleep and other behavioural functions in humans3. Suvorexant is a first-in-class drug for the treatment of insomnia developed by Merck & Co with the trade name Belsomra. Suvorexant binds to both human OX1R and OX2R with subnanomolar affinity, potently inhibiting orexin receptor signalling in cell-based assays, and promoting the transition to Spring 2016 Volume 8 Issue 1


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Drug Discovery, Development & Delivery rapid eye movement (REM) and slow wave sleep in animals and humans 4,5,6. The X-ray structure of Suvorexant bound to human OX2R was recently solved at 2.5Å resolution (7 PDB code 4s0v), and as shown in Figure 2, was used to drive the alignment of the compounds in the data set chosen for SAR analysis.

by maximum common substructure alignment. Activity Atlas models were then calculated for the aligned data set.

help scientists to identify gaps in their project data, and to see where more investigation is required.

Results The activity cliff summary 3D maps in Activity Atlas highlight, in a highly visual manner, the most critical regions in the SAR of the Janssen data set.

References 1. h t t p : / / w w w. t e d . c o m / t a l k s / d a v i d _ mccandless_the_beauty_of_data_ visualization 2. http://www.cresset-group.com/activityatlas 3. Li, J., et al., Br. J. Pharmacol. 171, 332-350 (2014) 4. Michelson, D. et al., Lancet Neurol. 13, 461–471 (2014). 5. Winrow, C. J. & Renger, J. J., Br. J. Pharmacol. 171, 283–293 (2014). 6. Cox, C. D. et al., J. Med. Chem. 53, 5320– 5332 (2010). 7. Yin, J., et al., Nature 519, 247-250 (2015) 8. US Patent 8,653,263 B2 9. https://www.bindingdb.org 10. http://www.cresset-group.com/products/ forge

Looking at Figure 4, we can see that the SAR of the central phenyl ring (pink circle in Figure 3) is crucial for modulating OX2R activity; the preferred substituents will be those which help create the correct pattern of positive and negative electrostatic fields around the molecule. Also, steric bulk in the 2-position is clearly favourable.

Figure 2: The crystal structure of Suvorexant bound to the human Orexin-2 receptor. The Data Set A large data set of approximately 380 compounds with OX2R pKi activity data ranging from 5 to 8.5 was recently published by Janssen in the US patent literature8. The structures of the compounds and the related OX2R activity data were downloaded from BindingDB9. The most potent compound in the series (Figure 3) was selected as the reference structure for the subsequent modelling work.

Figure 3 – the reference structure for the Janssen data set (OX2R pKi 8.5) When using any 3D analysis method, such as 3D-QSAR, it is necessary to generate accurate alignments for all of the compounds in the data set. Activity Atlas uses a 3D similarity metric to compare compounds, and the alignments were carried out using the program Forge 10. Field-based alignment was used to superimpose the Janssen reference structure to the X-ray crystal structure of Suvorexant. All of the other compounds were aligned to the reference structure 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 4: Activity cliff summary 3D maps for the Janssen data set with interpretation, observed SAR and positive electrostatic interaction potentials for substituents at the 2-position of the central phenyl ring. There is a critical SAR region also on the pyrimidine ring on the right side of the molecule (orange circle in Figure 3), where steric bulk in the para position is also beneficial for OX2R activity. Conclusions This visual analysis method was very useful for quickly summarising, analysing and understanding the SAR of this large collection of compounds gathered from US patent information. The relevant SAR information was summarised into one interactive visual representation for this chemical series, demonstrating the applicability and utility of this method for the SAR analysis of large data sets. A tool that can condense SAR data down into easily understandable visualisations makes it far easier and quicker to get to grips with the scope and quality of project data. Visualisation can

Dr Giovanna Tedesco is the Cresset Product Manager for computational chemists. Previously, she was a senior computational chemist at Glaxo where she supported a variety of drug discovery programs in the antibacterials and CNS areas, and led target-to-lead CNS programs. Email: giovanna@cresset-group.com

Katriona Scoffin is a freelance science writer and marketing professional with extensive experience in the life science industry. She currently works for Cresset, an innovative company that uses software to help chemists discover, design and optimize the best small molecules for their project. Email: katriona@cresset-group.com Spring 2016 Volume 8 Issue 1


Understand your SAR data at a glance No strong SAR in this region

Small halogen preferred in the position, shown by shape and a negative electrostatic pattern

Strong signal that benzyl is favoured here, shown by electrostatic and shape pattern

Larger substituents are disfavoured in this position

Electron-deficient aromatic ring favoured here

Navigate complex SAR with Activity Atlas models Activity Atlas condenses your structure-activity data into highly visual 3D maps that inform the design and optimisation of new compounds. ● ● ● ●

Read case study and see web clip: cresset-group.com/navigate Download free evaluation: cresset-group.com/forge-evaluation

Know where to focus future optimisation efforts Increase the productivity of your team Focus new molecule design towards novelty and activity Seamless communication of complex SAR data between research groups.

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Drug Discovery, Development & Delivery

Engineering of Enzymes for Industrial Biocatalysis Enzymes are important biocatalysts with many applications in medicine, food technology and the chemical industry. To further expand their reaction scope and to meet the demands of industrial processes, the enzymes’ properties are routinely optimised by protein engineering. Due to a rapidly increasing number of protein sequences and structures and powerful computational tools, rational approaches are nowadays complementing random approaches. However, in most cases combined approaches proved to be most successful. Natural enzymes are ubiquitous biocatalysts, which are capable of catalysing reactions with up to 106 s-1 enzymatic rate constants and exceptionally high regioand stereochemistry. More than a century ago, Rosenthaler recognised that enzymes can be applied to chemical transformations, when he used emulsin for the first synthesis of (R)-mandelonitrile. Nowadays, enzymes are used in many (industrial) applications, e.g. as biocatalysts in the synthesis of fine chemicals and pharmaceutical compounds or their intermediates, in food processing, in the pulp and paper industry, in bioremediation, in medicine in diagnostics and as therapeutics or as additives e.g. in cleaning products. Enzymes usually work under mild reaction conditions, needing little energy, but also avoiding unwanted sidereactions. Moreover, due to the specificity of enzymes, the need for protection and deprotection steps is circumvented. However, although natural enzymes catalyse a wide range of chemical reactions, they have evolved towards the specificities of their natural role. Thus, they are not available for many of the important conversions and substrates relevant for industry and do not fulfil the manifold requirements for enzymes used in industrial biotechnology. Today, enzymes are routinely engineered to introduce novel functionalities and to match process demands1–3. Among targeted properties are, for example, improved activity, high space-time-yield, substrate scope, stability (pH, thermal, solvents, high substrate and product concentrations, shelf life) and selectivity, 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

but also improved expression levels. Therefore, different strategies for enzyme engineering are applied (Figure 1).

cheap, fast and reliable high-throughput assays. While microtitre plate assays (preferably analysed photometrically,

Figure 1. Strategies for protein engineering by random, rational and combined methods. Directed enzyme evolution is based on the generation of a large pool of mutants and subsequent screening and selection of the best variants exhibiting the required characteristics. The advantage of directed evolution is that no structural information is needed and that variations at unexpected positions distant from the active site can be introduced. However, usually the changes are small and several rounds of evolution have to be applied and a high number of variants have to be screened, which is time- and labour-consuming. Thus, one of the most important factors for successful enzyme evolution is the availability of

but alternatively also by liquid or gas chromatography or mass spectrometry, their throughput depending a lot on the chosen detection method, library size: 103-105), agar plate assays (visual inspection, library size: 104-106) and selection assays (relying on a direct correlation between cell survival and the desired enzyme property, library size: 107) are routinely applied and need standard equipment, other approaches allow the screening of even larger libraries by compartmentalisation of single cells into microdroplets and the use of fluorescence-activated cell sorting (FACS) (library size: 109)4. However, Spring 2016 Volume 8 Issue 1


Drug Discovery, Development & Delivery the latter methods are limited by the requirement for specialised and still expensive equipment and the information obtained, as in most cases surrogate substrates, which lead to fluorescent products, need to be used, which leads to a fluorescent product risking optimisation for the “wrong” substrate (first law of directed evolution: “you get what you screen for”), and because only endpoint measurements are possible. Alternatively, the throughput of microtitre plate-based assays can also be increased by robotics. In contrast, in rational design approaches only a few variants need to be analysed. Rational design presupposes more detailed knowledge about an enzyme, like a pool of amino acid sequences for comparison or structural data (3D-structure or homology model). In many cases this is not limiting as, with the development of new sequencing technologies, the number of sequenced genomes is expanding exponentially and moreover more than 110,000 protein structures are deposited in the protein databank. A vast number of bioinformatics programs are available for analysis and prediction. Rational design usually increases the probability of beneficial mutations and, most importantly, reduces the library size, and thus, less effort and time has to be applied for the screening of the library. This is especially advantageous if no high-throughput assay system is available. However, relevant positions might be missed. As computational power accelerated and computational methods became significantly more accurate and easier to use in the past few years, the field of de novo enzyme design emerged5. De novo enzymes can be either designed by recreating known enzymatic functions in proteins with a different fold, or by introduction of activities that have not been observed before in natural enzymes into a chosen protein scaffold. The biggest challenge, however, is the design of de novo enzymes that are not based on natural sequences, thus designing the complete protein from scratch. Another emerging research field, which is currently still mainly applied on the laboratory scale, is the use of non-canonical amino acids in protein engineering to improve the stability and alter catalytic properties6. An alternative option to introduce novel functionalities into proteins is the creation of artificial metalloenzymes, which are described as a bridge between biocatalysis and metal catalysis by incorporating the www.ipimedia.com

catalytically active metal (complex) in protein scaffolds, enabling high activity and selectivity under mild reaction conditions. An increasing number of different approaches also involving protein engineering has been developed in recent years and extensively reviewed (e.g. 7). Interestingly, in many successful examples for enzyme engineering, a combination of rational and random approaches was the strategy of choice (semi-rational approach) (e.g.8). Semirational design combines advantages of rational and random protein design, creating smaller, smarter libraries based on knowledge derived from biochemical, sequence comparison, and/or structural data. By analysing and comparing structural or sequence data, interesting amino acids or regions in the protein are identified and subsequently mutated randomly or by site-saturation mutagenesis, one by one or in combination. Random combinations

of mutations or correlated mutations at targeted positions can result in synergistic effects that might have been missed in single site-specific mutagenesis. However, these combinatorial approaches increase the library sizes tremendously. To help to decrease the library size, various computational methods have been

developed in recent years that screen virtual libraries and eliminate mutations predicted to be unfavourable for the protein fold9. Uncountable examples for the different approaches mentioned above have been published in the last twenty years. In Graz, biocatalysis applying hydroxynitrile lyases (HNLs) has a long tradition and therefore HNLs are also a target of enzyme engineering. Many successful examples of protein engineering of hydroxynitrile lyases are described in literature (Table 1, for references please refer to 10). Often their application as industrial biocatalysts is restricted due to limited acceptance of unnatural substrates or low stability at the required reaction conditions. In particular, pH stability is one of the most important features of HNLs and a prerequisite of their technical applicability as the unselective chemical background reaction, which competes with the

enantioselective enzyme-catalysed reaction, increases at pH-values > pH 4.5 and destroys the enantiopurity of the product. In recent years, structure-guided design, site-saturation mutagenesis INTERNATIONAL PHARMACEUTICAL INDUSTRY 39


Drug Discovery, Development & Delivery by comparing the active sites of HbHNL and the esterase SABP2 (salicylic acid binding protein 2 from Nicotiana tabacum) and subsequent site-directed and site-saturation mutagenesis of several positions enhanced the reaction rate of HbHNL-L121Y16. The group of Asano employed rational design and directed evolution to yield MeHNL variants, which are significantly better expressed as soluble protein in E. coli. Several site-directed mutants of MeHNL were reported to possess improved thermal stability and higher organic solvent tolerance in comparison to the wild type (for review see17 and citations therein).

and random mutagenesis were applied to create several PaHNL5 (Prunus amygdalus) variants with improved activity and enantioselectivity toward challenging substrates by removing steric hindrance for bulky substrates or altering the hydrophobic interaction with the substrate11,12. The expression level of PaHNL5 in P. pastoris was significantly improved by substitution of the first amino acid leucine for glutamine, and replacement of the native secretion-signal by the signal sequence of the alphamating factor from Saccharomyces cerevisiae. The activity and enantioselectivity of the first bacterial HNL GtHNL from Granulicella tundricola was significantly improved by site-saturation mutagenesis of active site amino acids. Combination of beneficial amino acid exchanges resulted in a variant with 490-fold increased specific activity in comparison to the wild type. More importantly, GtHNL-A40H/ V42T/Q110H is a highly competitive alternative for the synthesis of several industrially relevant cyanohydrins13. In HbHNL (Hevea brasiliensis) and MeHNL (Manihot esculenta), a tryptophan residue in the entrance tunnel limits the access of bulky substrates. Exchange of W128 to smaller amino acids enhanced the conversion of bulky substrates in both enzymes14,15. Interestingly, this position was identified by rational design and random mutagenesis. Directed evolution of HbHNL-W128A resulted in further improved variants. Active site redesign 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

AtHNL (Arabidopsis thaliana) is significantly less stable at acidic pH (below pH 5.4) than HbHNL and MeHNL. In a rational protein engineering approach to stabilise AtHNL, eleven amino acids at its surface were exchanged to the corresponding amino acids from MeHNL, resulting in an active and more stable variant18. Rational protein design was also applied to alter the catalytic mechanism of the esterase SABP2, and introduce HNL activity19. Moreover, Asano and his group developed an algorithm for assignment of consensus and correlation residues of target proteins and applied it for designed (S)-selective HNLs 20. In the current millennium, more and more industrial chemical processes are replaced by biocatalysis applying enzymes. This was made possible by substantial progress in enzyme engineering. However, it will be still important to invest extensive research to fully understand catalytic reaction mechanisms of enzymes and how natural enzymes achieve their catalytic efficiency, but also their molecular dynamics and the folding of protein structures to be subsequently able to tailor and design proteins for specific processes. Acknowledgments This work has been supported by the Federal Ministry of Science, Research and Economy (BMWFW), the Federal Ministry of Traffic, Innovation and Technology (bmvit), the Styrian Business Promotion Agency SFG, the Standortagentur Tirol, the Government of Lower Austria and ZIT - Technology Agency of the City of Vienna through the COMET-Funding

Program managed by the Austrian Research Promotion Agency FFG. References 1. Steiner K, Schwab H. Recent advances in rational approaches for enzyme engineering. 2012, e201209010. 2. Strohmeier GA, Pichler H, May O, Gruber-Khadjawi M. Application of designed enzymes in organic synthesis. Chem. Rev. 2011, 111:4141–64. 3. Bornscheuer UT, Huisman GW, Kazlauskas RJ, Lutz S, Moore JC, Robins K, Stemmer P. Engineering the third wave of biocatalysis. Nature 2012, 485: 185-194. 4. Colin P-Y, Zinchenko A, Hollfelder F. Enzyme engineering in biomimetic compartments. Curr. Opin. Struct. Biol. 2015, 33:42–51. 5. Kiss G, Çelebi-Ölçüm N, Moretti R, Baker D, Houk KN. Computational enzyme design. Angew. Chem. 2013, 52:5700–5725. 6. Wiltschi B. Protein Building Blocks and the Expansion of the Genetic Code. In Synthetic Biology. Edited by Glieder A, Kubicek C, Mattanovich D, Wiltschi B, Sauer M. Springer Berlin Heidelberg; 2016:143–209. 7. Pàmies O, Diéguez M, Bäckvall J-E. Artificial Metalloenzymes in Asymmetric Catalysis: Key Developments and Future Directions. Adv. Synth. Catal. 2015, 357:15671586. 8. Reetz MT. The importance of additive and non-additive mutational effects in protein engineering. Angew. Chem. 2013, 52:2658–66. 9. Wijma HJ, Floor RJ, Bjelic S, Marrink SJ, Baker D, Janssen DB. Enantioselective Enzymes by Computational Design and In Silico Screening. Angew. Chem. 2015, 54:3726–3730. 10. Steiner K, Glieder A, GruberKhadjawi M. Cyanohydrin Formation/Henry Reaction. In Science of Synthesis: Biocatalysis in Organic Synthesis Volume 2. Edited by Faber K, Fessner W-D, Turner N. Georg Thieme Verlag; 2015. 11. Pscheidt B, Avi M, Gaisberger R, Hartner FS, Skranc W, Glieder A. Screening hydroxynitrile lyases for (R)-pantolactone synthesis. J. Mol. Catal. B Enzym. 2008, 52-53:183– 188. 12. Glieder A, Weis R, Skranc W, Poechlauer P, Dreveny I, Majer S, Spring 2016 Volume 8 Issue 1


Manufacturing Drug Discovery, Development & Delivery Test method: Method A – Membrane Filtration The method calls for the routine use of positive and negative controls. Wubbolts M, Schwab H, Gruber 16. von LangermannForJ, aqueous Nedrudsolutions: DM, complete sequence design utilizing Aseptically transfer of fluid A onsoftware. to the membrane and K. Comprehensive step-by-step Kazlauskas RJ. Increasing thea small quantity the INTMSAlign Sci. Rep. filter it. Transfer aseptically the combined quantities of the preparation Apparatus: engineering of an (R)-hydroxynitrile reaction rate of hydroxynitrile lyase 2015, 5:8193. Cellulose nitrate filters are used for aqueous, oily and weakly alcoholic under examination prescribed in the two media onto one membrane. lyase for large-scale asymmetric from Hevea brasiliensis toward solutions, and cellulose acetate filters are recommended for strongly synthesis. Angew. Chem. 2003, mandelonitrile byIf thecopying activeexamination has antimicrobial properties, wash the solution under alcoholic solutions. 42:4815–8. site residues from an esterase membrane(s) by filtering through it (them) not less than three successive 13. Wiedner Kothbauer B, Pavkovthat accepts quantities, aromatic each esters. of 100 ml, of sterile fluid A. Diluting Fluids: (IP,R,BP): Keller T, Gruber-Khadjawi Gruber Fluid A: Dissolve 1 g of peptic M, digest of animal Chembiochem tissue (such as 2014, 15:1931–8. Dr Kerstin Steiner works K, Schwab H, Steiner K. Improving Dadashipour Do notAsano exceed a Y. washing cycle of five times or 200 ml, even if it bacteriological peptone) or its equivalent in water 17. to make 1 litre, filter M, as a project manager been demonstrated during validation that such a cycle does not or centrifuge to clarify,ofadjust to pH 7.1 ± 0.2, dispense into flasks in has the Properties Bacterial R-Selective Hydroxynitrile Lyases: Insights and senior researcher eliminate the used 100ml Hydroxynitrile quantities and sterilize 121° C for 20 minutes. Lyasesatfor Industrial into Biochemistryfully , Discovery, andantimicrobial activity. The quantities of fluid at Austrian of should be sufficient a small inoculumCenter of organisms Applications. ChemCatChem 2015, Engineering. ACS Catal. 2011,to allow growth ofthe Industrial antimicrobialBiotechnolgy substance in the Fluid B:7:325–332. If the test sample contains lecithin or oil, use fluid A to each litre (approximately 50 CFU) sensitive to the 1:1121–1149. (acib) and specialises in presence of the residual inhibitory material on the membrane. of14. which has been added 1 ml of polysorbate 80, adjust to pH 7.1± Avi M, Wiedner RM, Griengl 18. Okrob D, Metzner J, Wiechert After filtration, aseptically remove theenzyme membrane(s) from the holder, 0.2, dispense into flasks and sterilise at 121° C for 20 minutes. engineering for H, Schwab H. Improvement of W, Gruber K, Pohl M. Tailoring a transfer the whole membrane or cut it in aseptically into biocatalysis. two equal parts. application industrial a Stereoselective Biocatalytic stabilized variantTransfer of hydroxynitrile one half to eachShe of two studied suitable media. Incubatechemistry, the media for Quantities of sample to be used: technical Synthesis by Substrate and enzyme lyase from Arabidopsis thaliana. not less than 14 days. biochemistry and biotechnology at For parenteral preparations: engineering: 2-hydroxy-(4'Chembiochem Whenever possible, use the whole contents of the container, but in any 2012, 13:797–802. Graz and obtained her PhD in oxocyclohexyl)acetonitrile as the 19. 1Padhi SK, FujiiObserve R, Legatt GA, TU the containers of media periodically during the 14 days of case not less than the quantities prescribed in Table 3(E), diluting where nanobiotechnology from the University model. Chemistry 14:11415SL, Berchtold R, Kazlauskas incubation. If the test specimen is positive before 14 days of incubation, necessary to about 100 ml 2008, with a suitable diluent such Fossum as fluid A. of Applied Life Sciences and sterilised Natural by 22. RJ. Switching from an incubation Esterase is tonot necessary. For products terminally further Resources in Vienna. She received a validated moist heat process, incubate the test specimen for not less For ophthalmic and other non-parenteral preparations: 15. Bühler H, Effenberger F, Förster a Hydroxynitrile Lyase Mechanism than seven days. Take anS,amount the range (A) of Table Roos within J, Wajant H. prescribed Substrate in column Requires Only Two Amino Acid an Erwin-Schrödinger fellowship and 3(E), if specificity necessary, using contents of container, and Chem. Biol. 2010, worked as a research fellow in protein of the mutants of more thethan oneSubstitutions. crystallography at the of St aqueous vehicles, andUniversity suspensions: mix thoroughly. For each medium use the amount specified in column For liquids immiscible with hydroxynitrile lyase from Manihot 17:863-71. Carry out the test described under for aqueous solutions but add a (B) of Table 3(E), taken from the mixed sample. Andrews. esculenta. Chembiochem 2003, 20. Nakano S, Asano Y. Protein evolution sufficient quantity of fluid A to the pooled sample to achieve rapid 4:211–6. analysis of S-hydroxynitrile lyase by Email: kerstin.steiner@acib.at filtration. Sterile enzyme preparations such as penicillinase or cellulose

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Clinical Research Systemic Epigenetic Biomarkers for ALS Improve Early Diagnosis, Treatment and Trials Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is a devastating, rapidly progressive and invariably fatal neurological disease that attacks the nerve cells responsible for controlling voluntary muscles and for which there is no diagnostic or prognostic test. The disease belongs to a group of disorders known as motor neuron diseases (MNDs), characterised by the gradual degeneration and death of motor neurons. ALS is one of the most common neuromuscular diseases worldwide, affecting around 2 in 100,000 people each year. About 5 to 10 per cent of all ALS cases are inherited (familial ALS). However in 90 to 95 per cent of all ALS cases, the disease occurs apparently at random and is not gene-linked. There is increasing evidence that the most common form of ALS (known as sporadic ALS) is the result of the long-term influence of environmental factors on the genome1 and, specifically, epigenetic alterations2,3. Most people with ALS die from respiratory failure, usually within three to five years from the onset of symptoms. However, about 10 per cent of those with ALS survive for 10 or more years. These differences in disease progression can be linked to epigenetics. Oxford BioDynamics (OBD) is developing and validating diagnostic and prognostic epigenetic biomarkers based on its proprietary, innovative EpiSwitchTM biomarker platform technology. The tests would enable early detection and prognostic stratification of ALS patients into groups with fast and slow progressing disease, in direct correlation with their ALSFRS-R scores, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale, which is used today to assess disability in patients with MNDs. The resultant prognostic epigenetic test could be used to inform patient recruitment into clinical trials, to determine therapeutic impacts on rates of progression and as a companion test for novel targeted therapeutic approaches. Additionally, the test would have value as a standalone diagnostic and prognostic test to inform strategies for the clinical management of patients.

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Currently, to deliver a confident diagnosis of ALS, a comprehensive diagnostic workup is needed that requires many different procedures, including electro diagnostic tests such as electromyography and nerve conduction velocity, blood and urine studies including high-resolution serum protein electrophoresis, thyroid and parathyroid hormone levels and 24-hour urine collection for heavy metals, lumbar puncture x-rays, including magnetic resonance imaging, myelogram of cervical spine, muscle and/or nerve biopsy, and a thorough neurological examination. These processes require hours of patient cooperation, and days of laboratory time. In contrast, the diagnostic tests being developed by OBD are non-invasive, quick to administer, and can be analysed in four hours. The Value of Systemic Epigenetic Biomarker Tests Diagnosing and treating ALS is currently expensive, and fails to match the critical time needs of patients, placing an economic burden on the patient, the payer and the community. Direct costs include those owed mainly to the healthcare sector for treatment of the disease, including GP contacts, outpatient specialist contacts, physical, speech and occupational therapy, complementary healthcare, hospitalisations, prescribed and over-the-counter medications and medical interventions to support nutrition and respiratory functions, e.g. percutaneous endoscopic gastronomy (PEG) or bi-level intermittent positive pressure (Bipap) ventilation. On top of these direct medical costs come nonmedical costs, including adaptations to the patient’s home, and adapted means of transportation, aids and appliances needed to perform life’s daily activities. Indirect costs are those representing lost resources including productivity losses due to absence from work, whether that is for the patient or for family members who take time off to care for them; these can be substantial if the disease affects workers earning high rates near the end of their careers. Intangible costs are virtually impossible to measure but encompass the reduction in the quality

of life. Despite intensive research into the biological basis of ALS, and numerous well-powered multicentre clinical trials, the disease remains untreatable. A major impediment to identifying drugs of therapeutic benefit in ALS is the absence of adequate biomarkers that can provide objective evidence of a favourable alteration in biological pathways known to be important in the pathogenesis. It is entirely plausible that drugs that could have an impact on the disease process for a specific cohort of patients have been systematically discarded, based on crude clinical endpoints in clinical trials. Importantly, it is likely that combinatorial approaches to diseases like ALS will be required and therefore it is critical to find improved ways of measuring the effect of drugs directly on disease relevant pathways. The OBD programme of work will directly contribute to knowledge, both within the UK and internationally, by increasing the biological understanding of disease heterogeneity and thus informing clinical and basic science studies of disease natural history. It will improve basic laboratory research by identifying key biological pathways underpinning motor neuron degeneration, and aid the pharmaceutical industry and its academic partners to select drugs of potential therapeutic effect and to allow targeting of specific sub-groups of patients. Academic researchers working on other neurodegenerative diseases will also benefit from the expansion of our understanding of epigenetic effects in these conditions and in understanding potential overlaps in pathogenesis. These benefits will not be limited only to ALS or UK-based researchers, as biomarker and therapeutic research in this area is necessarily a collaborative activity in a rare disease. As an example of this collaborative activity, today OBD is actively engaged in its efforts with the US North East ALS consortium (NEALS), Massachusetts General Hospital, Boston and Nuffield Department of Clinical Neurosciences, University of Oxford. It counts Professor Merit Cudkowicz, Spring 2016 Volume 8 Issue 1


Clinical Research Professor of Neurology, Harvard Medical School Director, MGH MDA ALS Clinic Chief, Neurology Service Co-Director of Neurological Clinical Research Institute, and Professor Kevin Talbot, University of Oxford, among its collaborators. OBD tests will have value clinically as they support diagnosis and prognosis, scientifically as they back up clinical research, and commercially as they add value to the marketability of drug manufacturers’ products. The tests will enable earlier patient diagnosis and accelerate clinical decision-making, allowing patients earlier access to wider clinical support for the manangement of their disease, improving quality of life. Additionally, the ability to exclude a diagnosis of ALS early in presentation will enable alternative diagnostic testing to be indicated, and appropriate therapeutic relief to be delivered sooner. OBD analysis will improve clinicians’ ability to offer a prognosis, by giving healthcare practitioners objective insight into individualised patient trajectories (e.g. fast vs. slow progressing disease), and would provide, according to key opinion leaders, a desperately needed tool for long-term patient management, enabling patient-centred effective care planning. For managers of clinical trials, applications in clinical trial recruitment will improve their ability to stratify patients into groups, such as those more likely to respond to treatment due to the stage of disease (earlier is better) and those more likely to show effects of therapy over a shorter trial duration due to the fast rate of progression. Such stratification could potentially improve clinical trial outcomes. In clinical trial monitoring, changes in prognostic biomarkers could provide a surrogate for earlier therapeutic efficacy, irrespective of drug mechanism of action. This could dramatically improve the way trials are designed, outcome measures being currently based on rate of decline in ALSFRS-R and survival, which is lengthy and costly. This would offer a great benefit to therapeutic developers, who could run trials more quickly and more quickly with lower patient numbers, and for patients who would neither get recruited into inappropriate trials, nor have to stay on ineffective experimental therapies for longer than is necessary. By further refining the biomarker panel together with a novel therapy, drug developers could deploy an approach www.ipimedia.com

combining a companion diagnostic with a therapeutic. This combination enables the identification of specific ALS patient populations for trial recruitment that are most likely to respond to therapy based on specific epigenetic or targeted molecular mechanisms, and provide a mechanism to measure early response to therapy. This work could also provide insights for preclinical researchers in ALS, to identify further epigenetic mechanisms involved in disease onset and progression, enabling the development of novel targeted therapeutic approaches.

chromosome conformation signatures has already identified 927 epigenetic ALS-specific biomarkers with significant fold change against controls and p<0.1. This offers a rich pool of potential biomarker leads for further evaluation. Significant epigenetic deregulations have been identified within the most relevant main loci: for their roles in familial type ALS, SOD1 and C9orf 72; for its role in sporadic type ALS, TDP43; and for their roles in neurodegeneration PANX1 and DNM3; T Cell Receptor Signalling and Toll-like Receptor Signalling Pathways.

Stratifying Patients Using Chromosome Conformation Signatures Our work focuses on developing for personalised medicine in disease areas where epigenetic changes are implicated in disease phenotype. OBD’s platform technology, EpiSwitch™, is based on the identification of a specific class of epigenetic biomarkers – chromosome conformation signatures (CCSs) which serve as early markers of gene deregulation and precede other epigenetic changes. This innovative technology offers the ability to rapidly develop simple, sensitive and affordable diagnostic products. CCSs have much to recommend themselves among the many different classes of biomarkers4:

Evaluation analysis performed on a cohort of 74 ALS patients and controls has identified a signature of five EpiSwitchTM biomarkers. In the pipeline of statistical analysis, the attribute space was reduced using either logistic regression or Random Forest approaches with linear forward selection. The libraries under the Weka package were used for these steps. The resultant EpiSwitch™ panel of five markers was the best for discerning the classes under investigation (Figure 1). When tested for validation in an independent blinded cohort of peripheral blood samples, the signature stratified ALS patients with 87.5% sensitivity.

• • •

They offer informative stratification of complex phenotypes, where genetic differences are strongly modulated by epigenetics, Have high biochemical and physiological stability, Have a binary nature, for ease of statistical analysis and construction of strong classifiers, Offer a signal that is detected early in the disease process due to its primary position in the eukaryotic cascade of gene regulation, Are detectable in blood samples.

These advantages mean chromosome conformation signature biomarkers are an excellent, innovative choice for the screening, early detection, monitoring and prognostic analysis of major diseases associated with aberrant and responsive gene expression, including ALS. Using its custom-designed EpiSwitchTM Array platform, OBD has conducted initial discovery and evaluation of potential systemic epigenetic biomarkers. Extensive analysis of epigenetic regulation on over 296 genes and 14,000 EpiSwitch™

Biomarker Discovery Technology The custom 15k EpiSwitch™ Array is used to analyse around 300 genetic loci (up to 50 candidate markers per loci), that are interrogated with the EpiSwitch™ Biomarker discovery technology. The array is built on the basis of the Agilent SurePrint G3 Custom CGH microarray platform, and each EpiSwitch™ probe is presented as a quadruplicate, thus allowing for statistical evaluation of reproducibility. The probes that are spotted onto the arrays are the chimeric fragments predicted to exist at the loci, as predicted by the EpiSwitch™ pattern recognition software. Samples representing ALS and control are labelled with Cy5 or Cy3 and assessed by competitive hybridisation for the prevalence of individual EpiSwitch™ marker candidates. The resultant data is analysed with proprietary processing scripts using Bioconductor in R: Limma. The normalisation of the arrays is done using the normalise within arrays function in Limma with Agilent and EpiSwitch™ controls. Probes that pass the p<0.01 FDR p-value are used for further screening. To reduce the probe set further, multiple factor analysis is performed using the FactorMineR package in R. The top INTERNATIONAL PHARMACEUTICAL INDUSTRY 43


Clinical Research following the treatment will help the development of predictive biomarkers for identification of potential responders and non-responders to treatment.

statistical and discerning EpiSwitchâ&#x201E;˘ markers from the R analysis are then taken forward to screening and reduction using the EpiSwitchâ&#x201E;˘ PCR assay. The EpiSwitchTM assay and its PCR platform present a simple, robust test that is readily transferable to healthcare or pharma R&D settings. Specialised test technology has already been transferred to several parties in Asia. OBD reference facilities in Oxford and Penang run EpiSwitchTM tests under industry quality control standards, with a current throughput capacity of up to 50,000 sample readouts per quarter. OBD is planning to commercialise its technologies primarily through licensing agreements in the US, where OBD is conducting a number of collaborative biomarker projects with leading pharmaceutical partners, and Asia, where OBD operates its second reference facility and is working with leading private hospitals. Extended evaluation of diagnostic markers starts on the EpiSwitchTM array platform using a custom-designed array based on loci of interest. If a diagnostic signature is confirmed (CV value of <30% and p<0.01 FDR p-value) the top performing markers are taken forward for validation using the PCR platform in an iterative process involving more than 100 ALS samples and 100 age-matched controls. The patients will be a mix of incident and prevalent, the latter being 44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

enriched for those patients within three years of symptom onset. The markers confirmed in the diagnostic work packages will also be evaluated for prognostic signatures using a pared-down version of the custom array from the earlier work package and tested using longitudinal samples from the fast and slow progressing patients (assessed at point of recruitment and at three and six months). Once the prognostic signature is confirmed (CV value of <30% and p<0.01 FDR p-value) it will be taken forward for marker refinement to improve the analytical qualities of the test, and then validation using the EpiSwitchâ&#x201E;˘ PCR platform and longitudinal samples from all available ALS patients. Determination of fast versus slow progression is based on the classification using the formula 48-ALSFRS-R score at presentation/ months since symptom onset.

An Impact Summary The identification of an epigenetic biomarker could have a major impact in a short to medium timescale of 3-5 years across all parts of the drug development industry, from investigators and trial patients to drugs companies and industry regulators, as well as having a spill-over effect on other areas of neurodegenerative research. Investigators would be able to streamline clinical trials, allowing drugs of potential effect to be pre-screened prior to entering full Phase II and III studies, and potentially saving considerable costs for the pharmaceutical industry that could be invested into the development of new therapies. People living with ALS would benefit from a more precise prognostication and personalised care planning because a sub-stratification of patients according to the biological mediators of clinical heterogeneity would identify fast/slow progressors. ALS is a heterogeneous disease and clinical trials do not generally distinguish between subtypes of the disease, which partly

Subsequently, blinded validations of the diagnostic and prognostic tests will be performed on independent cohorts. Apart from the diagnostic and prognostic tests, OBD is also planning to explore the potential for sub-stratification of ALS patients in clinical trials: a correlation of changing epigenetic profiles during treatment with primary endpoint outcomes will help the development of response biomarkers; a correlation of epigenetic profiles of patients at base line with primary endpoint outcomes Spring 2016 Volume 8 Issue 1


Manufacturing Clinical Research Preparation of test solutions: at the specified wavelength in accordance with the instructions of the Solution A: Solution of the product under examination at the initial lysate manufacture. may contribute to the failure of pharma they can plan and streamline services epigenomic era. Nat. Rev. Neurol. dilution (test solution) to identify treatments that might benefit for patients, especially if therapies alter 11, 266–79 (2015). Solution B: Test solution spiked with CSE at a concentration at or near Interpretation of results: sub-groups of patients. The identification the natural history of the disease. In 4. Crutchley, J. L., Wang, X. Q. the middle of the standard curve (PPC) The assay is valid only if of biomarkers would improve efficiency addition to these benefits to the research D., for Ferraiuolo, a &concentrations Dostie, J. Solution C: Standard solutions of CSE in water BET covering the linear 1. The standard curve is linear the range M. of CSE of clinical trial design and reduce waste. and development community working in Chromatin conformation signatures: part of the standard curve used; It would reduceBET the(NC) number of patients neurodegeneration, the has theof correlation idealr ishuman disease biomarkers? Solution D: Water 2. research The coefficient not less than 0.980; exposed to avoidable risk by restricting potential to improve 3. the The efficiency with Biomark. Med. 4, 611–29 (2010). mean % recovery of the added endotoxin in the positive Method: product control is between 50% and 150%. trials to appropriate groups based on which pharmaceutical industry resources Add solution characteristics. D, followed by solutions C, A, B. Add carry them up to support biological arelysate used,and freeing out the assay solution in accordance with the instructions of the lysate further growth in the biopharma industry, The concept of total quality control test refers to the process of manufacture. The wider community of and creating opportunities training a perfect product by a series of measures striving for to produce

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Calculation: neurodegenerative disease (Parkinson’s disease area. Magdalena Jeznach, BSc Calculate the endotoxin concentration of solutions A and B from the every stage in the production. In-process product testing is and related conditions, dementia and MSc is ALSofProject Manager required in order to check the conformance the product with regression equation obtained with solutions of series C. Calculate the degenerative livingendotoxin with References at Oxford Ltd. in theBiodynamics pharmacopoeias. mean percentageataxias), recoverypatients of the added by subtracting the the compendial standards as specified suchendotoxin diseases,concentration and the pharmaceutical Ahmed, A. & The Wicklund, M. P. responsible for pharmacopoeias have laid(OBD), down the specified limits mean in solution A from 1. the mean endotoxin industry, would benefit by a greater Amyotrophic lateral sclerosis: what £1.26mlnas concentration in solution B. within which the value should fallcoordinating in order to bea compliant understanding of the overlaps between role does environment play? Neurol. As the final samples Interpretation of results: ALS biomarker per the standards. taken forprogramme. the finished

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The assay is valid only ifestablished for ALS 2. Figueroa-Romero,significant diseases (already C. et al. still collaborative project ofbrings difference remains because minor together variation 1.andThefrontotemporal standard curve is dementia). linear for the Drug range of CSEIdentification concentrations of University ALS clinical Since experts, in theepigenetically specified limits Oxford in different pharmacopoeias. the used; would benefit from a greater regulators altered genesmarkets in have sporadic Chronos Therapeutics’ novel insights opened up due to globalisation, it is necessary 2. The coefficient of correlation r is not greater than 0.980; objectivity in clinical trial outcomes that amyotrophic lateral sclerosis. PLoS into disease therapy and OBD’s cutting3. The mean % recovery of the added endotoxin in the positive for a product to comply with the standards of the place where would come from the identification of One 7, e52672 (2012). it is to be marketed. edge EpiSwitch biomarker technology product control is between 50% and 150%.

epigenetic biomarkers. Providers of 3. Paez-Colasante, X., Figueroa- to develop diagnostic, prognostic and healthcare, policy-makers and public Romero, C., Sakowski, S. A., pharmacopoeias predictive biomarker tests. in different End point chromogenic method As the official are different health organisations benefit S. A.parts & of Feldman, E. Email:magdalena.jeznach@ Add solution D, followed bywould solutions C, A, B. TheGoutman, chromogenic the globe, there is a need for the harmonised limit from aand greater understanding of the and incubated L. Amyotrophic lateral sclerosis: substrate lysate are added to the solution for the within which a productoxfordbiodynamics.com should fall to meet the pharmacopoeial recommended time. Stop the reaction and so measure the absorbanceand therapeutics in the biological heterogeneity of ALS, mechanisms

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Clinical Research Genomics and Precision Medicine: Marketing Challenges and Opportunities In an age of big data, companies now have more power to respond to their customers as individuals. Ever since the first internet shops discovered that tracking users’ buying habits could help them to predict what other products users might be interested in, a personalised and tailored service is something companies strive to deliver and consumers increasingly expect.

In the US, the White House launched its Precision Medicine Initiative, with an initial budget of $215 million4, and stated that “the possibilities are boundless.” The Administration’s programme begins with a plan to collect genetic data on one million Americans so scientists can develop more diagnostics and therapies tailored to the characteristics of individual patients.

Personalisation is also reflected within the life sciences industry, enabled by the cracking of the human genome code in 2003. The resulting discipline of genomics studies the complete set of DNA within an individual, which helps to understand their predisposition towards certain genetic diseases, informs the best course of treatment, and ultimately contributes to the development of personalised medical solutions. As more detailed information becomes available about our specific genetic make-up and diagnoses are adapted accordingly, we as patients will increasingly demand pharmaceutical solutions tailored to our DNA rather than mass-market, one-size-fits-all drugs. The buzzword is “precision medicine”.

Of course, the life sciences industry itself has already been pushing ahead in this area, working on innovative ways to apply genomics to drug development and delivery. An early example of how genomics is changing patient care is the blood thinner Warfarin. Patients vary widely in their required doses and, in the past, this meant that initial doses for some patients were too high or too low, which led to negative side-effects. However, by reading individual biomarkers, doctors can now accurately determine the best starting dose for each patient, mitigating side-effects and potentially saving lives.

Genomics is a Thriving Market The global genomics market is already valued at over £8 billion1 and forecasted to grow rapidly over the coming years, due to government support and investment. In the UK, the 100,000 Genomes Project is set to receive £250 million over the next five years, announced as part of the government’s 2015 Spending Review and Autumn Statement2. Introducing whole-genome sequencing technology to the NHS is the ultimate goal of the project, which aims to complete patient sequencing by the end of 2017. Prime Minister David Cameron wants the NHS to be the first mainstream health service in the world to offer genomic medicine as part of routine care: “I am determined to do all I can to support the health and scientific sector to unlock the power of DNA, turning an important scientific breakthrough into something that will help deliver better tests, better drugs and, above all, better care for patients.”3

46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Another example of the development of precision medicine via the use of biomarkers is Kalydeco (ivacaftor) from Vertex Pharmaceuticals. The drug treats cystic fibrosis in patients who have any of nine specific mutations in a gene called the Cystic Fibrosis Transmembrane Regulator (CFTR), which causes thick mucus to accumulate in the lungs and digestive tract. Kalydeco is the first drug to offer a way to “work around” the defects caused by these particular genetic mutations.

Prognostic biomarkers are transforming cancer care. For example, genetic anomalies in malignant tumours can sometimes be used to predict the effectiveness of therapies. A preliminary study from the M.D. Anderson Cancer Center illustrated the potential benefits from matching targeted therapies with specific gene mutations across many cancer types. Patients with targeted therapies demonstrated a 27% response rate, compared to 5% for those whose therapies were not matched.5 In fact, personalised medicines represent 42% of drugs in the pipeline today, according to a survey by the Tufts Center for the Study of Drug Development.6 Life sciences firms are increasingly moving away from the old model of developing a single blockbuster product to address the widest-possible patient population to a more personalised approach. These companies are working to develop specialised drugs for smaller groups to match patients to the best therapies based on their genetic make-up and other predictive factors. For instance, the one or two drugs used to treat high cholesterol are splintering off into many slightly different therapies based on the genetic variables of particular patient populations. Precision Medicine Creates New Marketing Challenges However, while highly specialised drugs produce better outcomes for patients, they present a tough challenge for marketers. A medical solution that can benefit 30,000 patients instead

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Clinical Research of 3 million requires a special kind of advocacy as it enters the marketplace. It also requires a fundamentally different pricing model. Marketing teams must not only convince healthcare providers that their personalised drugs produce better outcomes, but that they also reduce the total cost of treatment. The education and messaging required to communicate the value of precision medicines is exponentially more complex. In this new landscape, the massmarketing approaches of the past simply won’t work, posing a significant challenge to the existing commercial model. Marketers must now deliver tailored information to healthcare providers based on very specific patient use cases. The education of all healthcare stakeholders on precision medicine must be more fluid, more accessible, and more bidirectional. The more specific the treatments, the faster and more targeted the information flow must be. Fortunately, just as genomic advances continue, so do advances in technology, which makes it easier for companies to personalise their approaches to customers. Next-generation data systems are emerging to address more intense sales and marketing demands by providing life sciences companies with something new and revolutionary: a single and complete view of the customer. Precision Medicine Requires Precision Marketing Traditional technologies in life sciences have resulted in a siloed approach to customer communications and touchpoints. Bits and pieces of information from customer interactions online and in person have remained largely isolated in different systems, or never captured at all. Like precision medicines for patients, successful commercialisation today requires detailed mapping of every interaction. What information are my customers searching for? Where are they spending time on my website? Which dinner meetings are they going to? What influencers do they listen to? These are the questions that anyone representing the company wants to understand, but without visibility into all possible data points across all channels, even the best performers can be blindsided. With traditional systems, companies can’t process all of this information in a timely 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

manner, and so can’t provide customerfacing teams with the best game plan for each customer. However, modern CRM systems make it easier to capture and bring together all customer interaction data for a single, complete view in real time, made available via the cloud. When this information is shared and understood by everyone, sales and marketing teams can precisely segment customers and target them with relevant information. With cloud-based systems, all of these rich customer details are easily accessible for internal groups, including the increasingly active medical science liaisons, who are talking to doctors on an entirely different level. Additionally, teams can bring valuable customer information back to the organisation, funnelled through the same system. External partners such as contract sales organisations can also efficiently contribute insight from their customer interactions in a single system. The same applies to regional affiliates for a truly holistic view of the customer worldwide. It is also now possible to capture data in large enough sets and then apply data science to anticipate customers’ needs before they ask. By correlating large volumes of customer engagement data with actual customer behaviour, commercial teams predict what they want and serve it up preemptively. As an example, if you know that a specific segment of healthcare providers responds to a unique sequence of information consumption, you can proactively provide the same sequence of information to similar customers. A modern CRM system can gather the information necessary to make these kinds of predictions. Such a system can provide strategic recommendations for ways to interact with a customer – through which channels and with tailored information. Life sciences companies can also begin to provide this on demand – how and when healthcare providers need it. This is critical as the rise of increasingly complex treatments requires an ongoing, bidirectional flow of information, compared to the old push model of message delivery. The technology is now available to make personalised marketing a reality. But it takes more than technology. It takes a new way of thinking – one that

will fundamentally transform how the life sciences industry approaches this new world of personalised medical solutions. References 1. h t t p : / / w w w. t e c h n a v i o . c o m / report/global-genomicsmarket-2014-2018 2. https://www.gov.uk/government/ publications/spending-reviewand-autumn-statement-2015documents/spending-review-andautumn-statement-2015 3. https://www.gov.uk/government/ news/human-genome-uk-tobecome-world-number-1-in-dnatesting 4. https://www.whitehouse.gov/thepress-office/2015/01/30/factsheet-president-obama-s-precisionmedicine-initiative 5. http://clincancerres.aacrjournals. org/content/18/22/6373.full 6. http://www.phr ma.org/sites/ default/files/pdf/pmc-tuftsbackgrounder.pdf

Jan van den Burg, Vice President, Commercial Strategy, Europe. Jan, our VP, Commercial Strategy, is responsible for strategy and product marketing for our Veeva Commercial Suite of Applications, focusing on the European market. He has over 20 years’ experience in the software and services industry, mostly dedicated to Pharmaceuticals. Most recently, Jan was leading the Life Sciences Sales & Marketing group in IBM Global Business Services, engaging at strategic level with top 20 Pharmaceutical companies on Customer Relationship Management, Closed Loop Marketing, Multichannel and Digital Marketing as well as Digital Asset Management. Prior to IBM, Jan set up and ran the European business for Proscape Technologies, the then-leader in Closed Loop Marketing, successfully developing the market from inception, establishing the concept and leading the early implementations. With a BSc in Engineering and an MSc in Business Administration from the University of Twente, in the Netherlands, Jan began his career at Capgemini, followed by a move to the UK where he worked with PWC Consulting. Spring 2016 Volume 8 Issue 1


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Labs & Logistics

Temperature-controlled Packaging: More Than Just an Insulated Box The demand to frequently transport temperature-sensitive products with greater compliance and often in more difficult conditions is increasing. This places temperature-controlled packaging manufacturers under immense pressure to achieve temperature stability in more efficient and robust ways. This has resulted in a marked shift in the temperature-controlled packaging sector, as manufacturers are having to provide increasingly more sophisticated packaging solutions, to ensure that the high-value payloads reach their destination on time and intact. More than simply just an ‘insulated box,’ temperature-controlled packaging solutions are highly engineered, innovatively designed solutions. The purchasing of temperaturecontrolled packaging is often seen as a ‘second’ priority to decision-makers; behind the requirements placed upon them by their high-value payload, manufacturers are continually challenged to validate the cost of their services and the products they provide. Often this is characterised by an attitude that ‘it’s just an insulated box’. The principal idea behind the GDP guidelines released in 2013 is that during the planning and execution of distribution, each decision must be undertaken with a ‘risk-based approach’, with the philosophy being that the sum total of the risk in the system must be below an acceptable level. It is the role of packaging manufacturers to design and provide solutions that help to minimise risk where they can. Each product offered by packaging manufacturers has built behind it many hours of work to develop it to best meet the requirements of its user. Often this materialises into simplifying the appearance, as through this simplification one of the biggest risk factors is reduced – human error. However, this only serves to reinforce the impression that ‘simplified products’ are low-value goods.

50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Where Have We Come From? Traditionally, passive temperaturecontrolled packaging utilised water/ ice-based coolants and foam-based insulation (such as EPS or PUR) to maintain internal temperatures. These systems are still used effectively today, especially because their cost base is much lower than using the newer technologies available.

controlling the conditions in which pharmaceutical products are distributed. As products have become more complex and costly, the need for stronger controls within the distribution network has also grown to ensure patient safety is maintained. In turn, this has led to a rise in the number of hazards that temperaturecontrolled packaging manufacturers need to overcome.

However, there are a number of limitations, one of the largest being that each design tends to operate in quite a narrow ambient temperature band. This means temperature-controlled packaging manufacturers have to utilise separate summer and winter packing configurations for optimum performance. The use of seasonality increases the risk of temperature excursions, as the wrong configuration can easily be used due to unseasonal weather, especially as the switch is often done on a predetermined date.

The publication of the GDP guidelines in late 2013 put more ownership on ensuring an intact cold chain on all parties involved in it. This meant that a lot of companies that had previously not used temperature-control are now using it, and everybody is viewing it in much more detail and gathering more data.

Furthermore, any ice-based system typically uses a combination of frozen and refrigerated coolant, plus the use of insulating spacers in order to control the flow of heat within the system. This leads these systems to ultimately be more complicated to pack, which means there is greater risk of human error. A single component forgotten or in the wrong place can have catastrophic consequences for the payload and a very high cost to the patient and/or the pharmaceutical company. As the industry develops to demand more robust systems, the physical properties and thermal limitations of these materials leads to larger and heavier systems, which in turn leads to much higher freight costs for the user. It is estimated that for every $1 spent on packaging, $5 is spent on freight, so it is incumbent on packaging manufacturers to minimise that freight cost where possible. The Challenge Grows In recent years, the pharmaceutical industry has undergone significant changes, including stricter regulations

Historically, temperature-controlled packaging manufacturers could rely on a one-size-fits-all approach in the design of temperature-controlled packaging, with many manufacturers providing parcels that will protect payloads (whatever they may be) for 72 or 96 hours, against an internally created exposure meant to represent some sort of shipping, usually within/between the USA and Europe. This model is no longer representative for a large proportion of movements within the pharmaceutical supply chain. It worked well when the pharmaceutical manufacturing and distribution market was more concentrated and shipping was required to relatively moderate temperatures. However, this is no longer the case. Different stages of the manufacturing process can happen on different continents, often with a global shipment taking place as it moves between each step. The final market for a drug can now also be anywhere, particularly following the rise of the Indian and Chinese pharmaceutical markets. These elongated supply chains are now much more likely to pass through regions with more challenging ambient temperatures, whether it is from an API manufacturing site in Korea, a layover in Dubai, or landing in Washington in the Spring 2016 Volume 8 Issue 1


Labs & Logistics middle of a snowstorm. As temperature-logging has developed, and manufacturers have been able to see how their products have performed, and the challenges the packaging actually faces, there has been a move towards needing to design solutions that are more effective at combating these risks. With the introduction of the new GDP guidelines, this has taken a further step forward with visibility of the supply chain taking ever greater importance. Along with increased ambient temperature challenges, the logistics network handling conditions is also a factor that needs to be considered. A system that may have worked flawlessly in Europe and the USA may not be robust enough for a country such as China, where the network infrastructure outside of the central cities is not as well developed. With GDP emphasising a risk-based approach, there has been a trend to over-specify the packaging requirements as, justifiably so, quality departments are unwilling to determine an acceptable risk level, instead trying to find a nearzero-risk solution. But demanding a package perform to a higher level, by allowing additional safety factors, does not necessarily provide greater useable protection or added value, but does ultimately increase costs.

The healthcare and clinical trial industries are constantly evolving and pharmaceutical companies will always introduce new challenges through new products with different requirements – in particular, the introduction of more personalised medicines. This means ‘last mile’ logistics is becoming increasingly more important, perhaps delivering to individuals rather than a hospital pharmacy and certainly introducing more diverse shipping conditions. Currently, this final mile after pharmacy isn’t covered by GDP, but it is expected in the future there will be more attention paid to it by the regulators. So What Can We Do? The key to selecting the right packaging is to accurately identify what the hazards are, such as destination, touch points and modes of transport, when identifying the route. This is the difference between utilising good and efficient products and services to protect pharmaceutical payloads, compared to selecting packaging that will either under-protect the product, or incur unwarranted extra cost. However, when identifying the route it is often difficult due to a lack of realtime insight data into the challenges a package expects to face. Hence the requirement for packaging to not only be thermally qualified by manufacturers, but also undertake operational qualification through the chosen logistics channel, before shipments of expensive product.

The two main causes of temperature excursions are shipments experiencing temperatures they haven’t been designed for – so the wrong packaging has been selected for the challenges it faces – and human error. The risk of human error can be largely reduced through user-centred design. With many companies’ high performance passive systems, they can generally only be packed one way. Furthermore, temperature-controlled packaging manufacturers may also include added safety measures, such as specialist labelling to visually indicate and verify the readiness for packing, so that there’s a secondary safety check to ensure that things are prepared properly before packing. As the challenges faced evolve, temperature-controlled packaging providers are having to evolve with them. This decade has seen the introduction of ‘high-performance passive systems’ which utilise new techniques and materials, but also require new ways of thinking about packaging in order to get the greatest cost benefit. Demonstrating the Difference Today, the new generation of highperformance temperature-controlled packaging solutions are not too dissimilar in appearance from the outside to more traditional passive solutions, which relied on water-based coolants and foambased insulations. However, this jump in technology has not only resulted in easier to use systems and greater protection, but also greater capital expenditure for the end user, causing re-use to become a growing sector of our industry. The new generation of systems comprise of similar key design components: an outer case, insulation and coolants in the form of bottles or bags. An outer case can be made from a range of materials, depending on the intended use: low-cost corrugate fibreboard, through corrugated plastic, up to high-specification rigid containers (typically moulded plastic for smaller units and metallic for the very largest). The case is then typically ‘lined’ with VIPs to give a very high degree of insulation. These panels are usually made from compressed silica boards placed within a pouch with an

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 51


Labs & Logistics impermeable metallic membrane. This is then evacuated and sealed to create a very low-pressure environment within the panel. The advantage of these is that the VIPs offer five to seven times as much insulation, compared to the same thickness of foam. Phase change materials are currently derived from one of three sources; plant oils, paraffins or salt-based solutions. These are tailored to provide protection at various temperature ranges, such as below -20°C, +2 to +8°C and +15° to +25°C, though in theory a PCM could be designed for any temperature you wish. The strength of PCMs is that during a phase change (typically between solid and liquid) the temperature of the material does not change, essentially absorbing or releasing heat as required. By coupling the PCM with the payload, this means that the payload temperature is kept stable too, as the temperatures will always try to equalise. This removes the requirement for mixed preparation coolants or insulating spacers. With the use of VIPs as highperformance insulation, this massively increases the length of time it takes the PCM to change phase and therefore prolongs the temperature-stability of the payload, even over longer distances and more extreme or varied climates. The combined benefit of using VIPs with PCMs therefore means prolonged duration, simplified preparation methods and reduced volumetric weight ratios, which brings shipping costs down. It is, however, the relative cost of the raw materials of the new technology that has a direct impact on the costs of packaging solutions. Moving from some of the most common materials available, to those that require more work to obtain and process, can only involve an increase in cost. Investment in this type of packaging can result in easier to use systems, and labour and stockholding efficiencies. Intelligent user-centred design, therefore, is becoming more and more of a key differentiator between systems on the market. These high-performance systems are also typically backed up by rigorous thermal testing protocols and reports. Historically, packaging was qualified against proprietary testing profiles, 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

which would demonstrate how a system performed against thermal challenges, but it was often difficult to compare systems from different manufacturers head-to-head due to variations in their protocols. The growing trend of different packaging companies testing their systems against ISTA 7D as a benchmark for thermal qualification has helped reduce this confusion for purchasers. The relative high cost of this packaging, along with the sophisticated materials and robust qualification data, means end users are looking for a greater return on their investment and expect systems to be multi-use rather than single-use, whereas in the past, packaging was seen as being a single-use consumable product. Some high-performance temperaturecontrolled packaging solutions are developed for multi-use, rented by the shipper and reused by the logistics provider, to reduce the environmental footprint and decrease costs. However, the reality is that they are not always used to their full potential and are sometimes only used once, therefore not achieving their maximum proficiency in terms of cost-saving and sustainability. With a lack of return logistics through some shipping lanes, hybrid systems utilising combinations of old technologies and new are becoming more commonplace, trying to bridge the price versus performance gap between the historical and current approach to packaging. These products and services are constantly maturing, but we are a long way from anyone being able to offer a comprehensive global solution. When a network is able to do this cost-effectively, this is likely to be the next big revolution in our industry.

Conclusion Cost will always be a key driver in decision-making and there’s a limit to what anyone is prepared to pay for what’s often a secondary consideration. However, by fully understanding the risks in the supply chain, temperaturecontrolled packaging is able to be a key pillar in avoiding problems, and generating overall cost savings. Our industry is constantly changing and we are always looking for new

materials and techniques. Finding and developing new alternatives will no doubt result in the next technology jump, but advancements in cross-border shipping and return logistics will ultimately be the next stage. The challenge to create better products with different advantages, easier to prepare, more size/weight-efficient and more cost-efficient is paramount for temperature-controlled packaging manufacturers as drugs become more specialist and temperature-dependent. However, without another step-change in technology, the market is moving towards making the existing packaging work more effectively. So the main differentiator between the many options on the market today is the added benefits of good design, quality thermal testing reports, operational efficiency, ease of use and reducing hazards. It is now more pertinent than ever to demonstrate the value of temperaturecontrolled packaging as a product in itself and not just an insulated box.

Neil Sherman is Technical Services Manager at Intelsius, responsible for overseeing new product development, assessing new marketplace technologies, assisting with technical sales enquiries and managing the ISTA-certified testing laboratory. He is responsible for driving continuous improvement processes and managing technical testing and reporting activities. He also contributes to Intelsius’ business strategy, maintains accurate records and supervises staff within the technical team. Neil holds a Master’s degree in physics from the University of York and has been instrumental in the design and development of some of Intelsius’ most innovative packaging. Spring 2016 Volume 8 Issue 1


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Technology

Reinventing Data Management, with R&D at the Centre R&D generates a wealth of vital data, which is pivotal to everything else a life sciences organisation does. Yet there is often great diversity in the way this is collected, retained and accessed. This lack of consistency compromises the ability to track products effectively, both within the business and out in the market. The new ISO Identification of Medicinal Products (IDMP) standards couldn’t have come at a better time then, says Steve Scribner, life sciences advisor to AMPLEXOR Group. Every business, and often every department, has its own way of doing things. In the life sciences industry this is true of the way companies and individual business functions record and manage information about drugs, making it difficult to gain a clear line of sight across a product’s life cycle and its performance in the market. This has implications for the business as well as public safety. It’s something that is now being addressed by the new international Identification of Medicinal Products (IDMP) ISO standards and pending regional implementation guidance, which seek to introduce a rigour and consistency to product data which has been lacking until now. IDMP aims to harmonise the way products are identified, along with information about how products should be used, consumed and packaged, and create a standard way of linking related data. All of this will make it easier to track drugs and their effects in the market, with associated benefits right across pharma organisations due to a new uniformity in the way information is collated and managed. Currently each part of a life sciences business – from early research, formulation, clinical trials and registration, to manufacturing and quality assurance, to marketing, sales and pharmacovigilance – has its own priorities and systems for recording information. IDMP challenges this scenario, imposing the need for a central repository for lots of detailed, interlinked product information that must now 54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

be recorded using consistent product identification. It means that, finally, the different parts of the business must start speaking the same language. Once the standards become mandatory (deadlines may keep shifting, but it’s only a matter of time before compliance becomes compulsory) companies will need to file IDMP data almost simultaneously when filing for a new marketing authorisation. And it all begins in R&D. Get product information management right from the beginning, and there will be opportunities to streamline and improve a wide range of data-related processes. Set the Pattern Early Long before a medicinal product enters the market, it is created in more rudimentary forms, and it is here that the product information trail needs to begin as organisations develop and move that product through its life cycle. This is the role of the ‘product identifier’, assigned once proposed combinations of chemical entities have been studied for their medicinal and commercial potential but before the compound is chosen to evolve through pre-clinical and clinical testing. Having a unique, consistent identifier throughout the research and development process allows an information trail to be gathered which will play an important role in the marketing authorisation process and, in due course, in IDMP compliance. Any gaps in this thread of knowledge could lead to delays in getting the eventual product to market, with associated commercial and competitive implications. The testing processes and each round of results must be easily traceable, through the different stages of trials and as the optimum route of administration and dosage levels are set. Marketing approvals are very specific concerning agreed dosages and methods of application for specific populations and possible demographics for use, and

the eventual marketed product name may vary from country to country. So it makes sense that life sciences companies have everything documented in a way that tells the complete story and can be easily accessed, shared and understood – within and beyond the organisation. Traditionally, this is where data capture and management have become very complex. Should companies define and track products by name and country, or by the chemical compound/ active ingredient? In the pharmaceutical industry, products have a large number of variants and are challenging to define in a consistent, holistic way. Yet, the need to do this from a regulatory perspective is acute because of the health implications and companies’ exposure to financial and reputational risk if anything goes wrong once a product is in the public domain. Once in use in the real world, products are subject to new rounds of tracking as individual customers respond to the drugs in discrete ways. The requirements for monitoring and reporting adverse events (pharmacovigilance), along with the effort to discover cause and concomitant drug interactions, needs to tie back in with the R&D information management, to build up the complete picture of the product’s performance. The sponsor is responsible for ascertaining any need to revise labelling or even voluntarily withdraw a drug from markets, if the analytics indicate that this is needed. (Ultimately, this intelligence will be fed back into future development processes.) It’s essential to have a global view too, not only for actions relating to drug recall, but also to follow up on regulatory requests from any or all markets, and for general reporting. Preparing for the Unknown It is because of the implications of information governance for customer safety and market confidence that international authorities are raising the bar for data collection and reporting. The onus is on life sciences companies to have all of the answers at their fingertips and be ready to submit at short notice. Spring 2016 Volume 8 Issue 1


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Technology must be to identify the steps that need to be taken to create a single, authoritative source of complete, accurate, reliable, up-to-date product data – which can be adapted, added to and brought in line with emerging and future requirements.

Five new standards around IDMP have been approved by ISO, which have an impact on regulatory reporting. Although the major regions are still preparing guidance on when and how to implement these standards, there is no time to lose in preparing for compliance. A consistent data profile that can be easily enhanced and amended as needs evolve and change means that companies can react with greater speed and ease to new events and emerging regulatory demands, and provide a better service to the public. Even in the initial phase of the pending IDMP guidance, more than 90 different pieces of information are required. This considerably exceeds the current requirements for XEVMPD (by a factor of three) – and the figure will rise to over 450 different elements once the new standards reach the later phases. Preparation should not be delayed. Companies will want to avoid rushing – which may prevent them delivering a scalable solution that allows for agile ways to meet broader and future needs. Compliance, and the ability to gain an accurate overview of a product at a glance, relies on having a consistent ID from its origins and a consistent dictionary-driven model of data collection – across R&D, manufacturing, packaging, labelling, safety and beyond, and for all markets. A positive side-effect of IDMP, internally to organisations, is that it fosters a consistency in data management that hasn’t existed before in life sciences – where information governance has tended to be confined to departmental/ application-specific silos. With mergers and acquisitions taking place on a regular basis in the sector, the diversity of systems and approaches to information management has reached unmanageable excess. Unravelling that complexity has 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

seemed beyond daunting. Setting the Stage for Holistic Data Management As companies realise the urgency of bringing order to their product information, not only for regulatory reasons but also to safeguard their competitive position in the market, they are finding that the only practical way forward is to create a holistic content repository – a master data resource, where all product-related information is consolidated, so that all departments and parties along the supply chain are talking the same language and referring to the same source data. A resource that meets the needs of IDMP reporting requirements, safety evaluation and new marketing authorisation demands simultaneously. Currently, that central repository (one that serves the whole organisation) is a rarity in life sciences –if it exists at all. But it must, and there is no time to lose. Putting R&D at the centre of those plans makes perfect sense, because of the wealth of product data it collects from the point of inception of a new drug (and receives back in the form of adverse reaction data). Because of the large disparity that exists today in the way most life sciences organisations hold and manage data, an important initial exercise will be to assess the various current product information sources on which the master data repository will be built. Some will exist only on paper, other content in electronic format – but conceivably not in a format or in sufficient detail for the purposes of IDMP compliance. Identifying the latest versions of information, or the quality of the information may prove a challenge too, so this is something else that needs to be planned into the transition. The goal

The initial challenge of defining a master data repository will become easier as identified best practices are distilled into standard, easily configurable solutions – those that can be applied to any life sciences company with relative speed (rather than each company doing its own thing in isolation). Emerging data and document management models, such as the DIA Reference Models for EDM, Labelling, TMF and GMP, offer organisations a good starting point for collating and storing content in the same standard format from one end of the product life cycle to the other. Governance Although the regulatory affairs function has typically acted as a collection point for compliance-related data up to now, organisations cannot leave the responsibility at this department’s door – particularly as there remains quite a bit of data that doesn’t pass through the regulatory team. Holistic product data management is much bigger than a single department, and needs its own champion – a responsible party who oversees the whole flow of data from R&D to eventual product withdrawal, and can help enforce consistency and provide governance from cradle to grave. It may be advisable to form a governance body that combines the interests of each department but speaks for the whole. Agility Improved response to regulatory and business changes will be a key capability that organisations will need for the future, for reasons of compliance and competitive advantage. The first draft of guidance on IDMP specifies that companies will have just 30 days to meet their IDMP data obligations once a marketing authorisation application has been submitted, so these submissions are not something that can be cobbled together in an ad-hoc fashion. In the absence of a fixed deadline or released guidance for bringing systems and processes in line with IDMP requirements, the degree of Spring 2016 Volume 8 Issue 1


Technology current preparation is largely down to companies’ respective cultural make-up and strategic priorities. Do they want to be ahead of the game and exploit all of the associated efficiency benefits of a streamlined data management set-up, or is there something they stand to gain by waiting and watching what their peers do? Of course, IDMP is just one of many new or improved regulations that are coming down the line. This is another reason why firms cannot afford to be too inert or rigid in their information management plans – and why it makes sense to get started sooner rather than later. Bespoke, single-purpose systems lock companies in and are the enemy of agility. They are expensive to create and maintain, cannot be readily adapted to new requirements, and are usually inflexible in their ability to support additional data input (e.g. following a company merger). The more companies that move to consistent models for capturing, storing and managing content, and open interfaces between systems, the easier it will be to combine

and blend different data sources and create a (secure) flow of content. Preparing for IDMP and more holistic product data management isn’t a onetime exercise either. Identified data sources will also need to be kept up-todate, by way of a continuous quality assurance process, and companies will need to find a way to do this that is as painless, straightforward and reliable as possible. That demands good governance. As the need for speed intensifies, having a uniform architecture and centralised master data architecture, and configurable/adaptable systems, is the only way organisations can prepare themselves for whatever the future holds. The more they aim for a consistent content management model, the easier they will find it to absorb and adjust to – or outsource – related requirements. One final piece of advice is to get involved proactively with standards bodies and industry organisations. This will allow you to gain an influence over,

and have early insight to, upcoming or changing regulatory requirements. Knowing what’s coming might not reduce the workload, but it can help companies avoid being off-balance, and offers them maximum opportunity to make any changes that will work positively for the business.

Steve Scribner is a Consultant with 45 years of experience in computer solutions implementation in business. For the past 22 years, he has focused on electronic document/ content management systems in the Pharmaceutical / Life Sciences industries. Steve has an extensive experience with managing multinational projects and looks for circumstances where his understanding of diverse cultures can help projects be successful. He has lived and worked in US, Western Europe and Asia.

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Technology

The Digital Age: Tackling the Challenges and Embracing the Opportunity The life sciences industry has always been incredibly innovative in its R&D and bringing new life-saving and lifechanging medicines, devices, diagnostic tools, and products to market. However, it has often been a late adopter of new communication technologies, platforms, and channels – perhaps understandably, given the highly regulated life sciences operating environment. In this digital age, with information instantly available with a few keyboard strokes or taps on the latest smartphone or wearable, our world is changing exponentially, and with it, the needs, wants, and demands of patients, carers, healthcare providers, and payers across the globe. Expectations are now for healthcare products and treatments to be accessible whenever and wherever they are wanted or needed, in the same way as consumable products. This paradigm shift brings both challenges and opportunities for life sciences companies that are developing and adopting different working models to try and keep pace and deliver against these changing needs. Where the real opportunity lies, though, is not with tactical tweaks, but with the companies that truly can engage with this changing world and see the bigger picture; those that are looking to offer services beyond a pill. Looking to deliver true value-added services and aiming to put the patient at the centre of their activities is not new. Life sciences companies generally acknowledge and agree that it is both necessary and financially and morally right; however, putting this into practice is complex, costly, and time-consuming, and requires new behaviour from all stakeholders. I spoke with Fonny Schenck, CEO of Across Health, Marc Sluijs, a digital health investment advisor, and Craig Le Grice, a cross-industry corporate strategist specialising in digital technology and transformational change, to get their views on how well life sciences companies are adopting new technologies, and where there may be opportunities to learn from other industries.

58 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Marc is convinced that there are significant opportunities for pharma companies that can extend beyond the pill to impact and improve patients’ behaviour and, in turn, their lifestyles. This could result in better health outcomes and, critically, robust data to support and justify why the approaches and product(s) of these companies are best. To do this, though, Marc believes companies need to take a step back and recognise that chronic diseases such as diabetes, cardiovascular disease and obesity are among the biggest issues in hand today, and that for a number of these, medication is not the solution. “If life sciences companies continue to focus on purely providing drugs, then they are only capturing a small part of the healthcare ecosystem and should instead be looking at the opportunities new technologies offer to extend up- and downstream to capture and influence a much greater share of healthcare,” he says. Fonny concurs with this, and adds, “If life sciences companies do not extend their go-to-market models, then they will find their product markets shrinking as entrants from other industries focus on lifelong prevention rather than cure.” This is centred around two very short periods in life only: the first-six-months and lastyear-of-life segments. “Life sciences is a highly profitable industry that has till now had high barriers to entry, and so there needs to be a reason to change.” A 2013 report by Capgemini showed that digital leaders outperformed their peers in every industry. The same report detailed pharma as being less mature than other industries, although it noted that “many are building capabilities in analytics and worker enablement, but most firms are just beginning their digital journeys, leaving many opportunities untapped.” Fast-forward two years and the findings from Across Health’s seventh annual survey on digital maturity in life sciences shows that for the vast majority of life sciences companies, little has changed. “Satisfaction with digital is

low, therefore budgets do not increase, which in turn leads to suboptimal programmes with limited impact and back to lower satisfaction…creating a plateau of improductivity.” However, what was clear was “a difference in speed in the market – around 14% is implementing multichannel very quickly, is spending significantly more than the average, and feels comfortable with impact measurement, etc….multichannel @ multispeed!” Craig’s view aligns with Marc’s and Fonny’s, believing that we’re living in a time of unprecedented change – and opportunity. When asked what the biggest opportunity that lies ahead is, Craig says, “Simply, we realistically have the opportunity to have everything we’ve ever wanted in terms of consumer/enduser engagement. “For years, marketers have desired one-on-one connections with consumers, but have been held back by the logistics of doing so. Big pharma has dreamed of a ‘one product, many applications’ scenario for key care areas. Research has yearned for (non-drug) test bases in the millions, not hundreds. Technology, digital transformation, and data bring all of these a step closer.” Are there any other industries that life sciences companies can be learning from? Fonny believes we can learn more from those working in the B2C arena than those in B2B. Marc suggests that some aspects could be learned from the gaming industry, as it has developed sophisticated approaches to engaging people in virtual activities that could be leveraged in life sciences. While many may think we could or should look to the technology sector, Marc’s view is that technology is an enabler, not necessarily the solution, and the big challenge is to figure out how we can effectively influence consumer behaviour in order for people to change habits that negatively impact their health. This is where technology can come into play, with tracking/monitoring devices allowing us to collect data on people’s behaviour and ultimately the impact Spring 2016 Volume 8 Issue 1


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Technology impact on patient adherence, will this open the floodgates for digital medicines? Looking to the upcoming year, Fonny and Marc are both excited about the technologies now available that allow things to happen on a much bigger and feasible scale and can be replicated and complemented with automated processes. Fonny believes creating and building intelligent data repositories will really assist companies in optimising their channel mix and digital strategies, improving their customer models and costeffectiveness. For Marc, what represents such a great opportunity is that we can now have a much more complete picture of health than ever before, way beyond clinical values and biometric data, which gives companies far greater insight into patients’ moods, social activities, and overall wellbeing. on their health. This will then allow the teams of specialists, data scientists, and clinical psychologists to establish drivers of behaviour and develop the algorithms to remind, reward, or motivate changes in behaviour at an individual level. This is not something new. UK supermarket Tesco led the consumer retail field tracking of consumer behaviour through the introduction of its Clubcard in the 1990s, which allowed the company to track consumer purchases and subsequently segment marketing activities based on purchasing behaviour. Imagine the data sets we would have now if we’d had the capability and regulatory environment to capture healthcare behavioural data when Tesco started these activities more than 20 years ago. Craig likes the nod to the retail sector – primarily because it serves millions at any one time, while having to adapt to individual needs. These are often very specific needs, led by desire – one of the hardest areas of consumer “want” to match products to. Craig also suggests that financial services is a sector of interest for life sciences. This is partly because it is also heavily regulated, and partly because much of its business is structured in the same way as that of life sciences – often with major “brand attractors” (such as current accounts for banks and over-thecounter drugs for life sciences) as loss leaders in order to build relationships 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and trust, so the investment in “life stagespecific” products (such as mortgages for banks and long-term care programmes for life sciences) can be realised later. The opportunity provided by technology, such as wearables, should be focused on gathering intelligence and insight, which would allow companies to close the gap between the two. Craig believes this is a win-win scenario – good for business and good for patients. Today, it is encouraging that a number of life sciences companies are beginning to catch up with other industries in their digital implementation, shifting some of their offline activities to online and adding digital to this mix, as well as shaping, organising, and resourcing around digital. However, these shifts are mainly incremental and still primarily product-focused. Life sciences companies which are making the strongest inroads interestingly appear to be the companies that have had, or are approaching, major patent expiry. AbbVie, AstraZeneca, Lilly, MSD, and Pfizer are referenced as companies that are well perceived in their activities. Many are watching with interest to see the outcome of Otsuka’s partnership with Proteus Health and their submission to the FDA of the first digital medicine NDA. The technology embeds a sensor in a tablet to digitally record ingestion and, with patients’ consent, share that information with their healthcare providers. If approved and shown to have positive

Clearly, new skill sets and knowledge are required to devise and deliver digital strategies in the rapidly evolving digital age the life sciences industry now finds itself in. Are you happy that you are ready for these changes? And, crucially, do you have the senior team to leverage these changes for maximum opportunity?

Susan Macdonald. A nursing graduate, Susan spent 17 years working in a number of commercial business development and project management roles for both ethical and generic pharmaceutical companies. Susan then spent 10 years working for a specialist life sciences executive search company, living in Europe and Asia where she managed their JV in China then their Asia operation from Singapore, before returning to the UK to manage key global client relationships and undertaking global, regional and country-level senior executive searches. In 2016 Susan founded MLA, a boutique life sciences resourcing company. Susan and the MLA team fuse their direct life sciences heritage, knowledge, skills and networks with those of their crossindustry specialist advisors to support life sciences clients wishing to attract transformational, senior-level individuals in this rapidly evolving digital world. Email: susanm@mlal.co.uk Spring 2016 Volume 8 Issue 1


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Technology Digital Health: Increasing the Quality and Efficiency of Care New technologies allow for direct patient care and necessitate an overhaul in the focus of healthcare industry business models It is becoming clear that in order to stay relevant in the future healthcare ecosystem, pharma companies must look to business models that foster much more direct patient engagement than previously. New methods offer significant potential in increasing the quality and efficiency of care. Digital health solutions could therefore solve the major long-term issues of pharma’s most important client groups – patients, providers and payers – all at the same time. In order to implement innovative solutions ahead of new entrants, pharma companies will need to undergo major transformation programmes and convert three completely different value chains: pharma, medical devices for measuring health parameters, and IT solutions to process and connect data. New Solutions from Non-traditional Sources Many of the innovative solutions that digital health offers are being developed by non-traditional entrants to the healthcare arena. They are now providing new offerings that are very quickly changing the dynamics of how the ecosystem works, and, in particular, how the individual patient is engaged. One telling measure is the amount of venture capital that is continuing to flow into the digital health market. According to digital health start-up accelerator Rock Health, USD2.1 billion was invested in digital health start-ups during the first half of 2015 – up 25% compared to the previous 12 months. The biggest portion, USD387 million, went to wearables and biosensing companies, but analytics and big data, as well as electronic health records, are other categories that are seeing significant investment activity and a vibrant innovation environment. The innovations coming from outside the traditional healthcare industry span a wide spectrum of products and services, but all take advantage of advances in digital technologies and the ability to analyse and present large amounts of data in new ways. From new biosensor technologies and smart devices to portals and physician guidance tools, there 62 INTERNATIONAL PHARMACEUTICAL INDUSTRY

are numerous exciting breakthroughs that allow enhanced self-monitoring capabilities and patient adherence – and ultimately superior clinical decisionmaking and treatment success. Add on the data analytics capabilities that are now being put to use by purchasing bodies (payers) and hospital systems, and it is clear that healthcare is in the middle of a profound transformational shift. Relationships are Key to Embracing Digital Health In order to understand the disruptive power of digital health and its impact on pharma, one has to take a closer look at the relationships within this well-connected ecosystem. Tr a d i t i o n a l l y, h e a l t h c a r e providers, payers and pharma companies have had a conventional supplier-consumer relationship. However, there are Table 1 now increasing demands from payers and providers around the delivery of better health outcomes and greater costeffectiveness. These provide a strong driving force for pharma companies to more actively engage in Table 2 the opportunities arising from the digital revolution and patient-centred care. More than ever, regulatory bodies now insist on pharma companies demonstrating benefits and costeffectiveness, with many countries introducing reforms that aim to restrain overall spending. Ensuring responsiveness to treatment and patient compliance, while minimising sideeffects, are therefore key success factors if

pharma companies are to meet society’s demands. A Customer-centric Vision Includes the Patient, Practitioner and Payer In order to achieve these new success factors, pharma companies need to begin a process of transformation. The proven classical, product-centric approach with an indirect value chain will not be able to embrace the required speed, new collaboration needs (as shown in Table 1), flexibility and ability to learn quickly. A pharma value chain in a digitalised environment needs to incorporate new characteristics. Therefore, as a first step,

the company needs to develop a vision of how it will earn money in the new digitalised world. Will the revenue model stay? Will the business model instead be built around new manufactured products or services? What will the portfolio and customer experience look like? A vision of how a transformed organisation can be structured is shown in Table 2.

Spring 2016 Volume 8 Issue 1


Technology In such a vision, pharmaceutical product offerings can be strengthened through complementary digital software/ digital services offerings. These help patients with their treatment, help practitioners with their work, and give them insight into the success of their treatments, while helping payers and legal entities to receive proof of efficacy. Depending on the pharmaceutical product, medical devices and sensors will measure the consistency of product usage and its success. The combination

Table 3 of all three product groups results in an integrated digital health offering that is able to give a new competitive advantage. The “customer” is at the centre of this vision. This includes not just the patient/ consumer, but also the practitioner and the payer. All products and services, as well as all administrative processes, focus on long-term customer value through customer group-specific journeys. To create action plans and concrete initiatives, the transformational need has to be cascaded down to processes, data and technology requirements, and management capabilities. The major challenge to success is the need to integrate organisations, concepts, processes and technology. A successful transformation programme typically incorporates the major pillars of the new vision within four fields of action, as shown in Table 3. 1. Integrated Offerings To define integrated digital health offerings, we have to set the overall future business model and its components, incorporating existing products and business units. By analysing the existing product portfolio and comparing it to the new business model components, gaps become apparent. We can define www.ipimedia.com

and decide where to build up skills and capabilities internally, and where to use new partnering models and external interfaces. The overall product strategy is communicated and a product development excellence project is set up, such as enabling an approach to personalised medicine. 2. Customer Management Customer management is the core of the transformation programme. Here we define the strategic components as well as the governance structures for a customer-centric and digitalised pharma company. The different customers (patient, practitioner and payer) are analysed and high-level customer journeys are defined. These journeys are the basis for more detailed use cases – experiences with the brand from the customer point of view – such as a treatment process or information-gathering across different touch-points. Especially for big pharma, it is not possible to drive this transformation through a deep-dive, top-down approach. Therefore, we favour a “highly aligned, but loosely coupled” approach in the execution of the programme, in which the detailed use cases will be run by dedicated owners who have endto-end responsibility for both budgets and success. The company will run a lean customer integration office where the use cases are consolidated. Existing company committees for budgeting and prioritisation will be extended so that top management is able to make decisions based on customer and business value. 3. Customer-focused Touch-points As major enablers of customer-focused use cases, touch-points and their backend capabilities need to be built and integrated. Based on the use cases and their requirements, we define and prioritise touch-point projects, such as online consumer chat or a new digital sales representative application. Overarching capabilities for an integrated journey are defined as well, covering customer data and customer relationship management, as well as knowledge management. Projects to

implement these basic enablers are the highest priority as they span multiple use cases and touch-points. 4. Big Data Analytics A digitalised and customer-focused value chain offers new opportunities for gaining insight, measuring success and driving improvements. As a basis, we recommend creating a lean, crossbusiness-unit, technology-focused big data analytics team that has the technical and consulting capabilities (covering data scientists, the provision of a big data cluster, etc.) to help business units with the implementation of new analytics methodologies. Within the business units, capabilities need to be created for each purpose, such as using the technology in R&D for personalised and precision medicine based on field data. Clear data analytics responsibilities are set for each business unit to enable fast learning, such as touch-point analytics to assess how well particular touch-points are accepted and how they can be improved. Conclusion The pharma industry today is facing a complex and difficult situation, in which parts of its business may be disrupted by new market entrants, whereas other areas will be suited to a traditional business model for many more years. The industry therefore needs to avoid introducing immature services too fast in areas where there is no urgency, and to correctly set priorities. Ulrica Sehlstedt Dr Ulrica Sehlstedt is a Partner in the Stockholm office of Arthur D. Little and a member of the Global Healthcare Practice. Nils Bohlin Nils Bohlin is a Partner in the Stockholm office of Arthur D. Little and leads the Global Healthcare Practice. Fredrik de Maré Fredrik de Maré is a Partner in the San Francisco office of Arthur D. Little and leads the US West Coast Healthcare Practice. Richard Beetz Dr Richard Beetz is a Principal in the Frankfurt office of Arthur D. Little and a member of the Global Technology and Innovation Management Practice INTERNATIONAL PHARMACEUTICAL INDUSTRY 63


Manufacturing

Comparison of Good Manufacturing Practice Compliance Requirements – European Union, United States and India ABSTRACT The intentions of the current study are to expedite the compliance requirements to support the regulatory approval of selected pharmaceuticals in the United States, the European Union and India. The literature search is done using different resources, such as regulatory authority websites, pharmaceutical review articles, journals and public domains. To ensure the quality, all pharmaceutical manufacturers are required to establish and implement effective a quality management system. Whereas the regulated markets like the European Union and the United States have wellestablished guidance compared to emerging markets like India on good manufacturing practice compliance, to assess the effectiveness of these quality management systems, inspections are carried out on manufacturing units. The foremost objective of the study is to distinguish the type of application or licence which triggers the inspection and the consequence of the inspection, as well as to provide the information observed during inspection by the agency. Key words: Good Manufacturing Practice, Inspection & Compliance. Introduction Pharmaceutical companies throughout the world are moving towards becoming more and more competitive, while regulatory agencies are being established in various countries across the globe. Regulatory authorities and organisations are responsible for the effective drug regulation required to ensure the safety, efficacy and quality of drugs, as well as the accuracy and appropriateness of the drug information accessible to the public. So, quality auditing should be done by the regulatory authorities to make sure that products are manufactured according to the standards. Regulatory bodies provide strategic, tactical and operational direction and support for working within regulations to expedite the development and delivery of safe and effective healthcare products to individuals around the world.1 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

In our study we are listing the following:

Good Manufacturing Practice Good manufacturing practice (GMP) is a system for ensuring that products are consistently produced and controlled according to quality standards. It is designed to curtail the risks involved in any pharmaceutical production that cannot be eliminated through testing of the final product.2 Purpose of GMP Inspections To ensure quality, all pharmaceutical manufacturers are required to establish and implement an effective QMS system. To assess the effectiveness of these QMS systems and to ensure GMP is followed, self-inspection and other regulatory audits must be performed.2 Depending on the criticality of the issue, a warning letter will be issued to the firm if it fails to comply with GMP regulations3 For example, on July 13, 2015, the FDA issued a warning letter to XYZ Company. Reasons: • •

Failure to record activities at the time they are performed and destruction of original records Failure to train employees on their particular operations and related GMP practices.

Data Source The literature search was done using different resources such as pharmaceutical review articles, public domains, journals and regulatory authority websites The literature review obtained: • Guidelines and/or regulation

documents

• • •

from

the

regulatory

authorities ICH guidance documents PIC/S guidance documents Review articles

Discussion A list of licences triggers the inspection to support regulatory approval in different countries, including India, the US and the EU. Conclusion Good manufacturing practice (GMP) is a production and testing practice that helps to ensure inbuilt quality product. Many countries have legislated that pharmaceutical companies must follow GMP procedures, and have created their own GMP guidelines that correspond with their legislation. The basic concepts of all of these guidelines remain more or less similar to the ultimate goals of safeguarding the health of the patient as well as producing good quality medicines. The quality objective can be achieved only through careful planning and implementation of quality assurance systems and practical implementation of GMP, and through inspections at periodic intervals according to the agency. The effective implementation of GMP requires extensive care and knowledge about the different components of GMP that should be incorporated from the inception of the manufacturing building and product development, through to production. The type and time of inspection during approval of the manufacturing unit licence and consequence of inspections related to GMP in EU, US and India are compiled. Spring 2016 Volume 8 Issue 1


Manufacturing EU

US

Product category

: Medicinal products

Product category

: Chemical / biological / medical device

Country of filing

: EU

Country of filing

: US

Regulating agency

: EMA

Regulating agency

: USFDA/CDER/CBER/CDRH

Regulating ministry

: Science Medicines Health

Regulating ministry

: Department of Health and Human Services

[9]

List of licences triggering inspection Agency

List of licences triggering inspection[7]

Type of

Type of

Fees for

application

inspection

inspection

Time of inspection

inspection EMA or competent authority

Manufacturing unit license

Inspection under

• £582

+

inspection

Manufacturing licence

in

Marketing

competent

authorisation

authority

and import

Product-related inspection

£792 £1936

+ When

Post-approval

manufacturing licence and risk-

inspection

based methodology

inspection

the

Pre-approval

manufacture EMA or

After applying for

Abbreviated

Inspection of systems used

Routine inspection

Full inspection

guidelines •

compliance

USFDA

When manufacturing unit breaches GMP

risk- £1936

based

assessing

USFDA

an

NDA

inspection

After making new drug

Routine inspection

application

Post-approval

application for MAA

inspection

If the site is located in the EEA, the competent authority of the member state where the site

USFDA

is located carries out the inspection.

ANDA

Pre-approval

After applying for abbreviated

inspection

new drug application.

For sites located in countries outside the EEA, the responsible authority for inspection (the

Routine inspection

supervisory authority) is the authority in whose territory the importing site is located. If the

Post-approval

supervisory authority is not able to carry out the inspection for any reason, it can be delegated to another EEA competent authority. If there is a mutual recognition agreement (MRA) in place between the countries where the

inspection Types and reasons for inspection 1.

Pre-approval inspection

[7]

 First time an establishment is named in an

site is located and the European Community, the results of GMP inspections carried out by

application submitted to agency

the MRA partner authority are normally recognised by the EU authorities.[10]

 First application filed by applicant  New molecular entity in finished formulations

Types and reasons for inspection 1.

Routine inspection

 When assessing an application for manufacturing

2.

 Inspections for grant / renewal of licences

Routine inspection

inspections for issuance / revalidation of COPPs

licence

scheme for use in international commerce only

 When manufacturing unit breaches GMP guidelines

2.

Triggered inspection

3.

Inspection under risk-  Inspection on systems used in the manufacture based compliance

3.

Post-approval inspection

 Product-specific soon after approval

4.

Full inspection

 When: previous inspection findings warrant initial establishment inspection; history of significant

Inspection outcome[10] •

Critical deficiency

Major deficiency

Other deficiency

Time of inspection

Pre-approval

for

licence

inspection •

Type of inspection

application

manufacturing

£1936

Triggered

Type of

When assessing an application

Routine

Agency

changes since last inspection 5.

Abbreviated inspection

 Permitted when: good history with no major changes to operations and no pattern of recalls and problems

[8]

Inspection outcome

US

www.ipimedia.com

No action indicated (NAI)

Voluntary action indicated (VAI)

Official action indicated (OAI)

INTERNATIONAL PHARMACEUTICAL INDUSTRY 65


Manufacturing

Finalised establishment inspection report with cover sheet, attachments, and exhibits

• Plumbing • Sewage and refuse

within 30 business days of the last day of the inspection

• Washing and toilet facilities • Sanitation

India

• Maintenance Product category

: Chemical / biological / medical device

Country of filing

: India

Regulating agency

: CDSCO/SLA

Regulating ministry

: Ministry of Health & Family Welfare

Equipment • Equipment design, size and location. • Equipment construction • Equipment cleaning and maintenance

List of licences triggering inspection Agency

• Automatic, mechanical and electronic equipment

Type of

Output

Type of

application

licence[4]

inspection[5]

• Filters

Time of inspection

Control of components and drug product containers and closures

Pre-approval inspection

Form-25 SLA

Manufacturing

(chemicals)

unit licence

Form-28 (biological)

• Receipt and storage of untested components, drug product containers, and closures After applying for

Routine inspection

licence for

Surprise

manufacturing unit

• Testing and approval or rejection of components, drug product containers, and closures • Use of approved components, drug product containers, and closures • Retesting of approved components, drug product containers, and closures

inspection

Licence CDSCO

for Form-46 (FF)

Routine inspection

• Rejected components, drug product containers, and closures After

applying

for

• Drug product containers and closures

manufacturing

Form-46A

Follow-up

product manufacturing

Production and process controls

of product

(API)

inspection

licence

• Written procedures; deviations • Charge-in of components

Types and reasons for inspection

• Calculation of yield

1.

• Equipment identification

Pre-approval inspection

 First time an establishment is named in an application submitted to agency  First application filed by applicant  New molecular entity in finished formulations

• Sampling and testing of in-process materials and drug products • Time limitations on production • Control of microbiological contamination

2.

Routine inspection

 Inspections for grant/renewal of licences

• Reprocessing

3.

Follow-up inspection

 Compliance verification inspection to authenticate the

Packing labelling control

results of corrective actions 4.

Surprise inspection or

 Surprise inspection will occur without any prior

unannounced inspection

notification

• Materials examination and usage criteria • Labelling issuance method • Packing and labelling operations • Drug product inspection

General points to be consider during inspection

• Expiration dating procedure

Manufacturing inspection on following

Holding and distribution

Organisation and personnel

• Warehousing procedure • Distribution procedures

Responsibilities of quality control unit

Personnel qualification

Laboratory controls

Personnel responsibilities

• Testing and release for distribution

Building and facilities

• Stability testing

Design and construction features

• Special testing requirements

Lightning

• Reserve samples

Ventilation, air filtration, air heating and cooling

• Laboratory animals

66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Spring 2016 Volume 8 Issue 1


Manufacturing •

Penicillin contamination

Records and reports •

Equipment cleaning and use log

Component, drug product container, closure, and labelling records

Master production and control records

Batch production and control records

Production record review

Laboratory records

Distribution records

Complaint files

Returned and salvaged drug products •

Returned drug products

Drug product salvaging

Compilation of GMP compliance (inspection) requirements Country

EU

US

India

Regulatory agency

EMA

USFDA

CDSCO

Regulations

Directive 2003/94/EC

21 CFR, PART 210 & 211,820

Schedule-M, Schedule-M III

Dosage forms

Chemical, biological, medical

Chemical, biological, medical

Chemical, biological, medical

covered

devices

devices

devices

• • Classification of inspection

Routine inspection

Inspection under risk-based

Product-related inspection

Routine inspection

• •

compliance •

Pre-approval inspection

Triggered inspection

Post-approval inspection Full inspection

• •

Abbreviated inspection CDER/CBER/

Pre-approval inspection

• • • •

Routine inspection Surprise inspection Follow-up inspection

SLA/CDSCO

Inspection done by

EMA/competent authority

Inspection fee

£1936

-

1500rs

Inspection report

Inspection report

Establishment inspection report

-

Critical

No action indicated (NAI)

Major

Voluntary action indicated (VAI)

Minor/others

Official action indicated (OAI)

Classification of observations

CDRH

Warning letter

• Consequences

EUDRA GMP

-

• •

Import alert

Clarification letter

Site close out

References 1. Pharmaceutical Regulatory Agencies and Organizations around the World: Scope and Challenges in Drug Development. 2015;1–9. Available from: http://www. pharmatutor.org/articles/pharmaceutical-regulatoryagencies-and-organizations-around-world-scopechallenges-in-drug-development 2. Manisha Reddy K. Importance of GMP Compliance Training. 2015;1–7. Available from: http://blog. commlabindia.com/elearning-design/gmp-compliancetraining 3. FDA. Mahendra Chemicals 7/13/15. 2015;1–5. Available from: http://www.fda.gov/ICECI/EnforcementActions/ WarningLetters/2015/ucm455345.htm 4. Drugscontrol.org. Forms and Fees. 2015;1–4. Available from: http://www.drugscontrol.org/FormsFees.asp 5. World Health Organization. Quality assurance of pharmaceuticals, Volume 2. Available from: http://apps. who.int/medicinedocs/documents/s14136e/s14136e. pdf www.ipimedia.com

6. Inokon UM, Pharm D, MA, R.Ph. Approaches to GMP Inspection. 2014 (June). Available from: http://www.fda. gov/downloads/Drugs/DevelopmentApprovalProcess/ SmallBusinessAssistance/UCM407991.pdf 7. FDA. Inspections 1. 552(7):1–4. Available from: http:// www.fda.gov/downloads/AboutFDA/Transparency/ PublicDisclosure/GlossaryofAcronymsandAbbreviations/ UCM212061.pdf 8. European Medicines Agency. Standard operating procedure: Co-ordination of GMP/GDP inspections. 2012;44(0). Available from: http://www.ema.europa.eu/ docs/en_GB/document_library/Standard_Operating_ Procedure_-_SOP/2012/09/WC500133133.pdf 9. European Medicines Agency. Questions and answers: Good manufacturing practice. 2015;1–7. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/ regulation/q_and_a/q_and_a_detail_000027. jsp&mid=WC0b01ac05800296ca 10. European Medicines Agency. Good Manufacturing Practice : An analysis of regulatory inspection findings in the centralised procedure. 2007 (January). Available from: http://www.ema.europa.eu/docs/en_GB/document_ library/Other/2009/10/WC500005009.pdf

B. Naga Vamsi M Pharm Regulatory Affairs Group, Department of Pharmaceutics JSS College of Pharmacy, JSS University, Mysore. Email: vamsi.bachu770@gmail.com Balamuralidhara V. Assistant Professor Regulatory Affairs Group, Department of Pharmaceutics, JSS College of Pharmacy, JSS University, Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India Email: baligowda@gmail.com Shenaz Z Khaleeli Technical Director, Pharmaleaf India Pvt. Ltd, Bengaluru. Email: shenaz.khaleeli@pharmaleaf.com

Srinath S Technical Manager (QA & RA), Pharmaleaf India Pvt. Ltd, Bengaluru. Email: ssrinath3060@gmail.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 67


Manufacturing

Parenteral Manufacturing and Industry 4.0

Please donâ&#x20AC;&#x2122;t be surprised that Industry 4.0 has anything to do with parenteral manufacturing. You may also have heard about it as Internet of Things (or IoT) or the next manufacturing paradigm. Actually it has to do with â&#x20AC;&#x153;everythingâ&#x20AC;? - and therefore also with parenteral manufacturing. Industry 4.0 will be a game-changer in how the end-user (the patient) will interact with all the partners who are involved in all aspects of the wellbeing of the end-user. Real-time data on the status of the health situation of the individual will have the possibility to flow seamlessly to an array of partners. You might already now have an Apple Watch on your wrist, which has the possibility to submit data on your health situation to relevant partners if you should want to do so. However, this is only the first step in a new area of exchange of information, which can be used to make healthcare decisions not only around you, but also for a larger population.

leading areas of sterile manufacturing are within semiconductors, cell phones and automotive parts; not in pharmaceuticals yet. This is partly because the technology for pharmaceutical manufacturing is not available yet, but probably also because the industry does not have the innovation skills and the culture to adapt those new technologies. Some of the more advanced sensors

have found their way into closure integrity through headspace laser monitoring and rapid microbiology measurements. Machines are starting to include integrated checkweigher equipment after filling, as well as integrated camera inspections and environmental monitoring. However, only a few lines can run with high efficiency without operator intervention, and the best current protection of isolator filling lines are still

Industry 4.0 will also affect the manufacturing of sterile products, being one of the most challenging areas of pharmaceutical manufacturing. Not only is it complicated and difficult, but it is one of the most vulnerable areas from a patient and regulatory perspective. Patients and regulators expect highquality products but still there have been many manufacturing issues, even in recent years. These include finding particles, including human hair and other impurities found in parenteral products. It has caused severe inspections, which in some situations have resulted in warning letters, consent decrees and drug shortage situations. Part of the problem is due to several existing facilities becoming aging facilities that do not live up to current expectations. Many of the new technologies that are part of Industry 4.0 will enable better control of the manufacturing processes. A rapid development within sensors, cameras and advanced controls are benefiting many industries but are struggling to be utilised in pharmaceutical manufacturing equipment. Some of the 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Spring 2016 Volume 8 Issue 1


Manufacturing

complex and time-consuming. Besides, it is still inflexible and time-consuming in regard to changes in products, format parts and supply of materials. The ultimate goal could well be to have the operators totally out of the cleanrooms. There is considerable inspiration to be found in the semiconductor industry, where this has been the norm for many years, simply in order to ensure the high yield of silicon wafer processing so that microchips are ensured a high buildin quality. Manufacturing equipment for semiconductors has been highly automated through robots and highly efficient systems that ensures the high effectiveness that is necessary with the low margins earned in this business. In pharmaceuticals, aseptic processing robots are still only used rarely. The main focus has been on the overall equipment efficiency and almost no companies have had the courage and focus in innovation to go to the next level. It has been pointed out in recent reports from McKinsey and other consulting companies that the opportunity is there for pharmaceutical manufacturing â&#x20AC;&#x201C; but with limited impact so far. With Industry 4.0, new types of sensors www.ipimedia.com

and interconnectivity in the near future must be expected; bioreactors with buildin cell-level measurements of activity and build-in wireless communication. The first tablet products with build-in monitoring have been FDA-approved and advanced sensors for process analytical technology (PAT) have been state-of-the-art in tablet manufacturing for some years now. In fact, some OSD facilities have implemented continuous manufacturing and have in this way avoided the inflexibility and risk of traditional batch manufacturing. Still, the examples from parenteral manufacturing are few and there have only been a few successful case studies so far.

The new paradigm of single-use biopharmaceutical manufacturing opens a new opportunity to rethink the way we measure, monitor and control the bioprocessing. More and more process steps have become available with singleuse technology and the new solutions are still so new that you may not have heard of them yet. Some will be shown at this yearsâ&#x20AC;&#x2122; Interphex exhibition in New York, following the new product introductions shown at the 2015 Achema exhibition in Frankfurt, but still the technology is evolving so fast that the new solutions becomes available nearly on a daily basis. So one has to stay tuned.

However, the opportunities are available. Bio manufacturing would benefit tremendously from adopting the principles of continuous manufacturing, although there is a gap on the sensor side. Instrumentation is more complex because connectors add a risk to the integrity of closed systems. Wireless data transfer is an integral part of the Industry 4.0 paradigm. The sensors are starting to arrive. Battery life is improving and the necessary energy for measurements and data communication is decreasing. It is becoming possible and it is very much needed.

Every single-use technology has some challenges around instrumentation, as it is important to try to avoid ports for instruments. In general, ports should be avoided as they add significant risk to the manufacturing process through, e.g., infections or other sources that threaten the well-controlled environment. However, there are benefits in operating within a closed system in modern singleuse manufacturing, as well as improved technologies which are constantly developed to solve those challenges. These include the benefit of taking advantage of Industry 4.0, which should be able to INTERNATIONAL PHARMACEUTICAL INDUSTRY 69


Manufacturing add significant benefits compared to the traditional instrumentation solutions. Industry 4.0 is all about connectivity. It does not have to be wireless connectivity, but part of the Industry 4.0 solutions are actually based on wireless technology, mainly WiFi or other wireless communications. There are wireless industry communication standards, while the wireless instruments for biopharmaceuticals are still a mix of many solutions, with no clear winner on the communications approach, unfortunately. One of the key areas is standardization, and for single-use bioprocessing it should preferably be based on sensors that require little or no power supply. Sensors that run on batteries or which can be charged wirelessly would be preferred, as solutions that communicate directly from the process liquid hold the highest potential. Everybody wants to avoid connectivity problems, and the risk of having wireless communications hacked within a closed facility are possible to handle. Thus, there is a need for a new generation of single-use sensors for single-use bioprocessing solutions that can be used in closed systems such as bioreactors, with no need to add or charge batteries. Industry 4.0 is not only connectivity and networked communication between devices, be they processing equipment or pharmaceutical products. The nextgeneration pharmaceutical products can well be imagined to include further integration between processing equipment and pharmaceutical products. One example could be an “artificial pancreas” insulin pump with associated blood sugar measurement. Another interesting example is the product that FDA approved in 2015 which communicates to ensure the patients’ compliance with the prescribed treatment that may last several weeks. In these examples and others, innovation has been around for some years and the future requires better and more efficient communication. But what about in the manufacturing of pharmaceutical products? Here the picture is very different. There is a strong belief in many pharma companies that new technologies should be, if not directly avoided, then considered very carefully. 70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Or in other words, someone else should do it first. This is despite the fact that the FDA is actively promoting pharma companies to think differently in terms of “emerging technologies” and their public support for some of the new technologies such as continuous manufacturing. Despite the new FDA effort on various initiatives to stimulate “an agile and flexible pharmaceutical manufacturing sector”, the willingness to try new technologies is still low. Hopefully times are changing when the FDA actively promotes new technology and solutions such as continuous manufacturing, stronger supplier engagement, process analytical technology (PAT) and other forward-looking initiatives. The pharmaceutical industry has a great opportunity to accept the invitation from the FDA’s Emerging Technology Team and seriously work with the regulators in the FDA and the suppliers to the industry, who want to provide innovative solutions. This could form a triangle where the next generation pharma needs to start. Serious pharma companies now realise that they need to change and also that the FDA is changing attitude to new technologies, as long as new technologies are evaluated based on science and a risk-based approach, with a focus on quality, safety and efficacy of the pharmaceutical product. The industry is missing some of the good, thought-stimulating examples that lead the development towards the next generation of parenteral manufacturing. Industry, suppliers and regulators need to work closely together, similar to 20 years ago when the first solutions for barrier technology and isolators were developed. These solutions are now state-of-the-art in parenteral facilities, although many aging facilities still have a long way to go. However, with a strong and trustbased cooperation between visionary pharmaceutical companies, innovative equipment manufacturers and regulators looking for emerging technologies, it will be possible. The real question is not whether Industry 4.0 is applicable to be part of the solution for the parenteral manufacturing of the future, but when the breakthrough will come.

Gert Moelgaard has more than 25 years experience in the pharmaceutical and biotech industry, including more than 15 years in senior management of NNE Pharmaplan, an international engineering and consulting company with focus on the pharma and biotech industry. He has been engaged in several projects and assignments within pharmaceutical manufacturing as well as validation and quality management.He has previously worked in Novo Nordisk, NovoNordisk Engineering and NNE Pharmaplan. He is past chairman of ISPE and been engaged in international guidelines, conferences, courses and articles throughout his career. Email: gert.moelgaard@gmail.com

Morten Munk has over 25 years of industry experience in biopharmaceutical development and manufacturing and is a globally recognized technical expert in the field. He has authored or co-authored a number of technical articles and guidelines. Due to his technology expertise coupled with thorough business understanding, Morten is frequently invited to give scientific and technical presentations at international conferences. In addition, Morten is active in the biopharmaceutical community as member of scientific committees for various international conferences and as volunteer in international industry organizations such as ISPE and PDA. Morten Munk joined NNE Pharmaplan in 2015 as Senior Technology Partner, supporting all aspects around biopharmaceutical development and manufacturing. In 2001 Morten co-founded CMC Biologics A/S, where he held a position as Vice President for Business Development. Prior to founding CMC Biologics, Morten held a position as principal scientist at Novo Nordisk A/S in which he was responsible for the CMC part of several projects, which have bene commercialized successfully. During his career, Morten has completed work assignments in both the US and EU. Morten Munk has special competences as biopharmaceutical technical expert. He is an expertise in Process Development, Facility Design, Single Use Systems, Process Validation, QbD, Tech Transfer, Continuous Processing, Regulatory Affairs and International Business Development. He is Co-organizer, moderator and speaker at international conferences and advanced courses. Morten Munk is an author and co-author of technical articles and guidelines. Spring 2016 Volume 8 Issue 1


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Manufacturing

Designing for Quality Over the past several years, there has been a steady rise in new biologic drugs coming onto the market for the treatment of chronic conditions such as multiple sclerosis, rheumatoid arthritis and autoimmune diseases. This trend is likely to continue in the future, with the IMS Institute for Healthcare Informatics predicting that the market for biologics will grow to $221 billion by 20171 . Along with this new class of drugs comes a corresponding increase in self-administration systems, which offer patients who must repeatedly self-dose the freedom to do so outside of the doctor’s office or clinic. As the industry grows, the need for safe and effective packaging that addresses both the specialised characteristics of injectable biologic drugs and the high-performance requirements of selfinjectors is of increasing concern for drug manufacturers. In order for a treatment to be effective, it is important to ensure that the drug’s delivery system is easy to use, reliable and effective. As part of an integrated delivery system, packaging components play an important role in drug quality, patient safety and device performance. They, therefore, must be given careful consideration as part of the drug development process. Regulatory Calls for Quality Driven by concerns for patient safety, regulatory agencies around the world are asking drug and packaging manufacturers to build quality into their products from the start to ensure consistent quality throughout a drug product’s life cycle. With many sensitive biologics coming on the market as combination products, the compatibility of packaging components with injectable drugs and their delivery systems is being closely scrutinised. In the United States, the Food and Drug Administration (FDA) defines a combination product as, “A product comprised of any combination of a drug and device; a device and biological product; a biological product and a drug, or a drug, a device and biological product.”2Manufacturers of combination products in the US must abide by two 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

FDA regulations for good manufacturing practice: • •

cGMP Finished Pharmaceuticals part 21 CFR 210-211 QSR Regulation for Devices 21 CFR 820

Some of the primary areas covered by CFR 820, and that differ from CFR 210211, include management responsibility, purchasing controls, corrective and preventive action and design controls. As part of the industrialisation of syringe plungers using the QbD approach, aspects of CFR 820 must be incorporated into the manufacturing process. These regulatory requirements are challenging drug-makers to look for consistent, reliable, high-quality packaging components that meet the standards of good manufacturing process as well as the high expectations of end users. To address these challenges, the adoption of quality by design (QbD) concepts in the design and manufacturing of packaging components is gathering momentum within the industry. QbD delivers an improved, data-driven output, providing manufacturers with superior product and process understanding that minimises risk, emphasises patient-critical quality requirements and enhances drug product effectiveness. The scientific, risk-mitigation-based QbD approach is fast becoming an essential strategy for bringing highquality therapeutics to market quickly and efficiently. By building QbD principles into design and development from the very beginning, manufacturers can decrease variability in the manufacturing process and the end product. Highquality components designed using QbD processes can enhance the performance of drug delivery systems and protect sensitive drug products with exceptional cleanliness and barrier properties, while helping to ensure patient safety and drug product efficacy. Growing Demand for Quality in Drug Delivery Combination products such as prefilled syringes, auto-injectors and other self-

injection systems are rapidly gaining momentum among drug manufacturers. According to the recent “Drug Delivery Products” report from industry market research firm The Freedonia Group3, demand for parenteral drug delivery products is projected to rise more than 10 per cent annually to $86.5 billion in 2019, with prefillable syringes accounting for the largest and fastest growth among parenteral devices. Market trends toward home-use and patient self-administration of drugs used to treat chronic conditions have made prefillable syringe systems – and selfinjection systems that utilise prefillable syringes – ideal choices for many singledose drugs. For drug manufacturers, prefilled syringe systems for vaccines, biologics and other injectable drugs offer convenient, fixed-dose options that are easily adaptable to automated injection devices. Additionally, prefillable syringe and self-injection systems may be able to reduce therapy and injection costs, as well as significantly reduce overfill when compared to single-dose vials. Prefillable syringe systems may also optimise the number of doses from the existing drug supply, while offering delivery options that can help to differentiate drug products in an increasingly crowded market. For patients, prefillable syringe systems offer ease-of-use and enhanced convenience for those who require frequent dosing and, when combined with an auto-injector system, can provide a more portable drug delivery system. Use of a prefilled syringe system also has the potential to minimise microbial contamination and reduce medication dosing errors. With many biologics in development taking injectable form, drug manufacturers are increasingly exploring prefillable syringe and selfinjection systems for their administration. However, these advanced therapies often have very specialised needs. Many biologics are highly viscous, which may require larger containment systems and slow dosing of large volumes of the drug over time. Additionally, because of their Spring 2016 Volume 8 Issue 1


Manufacturing product life cycle.

sensitive chemical composition, biologics pose the risk of adverse interaction and incompatibility with the materials of their container/closure system. The demands on packaging components are changing in this new era. It is essential to package these new drugs with high-quality components that can help protect safety, efficacy and purity. By considering the impact that prefillable syringe systems and their components can have on a particular drug product early in the drug development process – and employing QbD strategies to overcome development challenges – drug manufacturers can minimise the risk to quality and position the product DEC_IPT_148x210+3_02-2016 16.02.16 10:27 Seite 1 to meet the needs of the ongoing drug

Understanding Quality Attributes The QbD approach promotes a holistic understanding of the drug product, its integrated delivery system and the manufacturing process. Employing a QbD strategy starts with product development. When designing and developing a product using QbD principles, manufacturers must define desired product performance goals and identify critical quality attributes (CQAs). The product and process can then be designed to meet those attributes, potentially improving understanding of how material attributes and process parameters impact CQAs and enabling manufacturers to mitigate variability. As a result of this knowledge, a company can continually monitor and update its manufacturing process to ensure consistent product quality. One class of products in particular that is essential to understand and assess during the QbD process is prefillable syringe plungers. Plungers (also called pistons and stoppers) are critical elements

because they serve as the primary seal for container/closure integrity, help maintain the purity of drugs during shelf-life, and function to transfer contents of the barrel and deliver drugs to the patient. Plungers are typically made from butyl rubber and can be coated with a fluoropolymer film that can increase lubricity and serve as a barrier between the drug and the elastomer, reducing the potential for extractactables and leachables. As industry demands for higherquality components have evolved, there is growing need for plungers developed using QbD processes. The design and manufacturing of high-quality plungers should follow a development life cycle programme that uses a quality target product profile (QTPP) to establish CQAs for control of breakloose and glide forces. The QTPP can serve as a guideline throughout the development process – which should include risk-based design inputs, finite element analysis (FEA) modeling, data generation on multiple concepts and final product performance verification with barrels from multiple suppliers – to ensure that targeted

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 73

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Manufacturing specification values for breakloose and glide force are met. Benefits of a QbD Approach By applying a holistic, QbD approach to the design and development of plungers and other prefillable syringe components, packaging manufacturers can gain a thorough understanding of both the product and the process. This, in turn, enables multiple benefits for manufacturers and end users: Improved Functionality – High-quality plungers can enhance the functionality of prefillable syringes and self-injection systems. Using QbD principles can help to optimise breakloose and glide forces – aspects that are very important when syringes are used in combination with an injection system. By optimising a delivery system’s functional and dimensional performance, it is possible to improve the consistency of injections and the rate of injection times. Patient Confidence – A self-injection system needs to function consistently and reliably in order for patients to have confidence that it will work. QbDdesigned components allow for largersize delivery systems and greater volumes of doses which may enable home administration, and encourage device use and more accurate dosing – all of which can help boost a patient’s confidence in their use of a self-injection system. Risk Mitigation – The use of clean, highquality components with injectable drug products can lower the risk of extractables and leachables, helping to ensure the drug and its packaging meet both strict standards for quality set by regulatory agencies and the needs of modern suppliers for more robust products. Efficient Manufacturing – Employing a QbD approach in the manufacturing process can significantly reduce plunger variation from part to part. This can help facilitate more efficient manufacturing processes and support a reliable supply of drug products. Use of QbD principles ensures that components are developed using sciencebased and data-driven decisions, and that they meet critical specification for defects, visible and sub-visible particulate and extractables consistently. The knowledge gained throughout the QbD 74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

process can be used on an ongoing basis to maintain continuous improvement by the manufacturer. Selecting a Quality Packaging Partner Patient safety needs and increasing regulatory concerns are spurring drug manufacturers to look more closely at the quality attributes of the components they are using to package and contain their injectable drugs. Growing use of biologics and the trend toward self-administration means manufacturers need to select components that have a high level of reliability, consistency and compatibility with sophisticated drug products and delivery systems over the course of their lifecycle. Drug packaging components play a vital, but often overlooked, role in drug safety and efficacy. They are a critical part of integrated combination products and are essential to ensuring delivery systems are safe, intuitive and easy to use, but it can be difficult to know which component is the best-quality fit for a particular drug product. Fortunately, there are new component offerings on the market designed to address the need for high-quality packaging solutions. These include prefillable syringe plungers designed using QbD principles to provide high reliability for breakloose and glide force, dimensional accuracy and consistency, sub-visible and visible particulate control, and low parts per million (ppm) defect attributes.

a high-quality component for use in prefillable syringe systems that will meet demands for high quality, improved total cost, and increased safety and security for the drug product. By working with a packaging partner that employs a QbD philosophy, pharmaceutical manufacturers can employ high-quality packaging components that can help lower their total cost of ownership through reduced compliance risk, filling rejection rate and process costs. Full return on investment can be realised once a drug product is commercialised and has gained patient loyalty through ease of use, therapeutic benefit and high confidence in the delivery device. Perhaps most importantly, though, components created through a QbD approach offer features that are designed to ensure the highest levels of reliability, which ultimately helps the pharmaceutical industry to achieve its most critical goal: providing the safest and most effective drug products for their patients. References 1. IMS Institute for Healthcare Informatics. The Global Use of Medicines: Outlook through 2017. November 2013. 2. U.S. Food and Drug Administration. Combination Products. Accessed February 2016. 3. The Freedonia Group. Drug Delivery Products. December 2015.

When selecting components for primary packaging, it is important that drug manufacturers also look for products that have barrier film technology, are vision verified and that are “ready to use.” Careful consideration should be given to components that are designed and manufactured according to QbD principles and have optimal levels of dimensional and functional performance. These features can help minimise risk further down the line toward commercialisation. To maximise a drug product’s safety and efficacy, pharmaceutical companies and their drug packaging and delivery partners should build new quality principles into the entire manufacturing process, from design and development to commercialisation and administration. Selecting a packaging partner with expertise in QbD early in the development process can help drug makers choose

Mike Schäfers, Vice President, Global Product Management and Marketing Operations, West Pharmaceutical Services. Spring 2016 Volume 8 Issue 1


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Packaging Cold Chain Outsourcing: A Simple Answer to a Complex Question? Pharmaceutical manufacturers are facing a new challenge. The recent patent cliff and the exponential growth in the development of high-value pharmaceutical products, biologically developed therapies and live vaccines in the last ten years has resulted in a greater need for temperature-assured handling of drug product, from active ingredients to finished dosage form. This can be demonstrated by the fact that in 2013, seven of the top ten highest-selling pharma products were biologics1, with global sales contribution from biologic drugs forecasted to jump from 23% in 2014 to 27% in 20202. Side-effects of Growth There is a growing side-effect from the global expansion in demand for cold chain services for the pharmaceutical industry: a supply chain which is becoming more and more demanding and complex. Causes for this increase in demand include the previously identified growth in the biopharmaceutical sector, driven by the industry’s technological breakthroughs, resulting in more effective treatments by virtue of more effective mechanisms of action. This is further complicated by industry trends in the size and complexity of clinical trials, and greater regulatory demands for safety and efficacy data prior to drug approval. In particular, the growth in the biologics sector has increased the importance of robust and carefully managed global supply chains. These temperature-sensitive biological products often have shorter shelf-lives than small molecule therapies and therefore require specialist handling. With cost pressures and readily available patient populations, clinical investigator sites are increasingly in developing markets and remote locations; geographies such as Ukraine and Russia, Asia Pacific, and Latin America. Biologics add an increased complexity to the supply chain and require specialist handling during packaging, labelling, storage and distribution to ensure the product remains within its specific temperature range, which can vary from controlled ambient to cryo-store at -196 degrees Celsius. 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

This is a crucial issue because biologics are of extremely high value in terms of supply and cost, and are vulnerable to minor temperature deviations. Failing to maintain specific temperature ranges can have a negative effect on the efficacy of the drug. Additionally, the timescales for manufacturing these materials are often very long and replacements for damaged products may not only be costly, but could take many months - causing shortages in the supply chain. This can potentially have a significant impact on the clinical trial supply chain and, most importantly, there is the ultimate consideration of the risk to the patient. The Outsourcing Trend Historically, the pharmaceutical industry has taken a short-term tactical approach to outsourcing clinical supply chain services by managing specific peaks in demand. This is now changing to align with the biotech sector, which has developed a very different strategy: a large number of biotech companies have been founded on a ‘virtual’ model; outsourcing all manufacturing and distribution activities. This often leaves the organisation with little supply chain experience and no in-house clinical supply teams and services to support their requirements. They have had to rely extensively on external service providers to develop clinical supply chain strategies for the manufacturing, packaging (primary/secondary), labelling, storage and global distribution of high-value biological products. This outsourcing trend is being continued by pharma companies who want to concentrate on what they do well and leave the specialist handling to the specialist outsourcing providers. Greater Opportunity; Greater Risk There is a lot at stake. To put it into figures: a recent Visiongain report highlighted that the global clinical trial supply and logistics market was estimated to have been worth $11.6 billion in 2013 and is predicted to increase to $16.34 billion in 2019 and further projected to grow to $22.08 billion by 2025. Analysts attribute this strong growth to increased outsourcing of clinical trial supplies and distribution, which is expected to drive

the market at a compound annual growth rate of about six per cent from 20152025. However, this globalisation of the clinical trial supply chain and increased access to new markets could increase risk to the supply chain. It will demand the development of distribution strategies to mitigate this risk of potential loss of often high-value product and, as a practical matter, effectively considered invaluable due to its limited supply. A key part of this strategy would be a fully audited global supply chain with a consistent approach to managing shipments via both standard operating and specialist training procedures. At the moment, for example, a temperature excursion during shipment is only recognised when the investigational product is received by the clinical site/end user and the temperature monitor graph is downloaded and reviewed. If there is an excursion, the product will remain quarantined until the sponsor confirms whether the temperature excursion is within allowable limits. If there has been a deviation and the product is deemed not suitable for use, this can result in a delay in patient dosing, postponement of patient enrolment, loss of the patients from the trial and/or trials to be delayed. Depending on scope and available supply, it may also warrant costly new manufacturing activities to feed the supply chain for resupply to the investigator sites. With the high cost and often limited availability of biopharmaceuticals, entire shipments may need to be rejected. The development of truly strategic partnerships, including a robust and simplified supply chain, is crucial to limiting risk. The aim is to reduce the number of ‘touch points’ where things can go wrong. Selection of an outsourcing vendor is an important consideration in the clinical supply chain. Importantly, this relationship should be evaluated in the context of a trusted strategic partnership. There are a number of questions to ask to verify their expertise in cold chain management and distribution: • •

Are they a specialist in this area? Do they offer a range of shipping solutions? Spring 2016 Volume 8 Issue 1


Packaging • • • • • •

Do they conduct their own shipper validation or do they rely on data provided by the shipper supplier? Are they capable? Do they have capacity, even at short notice? Are they flexible? Do they contract out to any thirdparty vendors and how are these relationships managed? If shipments have deviated from specified temperature ranges, how will this be managed and how will it be addressed to reduce risk with future shipments? In the spirit of a true partnership model, what ownership and accountability do they take to ensure safe packaging, labelling and effective logistics to the patient?

Responding to Change The response to the new pressures on cold chain services can be demonstrated by the drive of sponsor companies turning to specialist outsourcing providers to fulfil the needs of their temperature-sensitive materials. Proactive and collaborative management of service level agreements and key performance indicators is key to ensuring the patient receives the right product, at the right time and in the right condition (temperature maintained through the supply chain). Such performance indicators include operational metrics such as on-time despatch, on-time delivery, volume of temperature deviations, and gauging the overall safety and reliability of their logistical operations. An additional strong focus is the financial analysis in terms of spend on individual clinical trial activities. Setting and managing a clinical trial supply budget is an ever-evolving task, especially for global studies with distribution strategies which are focussed on responding to the requirements of patient enrolment. Online portals integrated into supply chain operations present opportunities to extend visibility to sponsor companies into logistical touch points. This visibility can help foster a partnership model by providing real-time information about inventories and locations, shipment status, and acceptance at the investigator sites, thereby reducing study lead-times and consolidating communication channels. Software can be extended to electronic document approvals and sharing, www.ipimedia.com

order transactions, integration into IRT technologies, and so many other facets of business integration. This integration fosters a more effective supply chain and ultimately more effective study execution. Smarter Technology A smarter supply chain has many facets, but central to the entire process is the refrigerated packaging and labelling of products that have limited stability data outside of refrigerated temperatures, and when refrigerated room space may be at a premium. When packaging and labelling cold chain products, it is crucial that the total time the product is outside of the appropriate storage temperature is minimal. The preferred packaging option delivered by the majority of vendors offers limited packaging suites for refrigerated labelling and packaging operations. Cold room space is often at a premium. To address this and to ensure secure and efficient packaging, the industry must look for innovative and smarter ways to address these challenges. One such method is the use of a fully validated cold plate technology in which the product is stored whilst being packed and labelled. This method offers a unique solution to overcome the standard hurdles. This is specifically favourable when a just-intime service is required and removes the need for personnel to physically conduct labelling and packaging in a dedicated 2-8°C packaging room. Investigational therapies can be extremely invaluable, or practically immeasurable, in the case of cell therapy. Supply chain visibility can help mitigate risk. Technologies exist for an integrated electronically monitored platform that orchestrates supply chain activities for advanced therapeutic medicinal products, utilising a single, compliant and FDA-validated technology platform. These combine proven technologies that economically and effectively integrate and risk-manage the cell therapy supply chain. Any paper-managed cell therapy supply chain quickly becomes inefficient and risk-prone due to shifting regulatory requirements and linear complexity as demand scales up and scales out. A successful and scalable cell therapy supply chain demands standardised processes, automated electronic records, integrated temperature-sensitive logistics, real-time visibility and end-to-end traceability to ensure final product quality.

In some instances, reversing the logistical order of standard practices can help mitigate risk and drive efficiencies. For example, storing vials at temperatures as low as -196°C also presents huge challenges for ensuring the all-important labels are able to be applied. Bespoke solutions have been developed by working with the product manufacturer to design, print and pre-label vials prior to filling and freezing. As another example of adding visibility and safety to the supply chain, bespoke barcoding systems have also been developed to incorporate cold chain traceability during the picking and packing of products and reduce errors. This forces the operator to scan individual identifiers, ensuring the correct kit is picked at every stage of the shipper packaging process and confirms the ‘start’ of the temperature monitor. Partnerships leverage innovative logistical models to ensure success. Flexible and just-in-time strategies must also be applied, taking into account the availability of the product, multiple protocols and the possibility of additional countries being added after the trial has commenced. For example, multilanguage booklet labels can provide flexibility, but are typically produced based on the countries planned at the commencement of the study. If unplanned countries are introduced during the trial, this can make the existing labels redundant and add time and expense due to requiring updated booklets and the subsequent relabelling of inventory. An alternative strategy is to label supplies on a just-in-time basis, whereby supplies are labelled with country-specific labels only after distribution orders are received for shipments to clinical sites. Just-intime labelling can be performed as either a discrete labelling operation in a packaging suite, or may be integrated into the distribution process, in some instances in an approved regional depot closest to the remote investigator site. Non-standard Temperatures The growth of the pharmaceutical industry has brought with it the development of new drugs which may require nonstandard storage temperatures, for example -40°C. The requirement for this temperature range is increasing as biologicals are inactive below -35°C and it is possible to build pallet storage warehousing at this temperature for the INTERNATIONAL PHARMACEUTICAL INDUSTRY 77


Packaging storage of bulk materials prior to fill finishing and therefore maximising the shelf-life of these expensive products. These very specific product needs may warrant construction of a bespoke solution from the outsourced partner in the form of a tailored stand-alone facility.

that can be developed to reduce timelines. This would include developing a method to adapt the cold plates to support validated packing on dry ice, maintaining temperatures below -20°C and containing CO2 levels to a minimum for a safe working environment.

Speed and Control The emerging need to improve distribution strategies is why cold chain specialists are striving to identify innovative methods to improve temperature-controlled shipping systems. Instead of relying on validation data from the traditional suppliers of shipping containers, logistics providers are looking at their own methods of validation of shippers to ensure the integrity of the cold chain under ‘forced’ demanding conditions.

Other innovative developments could include a method which enables the utilisation of automated labelling equipment within a large 2-8°C environment to support high-volume packing runs, which cold plate technology is unable to support.

For example, a new phase-change frozen shipping system (-15 to -25°C) has been recently validated, which involved extended conditioning times for the frozen plates, requiring one-month storage at -30°C. The clinical market is so fast-paced, dynamic and difficult to forecast that actually one month’s conditioning is completely inefficient. With the aim of speeding up the process, suppliers’ validations are being challenged and new custom methods for conditioning these systems have been created, which enable a significantly reduced conditioning process for the frozen shipping systems: from one month to 48 hours. This can be achieved by employing ultra-low temperature conditioning of the plates at -70°C for 48 hours, compared to the supplier’s method of one month at -30°C. Coupled with increasing the conditioning time at ambient (in order to expel the required amount of energy prior to pack-out), this ensures controlled frozen temperatures are maintained during transit. This ability to continually challenge the supply chain by qualifying shipping systems at-site and utilising bespoke test environments may prove to be a crucial capability for successful operators in the future, and result in completely removing temperature deviations from incorrect packaging of shippers. These solutions continue to be developed in the spirit of partnership and prevention. An Ongoing Challenge Although the cold plates are currently validated for refrigerated packing at 2-8°C, there are still more processes 78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

To meet the challenges of the future, the industry requires a shift towards realtime 24/7 monitoring of the temperature of specific shipments, involving faster processes and new strategies. Stocking strategies at central hubs, depots and clinical sites may be designed to conserve valuable inventory by shipping little-andoften, but this in turn can result in higher shipping costs. More cost-effective solutions are forecast to be in increased demand; met through new packaging and monitoring technologies, including reusable packaging and phase change materials that allow cooling for more specific temperature ranges. There is also speed. Innovative operational and logistical concepts for those studies requiring a rapid start-up have been developed to further accelerate products through the supply chain, without compromising quality and regulatory requirements. Cold Chain Conclusions An increasing proportion of worldwide drug sales are forecast to be derived from biological products. As the biopharmaceutical market is growing rapidly, outsourcing/partnering cold chain activities to specialists is critical as a result of the increasing complexity of the biopharmaceutical supply chain. In an industry where the patient is at the forefront of everything that we do, developments in activities such as packaging, storage and shipping technologies will continue to be made in response to the unique challenges this sector provides - to ensure that the right drug gets to the right patient at the right time, and within the right temperature range. Longer-term Development of the Biologics Supply Chain? As we have seen, the current supply

chain is constantly evolving to cater for – and predict – the pharmaceutical industry’s developing technology and requirements. We are currently seeing the trend towards custom parenteral delivery forms, such as the auto-injector to aid patient convenience for injectable medicines. This trend further complicates the temperature-controlled supply chain for biologically developed medicines because of the unique nature of these devices. On the horizon, however, is the even longer-term prospect of a radical upheaval that could bring a step-change in the supply chain – the oral biologic. If injectable biologics – with all their cold chain supply implications – are replaced by tablets which are able to be packed and shipped at room temperature, that would be a revolution which would provide the possibility of a vastly less expensive supply chain, faster, and easier to manage.That is some way off. One of the problems that must be solved is that, unlike current methods, orally delivered biologics break down in the gastrointestinal tract and become inactive. But if this roadblock is cleared, it would remove the need for cold chain packaging, labelling storage and distribution strategies, and eliminate associated complexities. It would be the ultimate simplification of the supply chain. Just as biologics are now enabling new research and treatments, new developments could utterly reshape the supply chain. For progress to continue, each side must keep pace with the other. Adapted from the CPhI Annual Report 2015. References 1. The Global use of Medicines: Outlook through 2017. Report by the IMS Institute for Healthcare Informatics 2. EvaluatePharma, World Review 2015, outlook to 2020, June 2015

Fiona Withey is Managing Director, PCI Clinical Services, UK. Fiona has a BSc in Biology and Chemistry and a PhD in Biochemical Engineering from the University of Wales and was formally Chief Executive Officer of Biotec Worldwide Supplies Group prior to the acquisition by PCI in 2014. Fiona serves as a member of the Wales Economic Advisory Board and the Welsh Government Life Sciences advisory panel. Email: info@pciservices.com Spring 2016 Volume 8 Issue 1


Packaging

Improving Adherence: Packaging’s Synergistic Role in Delivery, Communication and Education On February 9th 2016, the European Parliament and Council published the amended version of the Falsified Medicines Directive (FMD), detailing the characteristics of the security features that will be required on packaging for medicinal products for human use. It stated that both a unique identifier and an anti-tampering device will be mandatory, helping to address the current evergrowing threat of counterfeit medicines. Data released by the United States Food and Drug Administration (USFDA) states that approximately 10% of all pharmaceuticals sold globally are counterfeit. While counterfeiters are active around the world, not all markets suffer equally. Developed nations have the lowest amount of counterfeit pharmaceutical goods, with an estimated 1% penetration rate in Europe and the USA, whilst developing nations show particularly severe penetration rates. For example, it is estimated that up to 30% of all medicines in Africa and the Far East are fake. In 2011, the World Health Organization reported that 64% of all antimalarial drugs in Nigeria were counterfeit. These figures continue to grow due to increasingly complex supply chains, the increased sophistication of counterfeiters, a lack of enforcement capacity, and the expansion of ecommerce. It is widely believed that up to 50% of drugs available online are fake – with estimates reaching up to 70% in some African and Eastern European countries. In light of this, various anticounterfeiting efforts have been developed by pharmaceutical companies, and multiple legislations such as the FMD are being implemented by governments around the world. The biggest challenge present is the fact that there is no set global standard, which in turn makes implementation complicated and inconsistent. As such, both governments and companies must continue to work together in order to continuously improve. The effectiveness of these localised legalisations should not be underestimated, however; the EU FMD 80 INTERNATIONAL PHARMACEUTICAL INDUSTRY

has not only raised the issue of counterfeiting publicly in the pharmaceutical industry, but has also prescribed some specific solutions, such as serialisation and tamper-verification, that will require changes from data management throughout the supply chain to packaging. The solutions proposed for combatting counterfeiting generally fall into one or more of the following categories: • • •

Track & trace Tamper verification Authentication systems

As a leading global provider of packaging and authentication solutions, Essentra advocates implementing multiple measures to provide enhanced security, particularly before the new medicine verification system commences in early 2019. Track & Trace: Serialisation Serialisation is the system of tracking, tracing and verifying products via unique identification codes. These unique identifiers reveal a complete history of the drug; from the supplier to consumer, for the whole duration of the drug’s stay on the market and additional time necessary for returning and disposing of the pack after it has expired. The codes are commonly presented as a linear barcode, 2D barcode or a combination of numbers, and technologies for more advanced solutions are currently being developed. However, irrespective of the format, the code will convey key data elements about the drug contained in the box, such as the drug’s product code, national reimbursement and identification number, batch number and expiry date of the unique identifier. These data elements should in addition be printed on the packaging in human-readable format in case the barcode is unreadable. Codes and unique identifiers will be encoded by a standardised data structure and syntax to ensure that it can be correctly recognised and decoded throughout the Union by commonly-used scanning equipment. In addition to confirming the integrity of the medicine and helping to ensure that patients are taking the correct

reliable medicine, these data elements also facilitate withdrawal and return procedures should a recall be necessary. There still remain a number of challenges that the pharmaceutical industry must overcome when implementing an efficient serialisation system. Firstly, a uniform system must be put in place that meets the requirements at each level of the supply chain. This may require existing suppliers and companies within the supply chain to integrate new IT systems, databases and business structures, which could prove difficult both financially and administratively. Plus the creation of the required serial codes themselves will call for significant expenditure, particularly if additional elements are included. The more complex the structure of the serial codes, the more challenging standardisation will be across all companies in the supply chain. According to some estimates, the majority of the coding solutions currently used in the pharmaceutical and healthcare industries could be rendered obsolete due to the FMD. The key to the implementation of a successful serialisation system is the ability to run a functioning repositories system that supports end-to-end verification and allows for precise data management and the control of data integrity. The process of track and trace will mean that every point within the manufacturing chain will have to carry out a stop-check, resulting in the collection of a large amount of data. Each individual unit will have a unique identifying code and, once printed and supplied to the public, must be decommissioned in the repositories system so any other pack that has the same code cannot be verified. If, under certain circumstances, a box is accidentally damaged and made unusable, the code must be recorded as inactive in the system. The organisation of this vast network of data will prove challenging, so companies and governments must work together to create a successful way of managing it effectively. One country that is currently running a comprehensive track and trace infrastructure is Turkey. The system Spring 2016 Volume 8 Issue 1


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Packaging was initially implemented as a means of combatting insurance fraud, but is now capable of tracking and tracing all products within, and entering, the country. Goods are constantly documented as they advance through the supply chain, and when the goods finally reach the consumer, these unique identifiers are cross-referenced with the master database to confirm the product’s authenticity and original manufacturer. Without this confirmation, there is no way for reimbursement through Turkey’s health system. Their system also utilises unique GS1 GTIN serial numbers through both human- and machine-readable formats. This provides both track and trace and an economic disincentive for people to use ‘out-of-system’ medication. Tamper-verification Indeed, while serialisation verifies the authenticity of the pack of medicine, counterfeiters can easily collect used genuine packs and refill them with fake product, reclosing the original packaging and passing the product off as genuine. This is already occurring in countries such as China, where counterfeiters obtain genuine boxes from patients leaving pharmacies. This demonstrates the need for a multi-layered security approach, to provide protection for both the packaging and the contents inside. Tamper-verification shows whether the packaging has been opened or altered since it left the manufacturer, ensuring that the content of the packaging is authentic. It provides the end user with confidence, allowing them to personally judge that the product they are opening is genuine and originates from the legitimate manufacturer. As stated in the Directive 2011/62/ EU, tamper-verification features must be applied to packaging of certain medicinal products as required. There are now nine categories of tamper-verification features included in the European Standard: • • • • • • • • •

Flaps of folding boxes closed with glue or closed with labels or tapes Specially constructed folding boxes Sealing labels and tapes Film wrappers Sleeves Breakaway or tear-away closure Display blister pack Blow-fill-and-seal-container (BFS) New and emerging technologies

82 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Beginning with folding boxes, tamperevidence can be built into the design of cartons via the use of glued locks, such as the reverse tuck end with glued flaps, or dagger locks. The side-walled glued skillet with scored top opening and the standard side-wall glue skillet with zip-tear opening provide additional solutions. All of these ‘built-in’ features entail the destruction of the original carton. In these cases, it should be noted that providing consumers with features that allow for easy opening of the pack, such as those with scored opening, help to eliminate frustrating experiences that could put the consumer off a particular brand or product. In the case of sealing labels, tamperverification can be provided with varying levels of sophistication. At entry level, simple labels with high-adhesive provide a clear visual indicator that the pack has been opened as the removal of the label will also remove part of the packaging. One example of this is a fibre-tear label, which irreversibly damages both print and carton board on to which it is affixed, including even varnished coatings. For brands that require a more consumer-friendly experience, labels which leave behind a visual cue on the original packaging upon removal can be utilised. One such example is a void release label that leaves a void message or pattern behind when the label is removed. Another option is a frangible label that uses a specially engineered substrate that disintegrates the label when attempting to remove from the carton board. Both of these labels leave a clean visual cue that alert the consumer that the original box has been opened. Authentication Systems Lastly, authentication systems help consumers to verify if packaging is genuine. Authentication solutions can come in different forms – overt, covert and forensic. Overt solutions are obvious to the naked eye and enable instant authentication through visual inspection, such as holographic devices and colour-shift inks. Covert solutions are more sophisticated as they often require specialist equipment to identify their presence, such as UV fluorescent inks and microtext. For an extra advanced layer of authentication there are also forensic solutions, which include molecular markers and biological tracers, which can only be

identified using laboratory equipment. Taggant systems are another popular solution, which in fact bridge covert and forensic layers of authentication. Taggant systems use transparent taggant inks which can be chemically engineered to provide customers with a unique signature, which are only readable through taggant readers throughout the products’ journey. Summary The optimal approach to protect against counterfeiting will include several layers of security to combine both overt and covert technologies, track and trace systems and tamper-verification, thus making it as difficult as possible for counterfeiters and the illicit trade to succeed. Such layers should, wherever possible, be intrinsic to the item or packaging to ensure that the item is authenticated rather than the security feature alone being authenticated. It is clear that the pharmaceutical industry must react to the threat posed by counterfeiters, not only to protect the integrity of brand-owners, but also more importantly, to ensure that patients are consuming the genuine medicine they require, particularly as there is now a three-year deadline. Implementing various levels of solutions, from serialisation to tamper-evidence, helps to ensure that pharmaceutical products are not falsified or have been altered by counterfeiters.

Ian Lemon. As Essentra’s Global Product Director Health & Personal Care Packaging, Ian Lemon is responsible for leading the company’s product offering in this category, as well as its new product development in line with customer and category needs and demands. He has over fifteen years of experience delivering value-added packaging solutions and has worked with several of the world’s leading FMCG businesses. Email: ianlemon@essentra.com Spring 2016 Volume 8 Issue 1


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Contact West today. North America +1 800-345-9800 Europe +49 2403 7960 Asia Pacific +65 6860 5879 www.westpharma.com West and the diamond logo, By your side for a healthier world™ and NovaPure® are registered trademarks or trademarks of West Pharmaceutical Services, Inc., in the United States and other jurisdictions. Copyright © 2016 West Pharmaceutical Services, Inc. #9634 •0316


Packaging

Automating the De-blistering Process This article provides an overview of why de-blistering is required, what issues this creates, and how automated deblistering technology can be implemented to improve run rates, increase efficiency, lower costs and help reduce risks to staff. Blister-packing Process Blister-packs are a very common means of packaging pharmaceutical tablets, capsules and soft gels. Such packs generally comprise a sheet of initially flat plastic or aluminium base material in which are formed a series of wells. A tablet is inserted into each of the wells, the open ends of which are sealed by means of a sheet of aluminium foil which is attached to the base material sheet. Each tablet is thus sealed in its own well until use, when the base material well is depressed by finger pressure and the tablet is forced out through the foil backing Reasons for De-blistering Although de-blistering would normally only be done by the consumer, there are various reasons that blistered product would need to be removed from the primary packaging and this occurs at multiple points along the product lifespan. During initial product packaging, when the blistering machine is being set up, product is required to be run through but is rejected until quality approval of the final blister is signed off. When you are dealing with high-value and in some cases very low batch sizes of capsules / tablets, these set-up blisters will be required to be de-blistered. Furthermore, any reject blisters generated throughout the run due to malformed blisters, leaks or out-of-registration sealing may also need to be de-blistered to ensure acceptable wastage limits are met and minimal reject capsules / tables are created. Another reason for de-blistering is related to incorrectly packed products, specifically issues with the blister-pack itself. This can be an incorrect livery, strength, language or variable data (batch number and expiry date) on the lidding foil or embossed into the base material. This would require the stock to be rejected, destroyed or recovered by de-blistering. Again based on the cost, availability

of the drug and required timelines, a decision will be made on the necessity for de-blistering. Another reason for de-blistering could be in the case of a product recall where the drugs are out in the market and a problem is found and the entire batch of that drug would be recalled to be inspected and evaluated. During this process, depending on the reason for the recall, the individual tablets / capsules may need to be tested and a large amount of de-blistering may be required. During clinical trials it is sometimes required to test the trial drug against a comparator. A comparator trial, rather than a placebo-controlled trial, means that the experimental drug is not being compared to a placebo, but rather to a drug that is already being used to treat patients. In this case, when a comparator drug is already on the market in a blister-pack format these will have to be purchased, unpacked, de-blistered and then re-packed or over-encapsulated (if this is to be used on a blinded trail) and then compared to the new drug during the clinical trial. If this is a large Phase III trial, then the quantity of blisterpacks that require de-blistering can be very high. Finally when the drug product reaches the end of its shelf-life, it needs to be destroyed. For expired blisters containing toxic product, there is often an expensive disposal process if the product is not separated from its packaging. In this case, a highly-controlled and safe method of de-blistering is required. Issues with De-blistering Blister-packs are designed to be opened by the end user and as such, hand processing is one method of deblistering. This can be appropriate for

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small numbers of packs and on an ad hoc basis, but if a large number of packs are planned to be de-blistered, carrying out this operation by hand is both timeconsuming and costly. Furthermore, a recent study carried out by the Health and Safety Executive found that manual de-blistering required operators to use forceful pinch grips, with the greatest force being exerted through the thumbs. Discomfort and other upper limb symptoms were seen to be commonplace after a shift involving de-blistering. It was established that during the de-blistering task, the wrists were held in bent and awkward postures and there was also rotation and flexion of the supporting wrist as the strips of tablets must be turned frequently. The posture taken up by the operators to allow them easy access to the blisters required them to sit resting their feet on the bar underneath the table. This posture created extra tension in the arms and neck, but it also meant that they could not comfortably place their feet flat onto the floor, leading to discomfort in the legs and back. The de-blistering task can be a long process, sometimes lasting an entire shift or more and it was reported that some operators find the task very monotonous and become fatigued and under-stimulated within this area. The outcome of this study points to the requirement of a better solution than a manual de-blistering process. Methods of De-blistering Due to the issues raised regarding manual de-blistering of large quantities of blisters, a number of machines have been devised for this task and each has benefits and drawbacks based on the volume, blister type and nature of the

Spring 2016 Volume 8 Issue 1


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Packaging

drug to be de-blistered. Working in a clinical trial supply chain company, we have experience of hand-processing, manual and semi-automated deblistering machines, choosing the most suitable process for the job. The first type of machine we utilise is a Poppitt dispensing digital aid which uses a single pneumatic punch to remove the tablets. This eliminates the necessity for repetitive thumb movements and awkward seated postures, and reduces the amount of force required to de-blister the tablets, eliminating the musculoskeletal risk. The blister strip is presented one pocket at a time into the machine, and when the tablet reaches the correct position it is automatically popped out of the strip and collected in a tray below. These machines are relatively small, portable and low-cost, and work with many sizes and shapes of blister and drug product. However this is still a slow and labourintensive process and can cause damage to the drug products if they are very friable, and is not recommended for use with capsules, soft gels or tablets with a score mark. These are best suited to small volumes of blisters containing robust tablets as they are quick to set up and do not require lots of specific change parts. A second type of machine we use to improve the de-blistering process is the Sepha press-out manual. This machine can empty tablets and capsules from blister-packs at a rate of up to 20 blisters per minute and is designed for use on small batches of push-through blisters in linear formats. They are portable, easy to set up and run, have a single change part making them very flexible and quickly adjusted, and they are fully cGMP compliant. This machine is best suited in operations which need flexibility for lots of different blister push-through formats. The mechanism is based around a set of rollers which the blisters are fed

86 INTERNATIONAL PHARMACEUTICAL INDUSTRY

through; pressure is then applied to the well of the blister, which forces the tablets through the foil lidding and out of the pack into a collection tray. This machine does not require any electricity or air supply as the rollers are turned by a hand crank. While this machine is quicker than processing by hand or by the single pneumatic punch-style machine, it is still not suited to large runs of blister-packs and can cause damage to some kinds of tablets and capsules. There have also been issues with pieces of foil from the lidding material separating from the pack and falling into the tablet collection tray. This leads to the tablets having to be inspected or passed through a metal detector to ensure that no foil fragments are left in with the recovered tablets. As this is an additional process, the time, number of operators and cost of the job as a whole is increased. A third type of machine, which we have recently purchased, has been designed to eliminate the risk of foil contamination in the recovered tablets and increase throughput for large de-blistering runs. The Pharma Engineering Stripfoil deblistering machine process is built around a highly-specialised adhesive tape. This has the primary function of stripping the aluminium lidding foil from beneath each pocket on the blister, allowing the tablets to be easily removed with very little force. This has the twin benefits of reducing the amount of waste due to damaged drug product and removing the risk of foil contamination in the recovered drug product. The blister strips are fed into the machine using a magazine stacking system, allowing a large number of packs to be prepared quickly and easily. The blisters are then presented to the adhesive tape which pulls them into the drive rollers and across the removal station. The adhesive tape removes the aluminium foil covering the blister pocket

and a second roller then gently pushes the drug product from the back side out of the blister and into a collection bag. The machine is easy to set up and has variable change parts, allowing for a variety of blister sizes, shapes and formats to be processed quickly and efficiently. The machine can run at a rate of up to 60 blisters per minute, making it the perfect tool for large de-blistering jobs. We have run direct comparisons on manual de-blistering and using the three various machines, showing an increase in productivity, reduction in operator health issues and improvement in quality and yield when using the automated options. In fact, we found that the Stripfoil machine was able to run with less than half the staff normally used on a manual run and had a per-shift output more than five times that of the manual process. The Stripfoil machine has been fully validated and has cut lead times and costs on comparator-based trials where we are required to de-blister large numbers of commercially-available drugs prior to the over-encapsulation process. Conclusion We have found that the use of automated machines for the de-blistering process has provided an increase in the quality, yield, speed and efficiency over the traditional hand de-blistering method. Even when the set-up and validation is taken into account, we have been able to shorten customerâ&#x20AC;&#x2122;s timelines and reduce costs based on the increased throughput and reduction in additional quality inspection. However, we are still conscious that hand de-blistering and some of the less automated machine solutions for de-blistering are still the best option when only a very small quantity of blisters is required to be re-worked, and as such, each job should be assessed and the most suitable method of de-blistering should be employed.

Luke Beedle is Sales Support Manager at Sharp Clinical Services Business Intelligence, Marketing, Project Management. Past role include Internal Business Development Manager at PCI - Packaging Coordinators Inc, Estimator / Project Manager at Brecon Pharmaceuticals. Email: luke.beedle@sharpclinical.com Spring 2016 Volume 8 Issue 1


Sharp Clinical Services is a leading provider of specialist clinical packaging and supply chain services. Our experienced team take pride in delivering a personal service on a global scale, caring for your product as if it were our own. The business is managed through a fully integrated SAP system which includes bar-coded stock management and tracking of customer projects. Sharp Clinical Services has a proven track record in managing the entire clinical supply chain and has a Global Depot Network of 18 depots supporting over 25 countries. Services Include: • • • • • • • • •

Over-Encapsulation and Placebo Manufacture Clinical Label Design and Print Clinical Packaging and Labeling EU Qualified Person (QP) Services Interactive Response Technologies (IVRS/IWRS) Comparator Sourcing Returns and Destruction Clinical Storage and Distribution Analytical, Formulation and Manufacturing Services

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Packaging Why do Pharmaceutical Glass Containers Break: The Underestimated Power of Strength Testing and Fractography Most times in our life we use products with little understanding of how and why the packaging was selected. We usually donâ&#x20AC;&#x2122;t think about the design specifications of the container and its crucial role in delivering the contents safely. It is only when a problem occurs that we dig deeper into the selection criteria and science that were used to specify the packaging system. In the pharmaceutical industry, glass is by far the dominant material used for the packaging of liquid and lyophilised drugs due to its impermeability and chemical inertness for drug product stability, transparency for ease of inspection, thermal stability for flexible use and processing, low extractables and leachables, and cost. Nevertheless, glass is not considered as the perfect container because of bias versus other materials (i.e. plastic, metals) with respect to breakage resistance (strength). We all know from our personal lives that glass fails and breaks more easily than plastic, but it is very hard to quantify these properties which give us a nagging sense of uneasiness when handling glass products. Most people have had the experience of replacing a glass incandescent light bulb, gingerly unscrewing the old bulb and screwing in the new bulb with some worries about breaking the bulb. While most people never experience a bulb breakage during proper replacement, that fear is always in the back of the mind from some other unrelated glass breakage event like cracking a wine glass from a drop or impact. For applications where glass is used, unless there is some overwhelming applied force (e.g. a baseball through a window) or extensive pre-damage (e.g. scratches, chips, cracks), glass breakage resistance is significantly higher than what is required in normal use. Despite sporadic breakage events which keep alive the bias, glass packaging is still the predominant primary container for liquid or lyophilised drug products. Investigations into the root cause of glass breakage typically prove human error (i.e. too high applied force, poor processing equipment generating surface defects, manufacturing defects, improper handling) and not inherent material limitation. 88 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Glass Breakage an Industry-wide Annoyance Although glass breakage events occur at every pharmaceutical company, the methods of strength or reliability testing and fracture analysis (fractography) remain relatively unknown and severely under-utilised to determine the root cause of failure and, more importantly, make the necessary changes to reduce future occurrences. Preventing future occurrences is a focus of pharmaceutical companies and regulatory agencies like the FDA. Breakages in the field are reportable events that require clear root cause and corrective actions. Fractography is the science of analysing the macroscopic (i.e. run of cracks) and microscopic (characteristic fracture surface markings) fracture patterns (Figure 1) of cracked or broken objects, to qualitatively and semi-quantitatively determine the root cause of failure. This requires three important components:

Training is usually done through a combination of coursework1,2, textbooks3-6, and steady practice. The equipment required for fractography is a capable stereomicroscope (enabling magnifications between approximately 5x to 150x), different types of illumination sources (reflecting, transmitting), sample dissection equipment like designated cutting tools, sample fixing equipment like putty or tape, specimen holder like a cup stage, tweezers or fine gripping tools, camera for documentation, and access to analytical tools like SEM-EDX for higher magnifications and, in case of foreign material or residue, identification of foreign material found in the vicinity of the fracture origins. Attention to detail and patience are crucial when dealing with samples that may contain many fragments that have to be individually examined and pieced back together, one at a time, to be able to find the root cause. The fractographic steps for determining the root cause of a breakage failure are: 1. collect as much information as possible regarding the history of the container, 2. observe, document, and interpret the macroscopic fracture patterns, 3. observe, document, and interpret the microscopic fracture patterns, 4. propose a consistent conclusion and 5. ensure the conclusion is consistent with all the data available. The success of root cause investigations depends strongly on the amount of information available to the investigator. Especially important for breakage of glass containers is:

Figure 1: Syringe with a damage in the flange section; macroscopic (top) and microscopic (bottom) view onto the fracture surface. 1. an experienced and trained investigator, 2. proper equipment, and 3. patience with attention to detail.

a. where was the container found, b. was the container inspected previous to this point and found to be okay, c. what materials were in contact with the container up to the point of breakage, d. what are the container manufacturing specifications (i.e. drawing, nonconformity allowances, etc.), e. is the breakage event limited to one sample or are other samples available? Spring 2016 Volume 8 Issue 1


Packaging Macroscopic fracture patterns (Figure 2) are the crack and crack branching patterns, visible by eye or with low magnification, which develop due to the momentary mechanical stress Figure 2: state (e.g. due to M a c r o s c o p i c flexural loading, crack branching vertical loading, pattern on a torsional loading, tubular glass vial. internal pressure, thermal stress). Microscopic fracture patterns (Figure 1, bottom) are characteristic surface markings left behind on the fracture surface from the breakage event that confirm location(s) of breakage initiation, direction of breakage (e.g. outer to inner surface, vice versa), instantaneous or delayed breakage (crack propagation interrupted or stepwise), approximate applied mechanical load (only possible if particular fracture surface markings are well-developed), blunt or sharp geometry of impacting object, and slow, subcritical crack growth that leads to time-delayed catastrophic failure. Fractography Example: Manufacturing or Processing Root Cause The power of fractography is best shown by example. SCHOTT pharma services was contracted by a glass converter to identify the root cause of failure for a cracked cartridge that was found after filling with drug product at a pharmaceutical company. The pharmaceutical company had filed a complaint with the glass converter for compensation for delivered pieces. The cartridge is shown in Figure 3, with cracking observed near the shoulder of the cartridge. Figure 4 displays the macroscopic run of the crack. The fracture origin was determined to be

Figure 3: Glass cartridge with cracked tip/shoulder section. www.ipimedia.com

located on the inner surface along with a contamination trace, as can be seen in Figure 5. The identification of the fracture origin on the inner surface along with an observed contamination trace, combined with information from the

syringe (Figure 6). Upon microscopic examination, the fracture origin could not be definitively found, having been blurred or made indistinct (Figure 7). Due to the repeatable positions of the cracks,

Figure 4: Macroscopic fracture pattern of a cracked cartridge; red arrows indicate the breakage propagation directions.

Figure 6: Macroscopic fracture patterns at two locations on a glass syringe; top: close to the syringe cone/shoulder section; bottom: close to the syringe flange section. Figure 5: Close-up view onto the fracture origin vicinity of the cracked cartridge from Figures 3 and 4; the position of the fracture origin coincides with a contamination trace on the inner surface of the cartridge; red arrows indicate the approximate breakage propagation directions. glass manufacturer and pharmaceutical company on contact materials to that inner surface region, resulted in the determination and confirmation that the root cause was due to contact with a washing, siliconisation or filling needle during processing at the pharmaceutical company. Thus, fractography helped to objectively prove the true circumstances for failure of the cartridge and resulted in the pharmaceutical company withdrawing the complaint. A second example came from a customer faced with odd appearance of cracks with no apparent beginning, in the barrel section of many glass syringes from a syringe lot at two repeatable positions on the

their odd appearance, no evidence for impact, Wallner lines3,4 indicating a general direction for the fracture origin but not being able to observe it and knowledge of the syringe manufacturing process, the root cause was determined and confirmed to be due to fused cracks formed from thermal stress during the manufacturing of the syringe flange and cone regions. The result was a justified complaint and a replacement of the syringes by the container manufacturer. Glass Strength: Misperceptions and Facts To understand the breakage behaviour of glass, it is essential to understand some basic concepts of brittle failure: every disturbance of the three-dimensional structure of the glass (e.g. pores, inclusions, cracks or any kind of surface defects) can appear as a concentrator for mechanical loads that may occur or are applied to the glass container (e.g. mechanical loads generated by an impact during glass-to-glass contact, bending, INTERNATIONAL PHARMACEUTICAL INDUSTRY 89


Packaging

Figure 7: Microscopic fracture patterns of two cracked glass syringes (cf. Figure 6). thermal shock, internal or external pressure, vertical load during capping). The magnitude of this load multiplication significantly depends on the position, size and the shape of the disturbance, as well as on the magnitude of the mechanical load. There may be disturbances which act as weak multiplier of applied stresses. Such disturbances can be considered as rather uncritical. On the other hand, there may be also disturbances which act as strong multipliers, which then have to be considered as critical. Now, if the combination of applied mechanical load and criticality of the disturbance reaches or exceeds a particular limit, glass breakage will occur originating from this location. This limit is a material constant and can be thought of as a measure of the “toughness” against breakage (it is actually called “fracture toughness”7). Thus glass breakage can be expressed as the simple equation: GLASS BREAKAGE OCCURS WHEN LOAD x CRITICALITY ≥ TOUGHNESS If none or only one of the two conditions are present (i.e. existence of a critical disturbance but no mechanical load, or mechanical load at positions without disturbances), glass will not break. As a consequence of this fundamental equation of brittle failure, the strength property of glass is not constant, but rather a 90 INTERNATIONAL PHARMACEUTICAL INDUSTRY

projection of its surface quality defined by the criticality of disturbances within its structure. It is then easy to understand that a high surface quality results in a high strength because, according to the equation above, a low criticality allows a high amount of applied mechanical loads until the load multiplication reaches the toughness limit. On the other hand, a low surface quality (equal to flaws or defects of high criticality) results in a low strength because a high criticality allows only a low amount of applied mechanical loads, until the load multiplication reaches the toughness limit. In this context, it has to be admitted that every glass surface contains flaws. Or, in other words, a perfect glass surface without any flaws does not exist. Each handling or processing step may introduce further surface flaws or may enlarge pre-existing ones, which can result in a reduction of the overall strength of the glass. Furthermore, as each individual glass object exhibits a unique surface flaw structure, its resulting strength is also represented by an individual value. As a consequence, a collection of strength values results in a statistical distribution. It is the shape of this statistical distribution which finally can be considered as a representative quantification of the strength of a collection of tested samples. So, as another important fact, “THE STRENGTH OF A POPULATION OF GLASS CONTAINERS CAN BE CONSIDERED AS A PROJECTION OF ITS SURFACE QUALITY AND WHICH HAS TO BE DESCRIBED BY A STATISTICAL DISTRIBUTION.” Such a strength distribution cannot be regarded as being stable, as there are numerous incidences during the lifetime of glass containers which can affect the surface quality of the glass. For instance, for a running production of pharmaceutical products, many process steps are conducted which lower the strength of the primary packaging material due to known or unknown and uncontrolled damages. Typical candidates are static glass-to-glass contacts in accumulation tables, dynamic glass-to-glass contacts due to sudden stops (impacts) at the end of conveying belts, glass-to-metal contacts with parts unintentionally protruding into the conveying path of containers. Without any knowledge of the strength, batches of low quality might enter the field, and complaints about broken containers

may arise, resulting in undesirable consequences such as quarantine of batches, production line shutdown, root cause and corrective action reporting to the FDA. It is an undeniable fact that glass containers normally have much more than sufficient strength for pharmaceutical packaging applications. This is proven billions of time per year, yet while the de-risking mantra of requiring zero container breakage is a worthy goal, the fracture statistics can help to reduce the gap to reality. A good risk management strategy thus would be to regularly test these strength distributions to determine the risk of breakage for each production batch, to keep the risk as low as possible of low-strength containers reaching the market. The determination of the statistical strength distribution of a particular batch of glass containers is the main purpose of such strength investigations. There are myriad challenges confronting pharmaceutical companies when they need to investigate glass strength as part of a breakage investigation. They quickly find out glass container strength is not normally part of the specification, glass strength data per manufactured lot is not provided by the glass manufacturer, and the strength specification for processing, transportation and usage is not known by the pharmaceutical company or contract filler. Adding to the challenge is the variety of strength testing methods available (and needed) to appropriately determine the strength of a given lot of glass. An important factor for the right test method is to mimic the mechanical stress under the application conditions as realistically as possible. Burst pressure testing is appropriate for assessing container strength during lyophilisation and as a general smart method to find the weakest point on the interior or exterior surface of a container. Axial compression testing is appropriate for assessing container strength during stoppering, shipping, and storage. Side compression testing is appropriate for assessing container strength during processing. Bending testing is appropriate for assessing the syringe cone during needle attachment, tip cap removal, and injection. Impact testing is appropriate for assessing container resistance to impact damage. All these destructive tests are designed to determine the location of the fracture origin (i.e. the “weakest” point of the container for a particular load situation). Therefore, strength testing with Spring 2016 Volume 8 Issue 1


Packaging subsequent fractographic investigation to determine the location of the fracture origin is a very powerful combination to determine the strength of a given sample set, the location of the fracture origin, and assess if the observed strength is “normal” or lowered due to a discontinuity or non-conformity. While some industrial standards are established for testing the strength of glass containers (primarily coming from the food/beverage industries)8-10, a few ISO standards have recently been released for prefilled glass syringes11, but none are in force from the major pharmacopeia regulatory bodies (USP12, EP13, JP14). Due to these complexities and the low overall incident rate of glass breakage, the strategy of the pharmaceutical industry today is to forgo strength testing and to assess the criticality of surface flaws/non-conformities (i.e. risk of glass breakage) by using optical/visual inspection with defect manuals. Industry standard defect manuals are available, for instance, from the PDA15, Edito Cantor Verlag16, and the glass manufacturers17. There are numerous non-conformities (scuffs, bruises, checks, cracks, etc.) which classify the criticality with respect to strength and integrity by their visual appearance, mostly by the largest lateral dimension (length, diameter). The danger in this approach is that defect manuals are designed for cosmetic assessment of containers, and the categorisation of non-conformities (disturbances) just by their lateral dimensions cannot provide an assessment to the criticality with respect to container strength, because optical and visual inspection cannot provide the full information required to assess the criticality of a disturbance in terms of strength (e.g. depth, shape, three-dimensional geometry). So judging the criticality of disturbances in terms of strength solely from their optical appearance can lead to misinterpretation, with disastrous consequences: Disturbances of small lateral dimensions might get classified as uncritical, but due to their shape they can turn out to be critical and might lead to breakage in the field. On the other hand, disturbances of large lateral dimensions might get classified as critical, but because of their shape are uncritical. Such batches might then erroneously get rejected or even be destroyed unnecessarily. Appropriate strength testing strategies routinely implemented into production processes can help to lower the risk of www.ipimedia.com

both incidences. The following examples show the usefulness of strength testing to determine the strength of glass containers and answer a variety of questions. SCHOTT pharma services was contracted by a client who was filling a product for clinical trial into vials and during post-fill inspection found approximately 20% of the lot had chatter marks / “scuffs” of varying size which were detected by visual inspection after processing. According to the PDA TR #43 cosmetic defect manual15, a scuff defect is “Minor” or “N/A”. The pharmaceutical company was concerned about risk of breakage at the clinic and contracted strength testing to be done to assess the strength criticality of the scuffs and whether or not the scuffed containers could be safely used or if new material would have to be made. Burst pressure testing was done on 100 samples featuring scuffs, 92 samples without scuffs, and 43 control samples (vials processed but taken out after depyrogenisation). As shown in Figure 8, a graph of breaking pressure on the y-axis versus the number of samples broken on the x-axis showed quite similar distributions, with even a little higher strength for the vials featuring scuffs compared to vials without scuffs. This difference in strength

forming process, shipping conditions and/or the process at the pharmaceutical company. When compared to the control vials which have not yet experienced the process at the pharmaceutical company (Figure 9), there was a significant reduction in strength, demonstrating the effect of glass strength reduction as a function of processing, regardless of

Figure 9: Cumulative failure probability (i.e. total probability of failure for the batch) in dependence on the burst pressure for glass vials with (rejected), without (accepted), and controls (unprocessed).

whether visual defects were observed or not. Strength testing is also invaluable for determining or selecting appropriate containers and/or drive springs for auto-injection devices. SCHOTT pharma services was contracted to perform flange strength testing on glass syringes by a client who wanted to determine and compare the device failure probability when using two different drive springs on three different lots of glass syringes (Figure 10). While performing flange strength experiments with flange support (genuine part) a slow, constant load rate as a destructive lifetime load rate test, all syringes dF/dt exhibited breakage Figure 8: Histograms of breaking strength in a range of forces syringe data of glass vials with (rejected, left) and far above the range without (accepted, right) scuffs. of the application forces. To get was mathematically determined to be an impression statistically significant. Additionally, a fractographic examination on every broken sample from the rejected lot revealed that not a single fracture origin coincided with a scuff. This means that while scuffs indeed represent a cosmetic defect, in this particular case they were proven not to decrease the container strength compared to containers without Figure 10: Scheme of flange strength scuffs. The higher strength of the rejected testing setup (top) and spring force/time containers was supposed to result from profiles (bottom). normal variations of the container hot k109z6

INTERNATIONAL PHARMACEUTICAL INDUSTRY 91


Packaging about the failure probability under real conditions (i.e. under the fast, complex force-time profile of the drive springs, Figure 10, above), a suitable continuous statistical distribution function was fitted to the strength data as a first step. In a second step, the mechanical loads of the true force-time profiles of the two drive springs were transformed to single “equivalent” force values which can be compared to the data of the strength experiments. An estimation of the failureprobability of the syringes under the load of the two different drive springs then is achieved by an extrapolation of the fitted continuous statistical distribution function

Figure 11: Weibull plot (i.e. total probability of failure for the batch versus flange strength) for three lots of glass syringes; the failure probability of each of the three lots under the mechanical load of the two different drive springs can be estimated by extrapolation of the statistical distribution functions fitted to the data (solid straight lines) to the equivalent forces Feq determined for the two drive springs (vertical lines). to the two equivalent force values of the drive springs (Figure 11). A last example demonstrates the effectiveness of root cause analysis and corrective action when combining strength testing with systematic fractographic analysis. SCHOTT pharma services was contracted to perform syringe strength testing on samples before and after a particular processing step that was introducing sporadically-observed surface flaws. The client wanted to know the extent of strength decrease, and whether or not the observed defects were responsible for the strength decrease. Burst-pressure testing of the syringe was conducted (Figure 12) on samples drawn before and after the suspicious process step, showing a statistically significant decrease in strength in the samples after the processing step as well as a narrowing of the strength distribution. Assessment of each syringe after breakage for the location of the fracture origin (Figure 13) found an enlarged population of fracture origins in the flange region after the 92 INTERNATIONAL PHARMACEUTICAL INDUSTRY

be aware of these methods and be able to employ them to address glass breakage events in a cost-effective and timely manner.

Figure 12: Histograms of breaking strength data for glass syringes before (left) and after (right) process step; solid lines represent statistical distribution functions fitted to the data. processing step (indicating the creation of additional surface flaws), as well as a second large population in the shoulder region in the lower strength regime as was found in the samples before the step. So the combination of systematic strength testing, in combination with fractographic examination, was able to reveal damage mechanisms on the outer surface in the flange and the shoulder section of the syringes. With this type of insight into processes, appropriate corrective and preventive actions were suggested to be applied to eliminate severe damage mechanisms and thus

References 1. SCHOTT pharma services two day on-site fractography training courses, http://www.us.schott.com/pharma_ services/english, accessed October 30, 2015. 2. SCHOTT pharma services two day training courses at laboratory centers, http://www.us.schott.com/pharma_ services/english, accessed October 30, 2015. 3. Fréchette, V.D. Failure Analysis of Brittle Materials, Advances in Ceramics, Volume 28 (1990). 4. Quinn, G.D. Fractography of Ceramics and Glasses, NIST Special Publication 960-16 (2007). 5. Varner, J.D. Fractography of Glasses and Ceramics VI, Ceramic Transactions 230 (2012). 6. Bradt, R.C. Fractography of Glass, Plenum Press (1994). 7. Lawn, B.L. Fracture of Brittle Solids – Second Edition, Cambridge University Press (1993). 8. DIN EN ISO 7458: “Glass containers — Internal pressure resistance — Test methods”; May 2004. 9. DIN EN ISO 8113: “Glass containers — Resistance to vertical load — Test method”; May 2004. 10. DIN 52295: “Testing of glass — Pendulum impact on containers — Testing by attributes and by variables”; March 2010. 11. ISO 11040 4: Prefilled syringes — Part 4: Glass barrels for injectables and sterilized subassembled syringes ready for filling; April 2015. 12. United States Pharmacopeia 39-National Formulary 34, November 2, 2015. 13. European Pharmacopeia 8.8, January 1, 2016. 14. Japanese Pharmacopeia 24, March 24,2011. 15. PDA Technical Report #43, Identification and Classification of Nonconformities in Molded and Tubular Glass Containers for Pharmaceutical Manufacturing: Covering Ampoules, Bottles, Cartridges, Syringes and Vials, Revised 2013. 16. Defect List for Containers made out of Tubular Glass, Edito Cantor Verlag, 2009. 17. SCHOTT pharmaceutical systems glass vial and glass syringe defect manuals, available upon request.  

Dr. Dan Haines Scientific Advisor for SCHOTT pharma services, earned his doctorate in Inorganic Chemistry at the University of Chicago. He joined SCHOTT in 2001 with a focus on developing glass coatings to control drug formulation interactions with glass surfaces. Since 2010 he is responsible for SCHOTT pharma services in North America providing analytical support of packaging material for pharmaceutical companies. E-Mail: daniel.haines@us.schott.com

Figure 13: Axial fracture origin position y (y=0 mm measured from top of the flange) vs. burst pressure data of glass syringes before (filled circles) and after (filled squares) process step. successively improve the strength of the product. Conclusion Strength testing methods in combination with fractographic investigations and appropriate evaluation procedures are available to provide the pharmaceutical industry the methodology for determining the root cause and help in identifying effective corrective actions for glass breakage events during processing, filling, shipping, or during administration. Every pharmaceutical company should

Dr. Florian Maurer, Senior Scientist for Strength and Fractography at SCHOTT, Inc., earned his doctorate in Materials Science and Engineering at Darmstadt University of Technology, Germany. He has been with SCHOTT for over nine years with his focus on strength, reliability and fracture analysis of primary packaging containers used in the pharmaceutical industry. His expertise is requested worldwide for onsite trainings, consulting services and contributions to publications. E-Mail: florian.maurer@schott.com Dr. Uwe Rothhaar Director of SCHOTT pharma services earned his doctorate in Physics at the University of Kaiserslautern in Germany. He joined SCHOTT in 2000 and focused his activities on analytical support around glass and glass surfaces. Over the last years he is responsible for SCHOTT pharma services providing analytical support of packaging material for pharmaceutical companies. E-Mail: uwe.rothhaar@schott.com

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