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Volume 6 Issue 3

Peer Reviewed International Pharmaceutical Industry

Supporting the industry through communication

Regulatory Scenario of Herbal Medicines A Global Review Key Considerations for Conducting Clinical Trials in Idiopathic Pulmonary Fibrosis Device Design Is Driving Innovation Impact of Sterilisation Method On Packaging Component Machinability Performance

Contents 06 Editor’s Letter REGULATORY & MARKETPLACE

International Pharmaceutical Industry

Supporting the industry through communication

DIRECTORS: Martin Wright Mark A. Barker EDITOR: Cecilia Stroe EDITORIAL ASSISTANT Orsolya Balogh BOOK MANAGER: Anthony Stewart BUSINESS DEVELOPMENT: John Unikowski DESIGN DIRECTOR: Fiona Cleland CIRCULATION MANAGER: Dorothy Brooks FINANCE DEPARTMENT: Martin Wright RESEARCH & CIRCULATION: Heather Bayran 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: 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 December 2014. 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. 2014 PHARMA PUBLICATIONS Volume 6 issue 3 - Autumn - 2014

08 Regulatory Scenario of Herbal Medicines: A Global Review In the last few decades there has been exponential growth in the field of herbal medicine and regulation of herbal medicines has become key to ensuring the safety, efficacy and quality of herbal medicinal products. In their paper, Balamuralidhara V., Shilpi Khattri, Vandana K. and T. M. Pramod Kumar of JSS College of Pharmacy, JSS University, Mysore discuss in detail herbal drugs regulations in India, providing also an overview of the regulatory status of herbal medicine in the USA, Australia and Europe. 18 The Interim Exec Community calls for a ‘Conscious Coupling’ of RPOs and Interims Specialists Pharmaceutical companies have widely adopted strategies to outsource elements of their business operations, as part of an ongoing drive to deliver a more flexible model that unlocks cost efficiencies and alleviates some aspects of risk associated with drug development. As Dafydd Wright, Director of Interims of RSA, explains, recruiting talent is one such element. However, pharmaceutical companies should be wary of saving on recruitment at the risk of missing out on the best candidates, particularly when it comes to senior staff. 22 The 3E Principle: Key Considerations for Selecting and Outsourcing to a Vendor Influenced by forces such as macroeconomics, politics, regulations, population growth and aging, there has been a major shift in the way biopharmaceutical companies conduct business. There is everincreasing pressure to comply with evolving regulations along with cost reductions in order to grow business. Dr Chitra Lele of Sciformix Corporation outlines the “3E Principle” of Effectiveness, Efficiency and Economics; key parameters organisations should consider when selecting an outsourcing partner to assist with knowledgebased activities in drug development and post-marketing stages of the product lifecycle. 28 Funding Options for R&D in the Life Sciences Sector Typically, funding for R&D and business growth has been hard to secure over previous years due to the financial crisis. However, now that the financial uncertainty is passing, there is a definite sense of increased confidence in the economy with funding options returning and becoming more readily available and accessible to life sciences businesses. Nigel Greenaway and Laura Herdman of Greenaway Scott discuss the various funding options available and the positive impacts and initiatives these bring to businesses in the life sciences industry. 34 Global Tracking Regulations Present Challenges and Benefits Lars Hoejberg of NNIT looks into serialisation, the foundation of any tracking system. Drug makers are facing an ever-increasing challenge as more countries implement serialisation and tracking regulations and set compliance deadlines, in an effort to ensure the safety and quality of prescription drugs being sold within their borders. Complying with regulations coming into effect will be a demanding task due to a lack of global harmonisation. 42 Get Ownership of your IP Right; Otherwise it can Turn into a Nightmare! When filing a patent application, there are lots of things to consider. Most of the attention is directed towards getting the disclosure of the invention right and ensuring that you have adequately covered your commercial product/concept to prevent your competitors from entering the market space. Jenny Donald of Forresters warns that too often, little thought is given to who actually owns the invention. And if you get this wrong, it can be incredibly difficult to rectify the situation at a later stage.


Contents DRUG DISCOVERY, DEVELOPMENT & DELIVERY 48 The Respiratory Drug Delivery Asia 2014 – A Preview The Respiratory Drug Delivery (RDDŽ) Asia 2014 scientific conference will welcome pulmonary and nasal drug delivery experts from all over the world to Goa, India from November 12-14, 2014. 50 Device Design is Driving Innovation Devices are playing an increasingly important role in medicine. Medical devices offer innovative examination and treatment options and drug delivery devices permit precise, customised and intelligent therapies. New drugs with innovative active ingredients are being launched in conjunction with equally innovative delivery devices, and Peter Wallrabe of Gerresheimer Medical Plastic Systems tells us why the development of innovative drugs goes hand-in-hand with the development of equally innovative drug delivery devices that guarantee stability, optimise bioavailability and ensure the necessary precision of dosage. 54 Improving Study Design in Diabetes Drug Development using Predictive Analytics Diabetes mellitus is a serious disease that arguably has reached global epidemic proportions. In their paper, Denise F. Messer, Claudia De Oliveira, Xiaoqiang Xue, Rick Turner and Erica Caveney of Quintiles scrutinise how predictive analytics can facilitate more efficient study designs in development programmes for new antidiabetic drugs for type 2 diabetes mellitus (T2DM), with


a brief recap of the essentials of the FDA and EMA guidelines and an account of how the drug development landscape has changed within the last decade or so. 66 How can Pharma Develop Paedriatic Medicine? In the evolving healthcare landscape, the key areas of patient engagement, education and empowerment are only just starting to be scrutinised in paediatric medicine. Dr Kate Hersov, UK CEO and Co-Founder of Medikidz discusses the many as-yet unexplored opportunities for the pharmaceutical industry to become established leaders in driving innovation in these areas. With a history of driving innovation through new approaches, the pharmaceutical industry is ideally placed to support healthcare professionals with new initiatives to provide engaging and appropriate educational tools for use with young patients. 72 Smart Pills for Oral Drug Delivery It seems that there are smart products of one sort or another everywhere we look, with new devices and models constantly being introduced. A smart pill is an ingestible capsule with miniaturised micro-electronics and may be used in a wide range of applications from use as a smart tool in drug development to a key element in a smart connected care environment. Jeff Shimizu of Medimetrics explains that this emerging technology presents significant opportunity for the pharma industry to exploit modern digital innovations and take a lead position in the future of healthcare.

Autumn 2014 Volume 6 Issue 3

SWISS 째Celsius Passive For your temperature sensitive supply chain


Contents possible applications. Fluid-bed technology opens up an enormous range of possibilities for optimising products – from better solubility, dust reduction, easier tabletting and fortification with vitamins to microencapsulation of active ingredients. Very gentle handling of the products and the diversity of the possible applications have made fluid-bed processing one of the most important formulation methods in the food and pharmaceutical industries. 102 Accelerating the Development of Generic Pharmaceuticals: Developing an Analytical Toolkit Suitable for De-Formulating Complex Reference Products In its report “Critical Path Opportunities for Generic Drugs”, the FDA emphasises the need for advances in the field of analytical sciences in order to accelerate the development of generic products. Here, Paul Kippax of Malvern Instruments highlights techniques that are especially helpful in the de-formulation of complex reference products, focusing on triple detection Size Exclusion Chromatography (SEC) and Morphologically-Directed Raman Spectroscopy (MDRS).

CLINICAL & MEDICAL RESEARCH 76 Key Considerations for Conducting Clinical Trials in Idiopathic Pulmonary Fibrosis Idiopathic pulmonary fibrosis (IPF) is a form of chronic, progressive fibrosing interstitial pneumonia that is of unknown cause, occurring primarily in older adults. The prognosis is extremely poor, with an average survival of two to three years following diagnosis. While the number of clinical trials in this area has increased in recent years, there remains an urgent and unmet need for new therapies. Vikki Brandi and Juan Gispert of Quintiles aim to identify key methodological, practical, and ethical issues involved in IPF clinical trials, focusing on country and site identification, feasibility, and study design. LABS AND LOGISTICS 88 Clinical Trial Logistics – Meeting the Needs of an Evolving Pharmaceutical Industry The management of clinical trial distribution has changed very much as a result of changes in the wider pharmaceutical industry. Martin Lamb of Biotec Services International discusses how this service has developed, and drivers for some of the change. While the management of the clinical supply chain is a critical part of drug development, it can be viewed as a high-cost, low-valueadding component of drug development for a pharma company to take on single-handed. But external clinical supply specialists, by spreading this cost over multiple sponsors, have been able to invest in improving distribution models to provide a truly global clinical trial supply chain. 94 Thermal Packaging and Good Distribution Practice: A Natural Fit? From the perspective of the thermal packager it has always been best to assume that whatever can go wrong will go wrong, and that however simple and user-proof the packaging, people will still find a way to do something bizarre with it. Katie Friday of Tower Cold Chain Solutions argues that the advent of the new guidelines is therefore to be welcomed, since they place a very considerable onus on all parties to comply with what are largely well-thought-out and sensible provisions. Beyond this, potentially, they spell an end to a period of significant frustration. MANUFACTURING 98 Tailor-made Product Attributes Mark Riemer of SternMaid GmbH & Co.KG explores fluid-bed technology, a formative drying process enabling a specific influence on the physical properties of solid and liquid products and their 4 INTERNATIONAL PHARMACEUTICAL INDUSTRY

110 When Two is Better than One: The Benefits of Two-Floor Production Facilities for Future-Proof Manufacturing Capability The impact of batch transfer methods on the ‘Lean success’ of a plant is starting to be recognised earlier in the plant design process. Before deciding on building and process room heights, proper attention must be given to materials handling processes. A singlefloor facility design is simply not flexible enough, and a multiplefloor plant could well be too expensive. A two-floor facility is a good compromise as it provides good agility for future demands with a modest investment requirement. Wim Spook of Matcon looks into the pros and cons of these different facility designs, exploring the benefits to the future requirements of the business. 114 Small Changes to Tablet Shape Bring Big Results Tablet shape is generally given the most consideration as new products are branded by marketing departments, whereas whole campaigns have been built around a tablet’s colour or shape. Dale Natoli of Natoli discusses the importance of considering the potential of small adjustments to tablet shape to influence everything from production efficiency to consumer acceptance. An improper tablet design can cost millions in lost production and possibly lead to a disastrous product launch. PACKAGING 118 Gentlewing: The Name Says It All Implementing innovations in the pharmaceutical market is an ambitious task. In an industry that requires precise and reproducible results, changes to current systems always involve certain challenges. According to Dr Marcus Knöll of Bosch, an external study can provide certainty, which was the case with the uniquely shaped 'Gentlewing' mixing device from Hüttlin GmbH, a subsidiary of Bosch Packaging Technology, based in Schopfheim, Germany. A study conducted by the University of Mainz, Germany, confirmed that the special design of the device offers several advantages to users – while achieving the same processing results as a conventional mixer. 122 Impact of Sterilisation Method on Packaging Component Machinability Performance: Steam vs. Gamma Evaluation of the 1ml Long Plunger The machinability of parenteral packaging components is recognised to have a significant influence on productivity of the drug product manufacturing process. As Simon Côté of West Pharmaceutical Services explains, there are various processes that can be used for washing and sterilising elastomers for aseptic fill, and depending on conditions of processing, the physical and functional characteristics of the component will be altered to some degree. In this case study, elastomeric components intended for aseptic processing are considered with respect to machinability on a lab-scale filling line. Autumn 2014 Volume 6 Issue 3



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Editor's Letter IPI`s Autumn issue is all about the pursuit of innovation. The process of innovation stems from an array of interconnected areas. Discover how making smart use of modern digital innovations might bring a revolution in healthcare.

Device design drives innovation and Peter Wallrabe of Gerresheimer Medical Plastic Systems warns that the development of a new device - from the initial idea to a small production run for clinical tests - is a demanding process as a result of the complex technological, design and regulatory issues involved.

Increasing competition, reimbursement concerns and expiry of blockbuster patents are putting the pharmaceutical industry under a lot of strain to move away from entrenched business practices, according to Jeff Shimizu of Medimetrics. Since pharma has already shifted its focus from pills to outcomes, and there is recognition of the role of the many factors beyond the direct action of the drug, those companies that can successfully combine drugs, devices, and technology to bring about better outcomes will be rewarded. Let the era of smart healthcare begin!

Experts say the old model of the pharmaceutical blockbuster is gone. Scrutinising the FDA`s report, Critical Path Opportunities for Generic Drugs, Gurfateh Singh and Paul Kippax of Malvern Instruments note that while the development pathways for generic and innovator drugs have much in common, there are also some critical distinctions to be taken into account. Commercialisation of a generic begins with de-formulation, the unpicking and rationalisation of those innate qualities of the reference listed drug (RLD) that deliver its performance. But as innovators push the boundaries of pharmaceutical product engineering and pharmaceutical products become ever more sophisticated, deformulation becomes even more strenuous. With increasingly complex RLDs, formulation scientists working on generics now need even better characterisation technology than was used for the innovator product.

The pace of innovation seems to be indeed speeding up. The biopharmaceutical industry is driving unprecedented progress in drug discovery and development, and innovation in drug delivery devices is needed for novel pharmaceutical compounds. But novel active ingredients used to manufacture essential pharmaceuticals are associated with new packaging and administration challenges. Their vastly more complex molecules have to be packaged differently and dosed more precisely than their humble predecessors. That’s why new drugs with innovative active ingredients are being launched in conjunction with equally innovative delivery devices.

Embracing innovation can also mean the chance to prompt a competitive advantage through the use of innovative business practices. Looking into the overall trends seen in outsourcing, Dr Chitra Lele of Sciformix Corporation addresses the opportunities and challenges raised by today’s marketplace, in

which no corner of the biopharmaceutical business (regardless of the “postcode”) remains unaffected by the pressure to increase the compliance and quality of products, whilst simultaneously improving on productivity and making significant cost cuts. A critical part of drug development is the management of the clinical supply chain. According to industry forecasts, clinical trial logistics spend will reach this year $2.99 billion, rising to $3.16 billion by 2018. Talking about the use of IRT technology to control overages and waste in clinical studies, which is becoming more critical as unit dose costs for new drugs continue to rise, Martin Lamb of Biotec Services International foresees that, in fact, the advent of mobile technology and lower-cost fully-configurable IRT systems is likely to increase the number of trials employing this technology. There is no sign whatsoever that biopharmaceutical development will slow down - quite the contrary - and in order to control increased costs and risks associated with the future developments, pharma needs to choose wisely between investing in expertise and assets internally, or working strategically with external partners to ensure the supply chain is efficiently cared for. Cecilia Stroe Editor Come and Visit us at CPHI/ICSE – Stand 3D35 7th – 9th October 2014 Paris Nord Villepinte, France

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

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

Catherine Lund, Vice Chairman, OnQ Consulting

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

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

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

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

Autumn 2014 Volume 6 Issue 3


Regulatory & Marketplace

Regulatory Scenario of Herbal Medicines: A Global Review Abstract In the last few decades, there has been exponential growth in the field of herbal medicine. It is becoming popular in developing as well as in developed countries owing to its natural origin and lesser side-effects. The growing use of botanicals is forcing moves to evaluate the health claims of these agents and to develop standards of quality and manufacture. Regulation of herbal medicines is a key means of ensuring safety, efficacy and quality of herbal medicinal products. This paper aims to facilitate the registration and regulation of herbal medicines by establishing the foundation of a harmonised regulatory standard to meet common demands of a region. Herbal drugs regulations in India are discussed in detail, followed by an overview of the regulatory status of herbal medicine in the USA, Australia and Europe. An overview and a comparison have been laid out to highlight the similarities and differences. Key words: Herbal Medicine, Traditional Medicine, Alternative Medicine, Complementary Medicine. Introduction Although modern medicine is welldeveloped in most of the world, large sections of the population in developing countries still rely on traditional practitioners, medicinal plants and herbal medicines for their primary care. Traditional Indian medical systems such as Ayurveda and Unani also rely heavily on plant products, and in the United States it has been estimated that 30% of patients now use herbal remedies1, 2, 3. Herbal medicines, which formed the basis of healthcare throughout the world since the earliest days of mankind, are still widely used, and have considerable importance in international trade. Recognition of their clinical, pharmaceutical and economic value is still growing, although this varies widely between countries4. Medicinal plants are important for pharmacological research and drug development, not only when plant constituents are used directly as therapeutic agents, but also as starting materials for the synthesis of drugs or as models for pharmacologically active compounds. Regulation of exploitation 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and exportation is therefore essential, together with international cooperation and coordination for their conservation so as to ensure their availability for the future5. The legal situation regarding herbal preparations varies from country to country. In some, phytomedicines are wellestablished, whereas in others they are regarded as food and therapeutic claims are not allowed. Developing countries, however, often have a great number of traditionally used herbal medicines and much folk-knowledge about them, but have hardly any legislative criteria to establish these traditionally used herbal medicines as part of the drug legislation. For the classification of herbal or traditional medicinal products, factors applied in regulatory systems include: description in a pharmacopoeia monograph, prescription status, claim of a therapeutic effect, scheduled or regulated ingredients or substances, or periods of use. Some countries draw a distinction between "officially approved" products and "officially recognised" products, by which the latter products can be marketed without scientific assessment by the authority5. The various legislative approaches for herbal medicines fall into one or other of the following categories5: • •

• •

• •

Same regulatory requirements for all products; Same regulatory requirements for all products, with certain types of evidence not required for herbal / traditional medicines; Exemption from all regulatory requirements for herbal / traditional medicines; Exemption from all regulatory requirements for herbal / traditional medicines concerning registration or marketing authorisation; Herbal / traditional medicines subject to all regulatory requirements; and Herbal / traditional medicines subject to regulatory requirements concerning registration

or Marketing authorisation.

Where herbal medicines and related products are neither registered nor controlled by regulatory bodies, a special licensing system is needed which would enable health authorities to screen the constituents, demand proof of quality before marketing, ensure correct and safe use, and also to oblige license-holders to report suspected adverse reactions within a post-marketing surveillance system6. Challenges Countries face major challenges in the development and implementation of the regulation of traditional, complementary / alternative and herbal medicines. These challenges are related to regulatory status, assessment of safety and efficacy, quality control and safety monitoring. Challenges Related to the Regulatory Status of Herbal Medicines Before manufactured drugs came into widespread use, herbal medicines played an important role in human health. There are great differences between countries in the definition and categorisation of herbal medicines. A single medicinal plant may be defined as a food, a functional food, a dietary supplement or a herbal medicine in different countries, depending on the regulations applying to foods and medicines in each country. This makes it difficult to define the concept of herbal medicines for the purposes of national drug regulation, and also confuses patients and consumers. Lack of Knowledge About Herbal Medicines Within National Drug Authorities: The general lack of knowledge about herbal medicines within national drug authorities and the lack of appropriate evaluation methods are factors that delay the creation or updating of national policies, laws and regulations for traditional medicines, contemporary / alternative medicines and herbal medicines. In order to meet these challenges, the WHO Traditional Medicine Strategy was developed, with its four primary objectives: framing policy; enhancing safety, efficacy and quality; ensuring access; and promoting rational use. Autumn 2014 Volume 6 Issue 3

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Regulatory & Marketplace Resolution WHA56.31 on traditional medicine was adopted at the Fiftysixth World Health Assembly in May 2003. The resolution requested WHO to support Member States by providing internationally acceptable guidelines and technical standards, and also evidence-based information, to assist Member States in formulating policy and regulations to control the safety, efficacy and quality of traditional medicines. Herbal Drug Regulations in India In the Republic of India, the national policy on traditional medicine (TM/ CAM) was introduced in 1940. National laws and regulations were also issued in 1940, and updated in 1964, 1970 and 1982. The national programme was issued in 1964. The national office, the Department of Medicine and Homeopathy, was established in 1995 as part of the Ministry of Health and Family Welfare. Herbal drug products constitute a major share of all the officially recognised systems of health in India, viz. Ayurveda, Yoga, Unani, Siddha, Homeopathy and Naturopathy, except Allopathy. The IMCC (Central Council of Indian Medicine) Act, Research Councils Indian Council of Medical Research (ICMR), Council for Scientific & Industrial Research (CSIR), Department of AYUSH (Ayurveda, Yoga & Naturopathy, Unani, Siddha and Homoeopathy) and the Drugs and Cosmetics Act 1940 (Amendment) regulate herbal medicines in India. Herbal remedies and medicinal plants to be incorporated in modern systems (allopathic) must follow the Drug Controller General of India (DCGI’s) regulations of the Central Drug Standard Control Organization (CDSCO). As per Drugs and Cosmetics Act 1940 amended in 1964, “Ayurvedic, Siddha or Unani drug includes all medicines intended for internal or external use or in the diagnosis, treatment, mitigation or prevention of disease or disorder in human beings or animals, and manufactured exclusively in accordance with the Formulae described in the authoritative books of Ayurvedic, Siddha and Unani (Tibb) systems of medicine, specified in the First Schedule”7. Herbal medicines are regulated as prescription and over the counter (OTC) medicines and dietary supplements. Herbal medicines may be sold with medical, health and nutrient content claims. India has two multi-volume 10 INTERNATIONAL PHARMACEUTICAL INDUSTRY

national pharmacopoeias, the Ayurvedic pharmacopoeia of India and the Unani pharmacopoeia of India. Both are considered to be legally binding. Regarding national monographs, several sources are used, including a national database on medical plants used in Ayurvedic medicine and monographs contained in the national pharmacopoeias. Recent amendments in Drugs and Cosmetics (First Amendment) Rules 2008 have introduced Schedule T for recording utilization of raw materials by Ayurvedic or Siddha or Unani licensed manufacturing units. Drugs and Cosmetics (Second Amendment) Rules 2008 permitted the use of excipients given in the Indian Pharmacopoeia or Bureau of Indian Standards Act 1986 or the Prevention of Food Adulteration Act 1954 and Food Products Order for use in Ayurvedic, Siddha and Unani drugs. Good clinical practice (GCP) guidelines published by ICMR also pertain to traditional drugs. According to these guidelines, traditional herbal medicines have been classified into three groups: 8 1. Traditional herbal drugs as per classical texts, regular use and prescribed pharmacopoeia Reverse pharmacology approach 2. Traditional formulations for a new indication / new process / new combination / new herbal- or plantbased new chemical entity (NCE) – acute, sub-acute and chronic toxicity data to be generated (Schedule Y of Drugs & Cosmetics Act, 1940) 3. Formulations – GMP-compliant Standardization Department of AYUSH, ICMR and CSIR Work together to achieve safe, effective AYUSH products for the identified diseases and to develop new drugs. No control mechanism is used for these requirements, as the long-standing use of herbal medicines in the Ayurveda, Unani and Siddha systems demonstrates their safety for human use. There are 4246 registered herbal medicines. Essential drug lists exist separately for the three systems of traditional medicine in India; the Ayurveda list has 315 herbal medicines on its essential drug list, the Unani list has 244 herbal medicines and the Siddha list has 98. These lists were issued in 2000 and 2001 respectively.

There are currently plans to establish a post-marketing surveillance system. In India, herbal medicines are sold in pharmacies as prescription and over the counter medicines, in special outlets, by licensed practitioners and without restriction. Annual herb sales figures, based on sales of 162 medicinal plants between 1999 and 2000, were estimated at 6705 million Indian rupees (US$ 149 million)9. AYUSH objectives are to control drug quality, laying down pharmacopoeial standards, overseeing working of the Pharmacopoeial Laboratory of Indian Medicines (PLIM), partnership with the Quality Council of India (QCI), and to oversee functioning of the Indian Medicine Pharmaceutical Company Limited (IMPCL). AYUSH also controls enforcement of good manufacturing practices (GMP), setting up of common facilities following the cluster approach and implementing the scheme for drug quality control. With the advent of an intellectual property rights (IPR) regime, AYUSH department has also started digitalisation of traditional medicinal formulations, knowledge and manuscripts, and documentation and promotion of local health traditions. The National Medicinal Plants Board (NMPB), Department of AYUSH has prepared India-specific guidelines on good agriculture practices (GAPs) on the pattern of good agriculture and field collection practices (GAFCPs) developed by the WHO for medicinal plants. In the preparation of this standard, assistance has been taken from GAFCPs developed by the WHO in 2003 and good agricultural practices enunciated by the GlobalGAP Secretariat, which is being implemented in over 80 countries. The standard provides requirements for good field collection practices on different aspects for harvesting and postharvest management of medicinal plants. Adoption of organic and good agriculture and collection practices is expected to lead to better resource management by sensitising farmers, growers and other stakeholders.

Autumn 2014 Volume 6 Issue 3


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The site currently boasts over 1,300 researchers, 120 academic clinicians, 960 inpatient beds, 15 on-site companies, an MHRA accredited Phase I clinical trials suite, a clinical research imaging centre housing CT/MRI/PET scanners, a GMP cell therapy manufacturing facility and an NHS clinical service laboratory. There are also three MRC Centres on site specialising in Reproductive Health, Inflammation Research and Regenerative Medicine as well as a BHF Centre for Cardiovascular Medicine. Future plans for the site include the construction of the Edinburgh Sick Children’s Hospital, which will provide an additional 600 patient beds and a paediatric clinical trials suite, and the Department of Clinical Neurosciences, both scheduled to open in 2017. Plans are also being

taken forward for further university research institutes, a second multi-occupancy building for companies wishing to locate on the site as well as on site hotel and conferencing facilities. The BioQuarter Commercialisation Team, established in 2010, has since created more than 10 new life science businesses and successfully negotiated industrial collaborations in excess of £20 million. The team actively encourage the generation of new ideas and its Annual Innovation Competition has generated more than 150 novel product or business concepts.

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Regulatory & Marketplace Route of Evaluation and the Registration Process: Applications for the registration of complementary medicines are made via the Over‐the Counter Medicines Electronic Lodgement System (OPAL) and the dossier is sent to the OCM. After the appropriate fees are paid, applications pass through four or five phases: pre‐ assessment, evaluation and peer review, possible consideration by the Advisory Committee on Complementary Medicines (ACCM), decision and, if acceptable, implementation.

Applicable laws: Drugs and Cosmetics Act, 2008 (DCA) Drugs and Cosmetics Rules, 1945 (DCR) Drug (Prices Control) Order, 1995 Drugs (Magic Remedies) Objectionable Advertisement Act, 1954Pharmacy Act, 1948. Marketing Authorisation Approval Process A flowchart for the process is shown in Figure 1.

and homoeopathic products. Complementary medicines may be either listed or registered, depending on their ingredients and the claims made. Australia has a risk-based approach, with a two-tiered system for the regulation of all medicines, including complementary medicines: • •

Lower-risk medicines can be listed on the Australian Register of Therapeutic Goods (ARTG). Higher-risk medicines must be registered on the ARTG.

Some complementary medicines are exempt from the requirement to be included on the ARTG, such as certain preparations of homoeopathic medicines10. Eligibility for Registration as a Complementary Medicine: Before submitting an application for registration of a complementary medicine, it is first necessary to establish that the product contains substances that are, in fact, complementary medicine substances.

Herbal Drug Regulations in Australia: They are termed as complementary medicines (also known as 'traditional' or 'alternative' medicines) and include vitamin, mineral, herbal, aromatherapy 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Essentially, if the substance is a designated active ingredient, that has an established identity and tradition of use, it is a complementary medicine substance. The Office of Complementary Medicines (OCM) also evaluates excipients that are used in complementary medicines and substances referred to the OCM by other regulatory areas in the TGA.

Pre‐assessment involves a brief review of the application data to determine whether the application is eligible for evaluation by the OCM. The pre‐ assessment process also determines whether the appropriate fees have been paid and whether key data have been provided. Applications passing pre‐assessment move to the evaluation phase. The submitted data are evaluated and a report of the findings is prepared. Evaluation reports are reviewed within the OCM to ensure consistency in evaluation. Comment may be sought from the ACCM which may make a recommendation to the Delegate of the Secretary of the Department of Health and Ageing. The Delegate assesses the evaluation report and any ACCM recommendations before deciding on the application. Relevant Regulatory Requirements: A number of important regulatory requirements relate to applications for registration of complementary medicines, including the following: 1. The Therapeutic Goods Act 1989 2. The Therapeutic Goods Regulations 1990 3. Therapeutic Goods Orders (TGOs) 4. The Therapeutic Goods Advertising Code (TGAC) Registration: 1) Lodgement: Applications for new registered complementary medicines are lodged electronically using the online application system currently used for registered OTC medicines. The submission of the data dossier remains the same ‐ the applicant is still required to submit a hard copy of the dossier to the OCM. 2) Pre-assessment of Registration Applications: There are three possible outcomes of the Autumn 2014 Volume 6 Issue 3

Regulatory & Marketplace pre‐assessment process:

discussed with the sponsor.

The Australian Register of Therapeutic Goods (ARTG) entry on the provisional record will be amended, if necessary, and the letter and its attachments will be sent to the sponsor. The sponsor will then advise the TGA of any necessary corrections to the provisional record and return the letter and its attachments to the ARTG entry officer, who will then issue a final certificate of Registration11 as in Fig 2.

The Therapeutics Good Administration (TGA) may reject the application if there are profound deficiencies, if no fees have been paid, if the medicine is not a complementary medicine or if the medicine is required to be in the Register for Listed Goods. The TGA may grant conditional acceptance where additional fees or additional significant information is sought and the evaluation cannot proceed until the fees are paid or the information is supplied. The TGA may accept the application where there are no obvious deficiencies, or only minor deficiencies that are not considered significant enough to prevent evaluation, and all fees are paid. The application then proceeds to the evaluation stage.

5) Finalising Registration Following ACCM Consideration: Recommendations from the ACCM and any other recommendations or information from the TGA will be taken into consideration by the appointed delegate of the Secretary of the Department of Health and Ageing. The delegate will make a decision on the application. A letter will be sent, formally advising the sponsor of the outcome of the application. If there are any conditions placed on the registration of the new complementary medicine, the sponsor will be notified of them and they will be

European Directive 2004/24/EC has taken full effect on 30th April 2011; it is illegal for companies to sell manufactured unlicensed herbal medicines within Europe without the appropriate licence i.e. a marketing authorisation (MA) or a traditional herbal registration (THR). The UK differs slightly from the rest of Europe in that herbal practitioners were regulated as from April 2012, allowing for unlicensed manufactured herbal medicines to be prescribed following a face-to-face consultation. There are several different routes to market for herbal products within Europe: •

3) Evaluation: In the evaluation stage, the quality, safety and efficacy of the product are critically evaluated and an evaluation report is produced. 4) Advisory Committee for Complementary Medicines (ACCM): The ACCM is constituted under Regulation 39 of the Regulations. Evaluation reports on most registration applications for complementary medicines are presented to the ACCM for consideration and recommendation to the TGA. Sponsors have the opportunity to provide written comment on the evaluation report prepared by the OCM. Sponsors will be sent a copy of the evaluation report and must respond within the given timeframe (usually five working days).

are therefore not classified as herbal medicinal products12.

• • • •

Herbal Drug Regulations in the EU: According to Council Directive 65/65/ EEC, which has been implemented into national law in all Member States, medicinal products require prior marketing approval before gaining access to the market. In almost all Member States, herbal medicinal products are considered as medicinal products. As such they are in principle subject to the general regulations for medicines as laid down in the various national medicines laws. This definition is in line with the EU Guideline "Quality of Herbal Remedies" (now replaced by "Quality of Herbal Medicinal Products"). It includes plants, parts of plants and their preparations, mostly presented with therapeutic or prophylactic claims. Different categories of medicinal products containing plant preparations exist or are in the process of being created. For instance, draft legislation in Spain includes the definitions “herbal medicinal products” and “phytotraditional products”. The latter are however not considered as “pharmaceutical specialties” and

Food (functional food, novel foods, dietary food for special medical purpose, foods for particular nutritional use – PARNUTS, food supplement), Cosmetic, Traditional herbal medicinal product (THMP), Medicine for human use (wellestablished use, full marketing authorisation), or Veterinary product.

It is important, therefore, to determine the classification of the herbal product (13). Registration: Two Routes to Market: a. Marketing Authorisation b. Traditional Registration a. Marketing Authorisation: To market a product as a licensed medicine with approved indications. Requirements are: • Product quality • Product safety • Product efficacy (clinical studies) of international standards14. b. Traditional Registration Under THMPD (Traditional Herbal Medicinal Products): To market a product under the EU Directive 2004/24/EC on traditional herbal medicines that came into force on 30th April 2004, the Directive provides a section below the "well-established medicinal use" area comprising those medicinal products with indication claims for relatively slight diseases and defined dosage levels and methods of administration, and which are of sufficient INTERNATIONAL PHARMACEUTICAL INDUSTRY 13

Regulatory & Marketplace pharmaceutical quality and proven safety. The efficacy must be plausible on the basis of long-standing use and experience. The time period of tradition must be at least 30 years within the EU, and products from outside the European Union must prove at least 15 years within Europe. The Directive is also eligible for combinations of herbal and certain non-herbal components, e.g. vitamins and minerals, provided that the action of the vitamins or minerals is ancillary to that of the herbal active ingredient. Any labelling and advertisement has to contain a statement that the efficacy and safety of the product are exclusively based on information from long-standing use and experience. In addition, the Directive provides the establishment of the Committee for Herbal Medicinal Products (HMPC) within the European Agency for the Evaluation of Medicinal Products (EMA) consisting of one representative from each EU Member State. The former Herbal Medicinal Product Working Party (HMPWP) was "upgraded" in this direction. The new committee carries out tasks related to the "well-established medicinal use" in the "normal" marketing authorisation procedure as well as to traditional herbal medicinal products within the simplified registration procedure. Its tasks furthermore relate to establishing Community monographs in these two areas as well as to set up a "European tradition list". The "traditional" registration procedure therefore offers an additional option for herbal medicinal products as an alternative to "well-established medicinal use"15.

herbal products will be more or less the same in both the marketing authorisation and THMPD registration, with the exception of demonstrating efficacy as this is replaced by the historical / traditional use of the products in THMPD 14. Herbal Drug Regulations in the US: Herbal medicines are not regulated as drugs in the United States, but they are given special status as “dietary supplements,” along with vitamins, minerals, other nutritionals, and homeopathic and Ayurvedic remedies 16. The Dietary Supplement Health and Education Act (DSHEA) of 1994 classifies herbs as dietary supplements. This law defines supplements quite broadly as “anything that supplements the diet.” 17. DSHEA states botanicals can be labelled and advertised as having certain healthy or nutritional properties as long as no “therapeutic claim” is made. Those botanicals making a “therapeutic claim” can be approved as drugs by the USFDA. The Food and Drug Administration (FDA) has published specific guidelines for industries manufacturing such botanical drug products. These guidelines explain when a botanical drug may be marketed as an OTC drug and when FDA approval of the new drug application is required for marketing. It provides guidelines for submitting an investigational new drug (IND) application for botanical drug products, including those botanicals currently lawfully marketed as foods and dietary supplements in the United States18 as in Fig 3.

medical device (e.g., gutta-percha) or a cosmetic, among other things. It takes into account the products’ accompanying labelling claims, advertising materials, and oral or written statements (21 Code of Federal Regulations (CFR) 201.128) (Food and Drug Administration (FDA), 2000). For products classified as drugs, the FDA regulates them under the authority of the Food Drug and Cosmetics Act and its amendments. Under current regulations, if there is no marketing history in the USA for a botanical drug product, if available evidence of safety and effectiveness does not warrant inclusion of the product in an existing, approved category of OTC (over-the-counter) drugs, or if the proposed indication would not be appropriate for non-prescription use, the manufacturer must submit a new drug application to obtain FDA approval to market the product for the proposed use. If existing information on the safety and efficacy of a botanical drug product is insufficient to support a new drug application, new clinical studies will be needed to demonstrate safety and effectiveness. The DSHEA extended the definition of dietary supplements beyond vitamins and minerals and established a formal definition of a dietary supplement using new criteria. The Congressionallymandated Commission on Dietary Supplement Labels (CDSL) suggested that some botanicals may qualify as OTC products under existing statutes; these state that a product may avoid ‘new

Requirements are: • Product quality • Product safety • Evidence of traditional use Simplified registration procedure for herbal products which fulfil the following criteria: • • • • •

Use without supervision of medical practitioners Specified strength Oral/external or inhalation only Evidence of traditional use Traditional use shows it is not harmful.


Marketing Authorisation: In the USA, the Food Drug and Cosmetics Act characterises a product primarily on the basis of its intended use. For a botanical product, this intended use may be as a food (including a dietary supplement), a drug (including a biological drug), a

drug’ premarket approval requirements and may be eligible for marketing under an OTC drug monograph if the product is generally recognised as safe (GRAS) and effective under the conditions for use for which it is labelled, and if the product has been used ‘to a material extent and for Autumn 2014 Volume 6 Issue 3

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Regulatory & Marketplace

a material time’ under those conditions. The FDA’s response to the Commission stated that it does not regard marketing experience outside the USA to meet conditions of historical use. Most botanical products in the USA are marketed as dietary supplements. Under the Dietary Supplement Health and Education Act of 1994 (DSHEA), an orally ingested product that meets the definition of a ‘dietary supplement’ under section 201(ff) of the Food Drug and Cosmetics Act may be lawfully marketed using a statement that: 1. Claims a benefit related to a classical nutrient deficiency disease (and discloses the prevalence of the disease in the USA); 2. Describes how the product is intended to affect the structure or function of the human body; 3. Characterises the documented mechanism by which the product acts to maintain such structure or function; 4. Describes general wellbeing derived from consumption of the product (section 403 r (6)(A) of the Food Drug and Cosmetics Act, 21 U.S.C. 343 r6(A))19. 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Under DSHEA, if dietary supplements contain new dietary ingredients that were not marketed in the United States before October 15, 1994, the FDA is required to be notified by the manufacturer or distributor at least 75 days before they are marketed (this differs dramatically from what the FDA requires for pharmaceuticals, a product category that has more restrictive regulatory oversight). However, the criteria for approval of herbal mixtures as medicines have started to relax from this requirement. In June 2004, the FDA issued new guidelines allowing the approval of herbal mixtures if they are shown to be safe and efficacious. According to FDA’s Guidance for Industry Botanical Drug Products, botanical drugs are derived from vegetable matter and are usually prepared as complex mixtures. Their chemical constituents are not always well-defined. In many cases, the active constituent in a botanical drug is not identified, nor is its biological activity well-characterised. Therefore, the chemistry, manufacturing and controls (CMC) documentation that should be provided for botanical drugs will often be different from that for synthetic or highly-

purified drugs, whose active constituents can be more readily chemically identified and quantified. Because of the complex nature of a typical botanical drug and the lack of knowledge of its active constituent(s), the FDA may rely on a combination of tests and controls to ensure the identity, purity, quality, strength, potency, and consistency of botanical drugs. These tests and controls include: 1. Multiple tests for drug substance and drug product (e.g., spectroscopic and/or chromatographic fingerprints, chemical assay of characteristic markers, and biological assay) 2. Raw material and process controls (e.g., strict quality controls for the botanical raw materials and adequate in-process controls) 3. Process validation (especially for the drug substance). In October 2006, the FDA approved the first such herbal mixture under the new guidelines, which was developed by the German company MediGene for treating genital warts16. Autumn 2014 Volume 6 Issue 3

Regulatory & Marketplace

Table 1: Comparison of regulations, major legislation and categories of India, Australia, the EU and the US Regulatory agency Major legislation or guidance documents

INDIA CDSCO Drugs and Cosmetics Act 1940 & Drug and Cosmetic Rules 1945

Category where Herbal medicines herbal products can be registered

AUSTRALIA TGA Australian Regulatory Guidelines for Complementary Medicines (ARGCM) Complementary Medicine

Mutual recognition




Herbal medicines are regulated as prescription and over the counter medicines and dietary supplements.

Level of evidence in supporting efficacy and safety; Early market access for low-risk complementary medicines through Listed medicine system (two-tier system) British Pharmacopoeia


Ayurvedic pharmacopoeia and the Unani pharmacopoeia

EU EMA European Union Directive 2004/24/EC

US FDA Guidance for Industry Botanical Drug Products

Traditional Herbal Medicinal Products, Prescription or OTC drugs Yes (for EU Member States only) 30/15 years of traditional use; Benefit-risk methodology

Botanical Drug Products (food/drug/medical device/cosmetics)




Clinical trials in the US required despite traditional use history; Marketing under OTC Drug Monograph versus Approved NDA


European Pharmacopoeia



Marketing Of Ayurvedic Products (Herbal) In Europe. Available at: http://www. speech%2015%20%20regulator y%20 requirements%20for%20marketing%20 of%20ayurved.pdf Herbal medicinal products in Europe. Available at: php?id=722. Accessed September 22, 2013 Liu F, Salmon JW, PhD. Herbal Medicine Regulation in China, Germany, and the United States, Integrative Medicine. 2010; 9(5):54-61 Bent S. Herbal Medicine in the United States: Review of Efficacy, Safety, and Regulation, J Gen Intern Med 23(6):854–9. Warude D and Patwardhan B. Botanicals: Quality and regulatory issues. Journal of Scientific and Industrial Research. 2005; 64:83-92. ARC monographs. Volume 82. Available at: Monographs/vol82/mono82-6A.pdf

United States Pharmacopeia (USP)

Comparison of regulations, major legislation and categories of India, Australia, the EU and the US is shown in Table 1. Conclusion Herbal medicine has become a topic of increasing global importance, with both medicinal and economic applications. European regulations are most comprehensive among most of the global regulations for herbal medicinal products. The FDA guidelines on botanical drug products established OTC drug and new drug application (NDA) parallel routes close to the route followed for a synthetic new chemical entity. Indian regulations are also developing vis a vis global regulations for herbal drug products. Indian regulations are still at a nascent stage when compared to the regulations of Europe and the US. Harmonisation of regulations, like that in European countries, could overcome the barrier for efficient trade as well as uniform standards for herbal medicinal products. References 1. Chan K. Some aspects of toxic contamination in herbal medicines. Chemos 2003; 52:1361–71. 2. Ernst E. Serious adverse effects of unconventional therapies for children and adolescents: a systematic review of recent evidence. Eur J Pediatr 2003; 162:72–80. 3. Chan TYK, Chan JCN. Chinese herbal medicines revisited: a Hong Kong perspective. Lancet 1993; 342:1532–4.

4. 5. 6.

7. 8.

9. 10.





Jayasuriya DC. A review of legislation concerning medicinal plants. 1990 Jayasuriya DC. The regulation of medicinal plants - a preliminary review of selected aspects of national legislation. DeSmet PAGM. Should herbal medicinelike products be licensed as medicines? British Medical Journal 1995;310:10231024. Drugs and cosmetics (first and second amendment) rules 2008. Ministry of Health and Family Welfare, Govt. of India. ICMR, Ethical guidelines for biomedical research on human participants. DirectorGeneral, Indian Council of Medical Research, New Delhi, 2006. National Policy on Traditional Medicine and Regulation of Herbal Medicines - Report of a WHO Global Survey 2005; 168 pages. Australian Government, Department of Health, Complementary medicines. Available at: industry/cm.htm Australian Government, Department of Health and Ageing Australian Regulatory Guidelines for Complementary Medicines (ARGCM) Part I: Registration of Complementary Medicines Version 4.2, August 2011. Available at: http://www. European Commission, Volume 2A Procedures for marketing authorization, Chapter 1, Marketing Authorization, June 2013. Available at: health/files/eudralex/vol-2/a/vol2a_ chap1_2013-06_en.pdf Tai-Ping Fan, Greer Deal, Hoi-Lun Koo, et al. Future development of global regulations of Chinese herbal products. Journal of Ethnopharmacology. 2012; 140(3):568-586. Available at: http:// pii/S0378874112001134 Gunawant D. Regulatory Requirements For

Balamuralidhara V. - Assistant Professor, Department of Pharmaceutics, JSS College of Pharmacy, JSS University, Mysore. Email: baligowda@ Shilpi Khattri - Ph.D. Research Scholar, Regulatory Affairs, JSS College of Pharmacy, JSS University, Mysore. Email: shilpikhattri@

Vandana K. is a Regulatory Affairs Executive in Liquent Parexel, Bangalore. She has done her M. Pharma (Regulatory Affairs) and B. Pharma from JSS University, Mysore. Email: vandu.kshatri@ T. M. Pramod Kumar - Professor & Head of Department of Pharmaceutics, JSS College of Pharmacy, JSS University, Mysore. Email:


Regulatory & Marketplace

The Interim Exec Community calls for a ‘Conscious Coupling’ of RPOs and Interims Specialists Pharmaceutical companies have widely adopted strategies to outsource elements of their business operations, as part of an ongoing drive to deliver a more flexible model that unlocks cost efficiencies and alleviates some aspects of risk associated with drug development. Recruiting talent is one such element. However, pharma companies should be wary of saving on recruitment at the risk of missing out on the best candidates, particularly when it comes to senior staff. Director of Interims of RSA, Dafydd Wright, explains. Volume recruitment relies on reducing risk through the use of IT systems and (often) subcontracted manpower to drive candidate attrition. Bespoke hiring at executive level uses a relationshipdriven, knowledge- and networking-led approach. The emergence of the recruitment process outsourcing (RPO) provider field has seen a downward shift in the quality of the talent acquisition process, often criticised by expert recruiters and candidates alike, because RPO services


are first designed to drive down cost per hire, without addressing how quality of hire will be maintained or improved in the new process. Pharmaceutical companies have an opportunity to address this to their own competitive benefit through demanding the utmost from their RPO provider to adopt a balanced approach to talent acquisition. This will require greater visibility on which subcontracted recruiting firms the RPO will seek to engage with downstream – and pharma clients need to drive home a pharmaceutical industry message that there is an expectation of working with expert recruiters as well as volume recruiters within the service model. This will benefit all levels of the hiring process, including interim management, drive better PR understanding of the hiring organisation's key qualities, leave successful and unsuccessful candidates alike with a sense of satisfaction beyond the process, and create a talent pull that will drive future hiring programmes.

Critically, pressure for this change is coming from the interim executive community of candidates and providers. Interim executive firms are not designed to – and simply do not want to – wade through mountains of job vacancies to identify the one relevant and available interim role. Neither do they want to sign up to preferred supplier agreements constructed for high-volume business models. Therefore they avoid positioning their services alongside the 50 or more recruitment firms that bear no resemblance to their core services for fear of a branding disaster. Most importantly, they do not want to lose sight of what matters – direct discussions with senior management to understand exactly what the client needs from the interim, what success looks like, and how an interim executive will add value. Interim candidates mirror these sentiments; they want relationship-driven outcomes and interesting projects to discuss their skillsets against – something that is lacking in standard RPO setups. At present, pharmaceutical industry

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Regulatory & Marketplace were built for unskilled or semi-skilled use. Interim executives take immense pride in the services they deliver, whom they deliver them to and the types of projects they see as attractive. They naturally seek commercial terms that reflect the value they will provide. So the service approach should be to understand the services an interim is prepared to deliver, the skills they bring, and how the value adds up against their proposed rate – which is often something that cannot be defined until a first meeting (postendorsement) with the client, and is not something the standard RPO model can bring to their pharmaceutical clients.

adoption of the standard RPO model has led to a separation of the suppliers, which fails to add value for all; and ultimately wastes valuable time. Let us examine a pivotal case study.

person-to-person communication, as opposed to an IT-led system, they would have been directed to the right person at the right time, with the right outcome for the client and for the RPO.

A medium-sized pharmaceutical organisation with a long-term established RPO needed a middleto senior-management marketing specialist, with projects ranging from pre-launch to lifecycle management. The interim requirement was circulated across 10 to 50 firms registered with the RPO and failed to deliver. The client subsequently engaged with a specialist executive interims firm directly. That firm restarted the discussion, understood the requirements and identified the "right" candidate. A few days later a service agreement was put into effect.

This example demonstrates fundamental differences in strategy to access top-tier talent. Business-critical solutions that rely on interim executive services only through mainstream RPOs are often doomed to failure; and when RPO providers address key performance indicators (KPIs) with their clients, these failings are easily lost in the volume of everyday recruiting metrics. Pharmaceutical businesses must instruct their RPOs to consider engaging specialists, for their own benefit and for that of their client.

Were the specialists at the executive interims firm just better at finding good candidates? Not in this case. Ironically, the "right person" had already been contacted for this project and submitted to the client under the RPO. However, under the volume process, the client had declined interest in the candidate. When asked why, they said the sub-supplier feedback had been sparse and incorrect representations had been made for the candidate. In contrast, the executive interims firm was able to rapidly get this individual in front of the client, with the right message of endorsement. Had the RPO process allowed for 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

A voice of choice is emerging from the interim executive community and this is as encouraging as it is concerning. Online forums are rife with gripes about volume-led/RPO approaches. Ask any interim candidate how appreciated they feel when the first question tabled is one of price; or when they are rejected at the first hurdle because the dialogue centres on, "But my client's maximum rate is‌ [not enough]". One recent conversation with an executive-level interim candidate centred on the fact they simply did not wish to be represented by a recruiting firm whose brand was more aligned to volume recruiting and that relied on weekly timesheet reporting requirements that

Interim executives appreciate honest and knowledgeable discussions on behalf of pharmaceutical clients, and when using qualified interim executive partners, pharmaceutical clients will see an uplift in quality and hence value, represented overall as better hits on target and a reduction in time to engage. Informed decision-making is about choice through excellent market intelligence. The pharmaceutical industry is in an ideal position to engage in proactive communication with their current and future RPO providers to require inclusion of specialist firms alongside generalists, as there is strength in variety. There will be differences in how to engage the two, but the model will evolve through client demand, pushing for value-led conversations between specialist recruiters and RPO firms to create valuable outcomes for all involved.

Dafydd Wright is an award winning leader in Interim Management specialising only in the pharmaceuticals and life science sectors. He favours a people-orientated, consultative approach which focuses on interim management as a solution rather than a fill-in. Dafydd has a degree in Applied Microbiology and has worked and lived in the UK and Finland. Email: Autumn 2014 Volume 6 Issue 3


When the Patient Recruitment Leader MediciGlobal is not Involved BECAUSE MediciGlobal wasn’t involved in recruiting for the trial, there were not enough patients. BECAUSE the trial did not have enough patients, the trial fell behind schedule. BECAUSE the trial fell behind schedule, the pipeline was changed. BECAUSE the pipeline was changed, revenue targets were missed. BECAUSE revenue targets were missed, investors lost faith. BECAUSE investors lost faith, the stock price plummeted. BECAUSE the stock price plummeted, the board issued a statement. BECAUSE the board issued a statement, “the CEO is cleaning out his desk”.

Wouldn’t it have been easier just to call MediciGlobal?

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Regulatory & Marketplace

The 3E Principle: Key Considerations for Selecting and Outsourcing to a Vendor Abstract Influenced by forces such as macroeconomics, politics, regulations, population growth and aging, there has been a major shift in the way biopharmaceutical companies conduct business. There is ever increasing pressure to comply with evolving regulations along with cost reductions in order to grow business. As companies expand their product portfolios into new geographies, regulatory scrutiny along the entire product lifecycle has seen a substantial increase, with all areas of the business being affected. The result of this is that the volume of outsourcing done by the biopharmaceutical companies has significantly increased. This paper will outline the “The 3E Principle” of Effectiveness, Efficiency and Economics, which are key parameters organisations should consider when selecting an outsourcing partner to assist with knowledge-based activities in drug development and post-marketing stages of the product lifecycle. The 3E Principle will be considered for each of the following service areas: safety and risk management (SRM), scientific writing, regulatory affairs and statistics and programming.

sponsor organisation, as well as what is being outsourced. Businesses must ensure that they are considering all the relevant factors and prioritising them appropriately when looking to contract work to external partners.

productivity and making significant cost cuts. Achieving this is a difficult balance, and established companies, along with smaller new entrants, are looking for new and innovative ways to manage their businesses in this new environment.

Market Shifts Produce Changes in Outsourcing Strategy The reasons for outsourcing now go far beyond labour arbitrage, which used to be seen as the core reason for using an outsourcing partner. Today’s biopharmaceutical companies conduct their business very differently from their predecessors – they are much more influenced by macroeconomics, politics, regulations, population growth and aging, as well as the “flattening” of the globe. This range of factors each provides its own set of opportunities and challenges which need to be assessed.

Expanding product portfolios and moving into new geographies allows biopharmaceutical companies to continue to compete within the growing global marketplace. However, having a portfolio of products on the market across multiple regions means organisations must comply with the differing requirements of multiple regulatory agencies. This requires significant time and people hours, and may also contribute to compliance issues due to lack of understanding or adherence to all applicable regulations.

The article will focus on the overall trends currently seen in outsourcing, and will demonstrate that the 3E Principle applies differently to each service area, and the drivers differ based on the size of the company, i.e., whether it is a mid to large or small business. It will conclude that those biopharmaceutical companies who outsource have a number of varying priorities, and the challenge that is of vital importance is for the outsourcing vendor to have the ability to deliver results effectively against the company’s strategic objectives.

The challenges presented to companies in the current market cannot be ignored. Companies are expanding their product portfolios and moving into new geographies, each with their unique nuances. Drug discovery and development are becoming more complex and resource-intensive, despite increased automation and advanced technologies, and there is enhanced focus on biologics. Regulatory scrutiny throughout the product lifecycle has substantially increased – fuelled by recent scares around product safety and a consequent increase in public and government awareness. We regularly hear about mergers and acquisitions, layoffs and facility closures, and with an increasing generics market, there is now more competition within the sector than ever before. Due to patent cliffs, pharmaceutical innovators took an anticipated loss of approximately $78 billion between 2009 and 20141.

Selecting the right vendor When selecting and subsequently outsourcing to a partner organisation, there are a number of different questions and considerations that are required to be made. These are dependent on the requirements and strategy of the

Thanks to the new challenges presented in today’s marketplace, no corner of the biopharmaceutical business, regardless of the geography, is immune from the pressure to both increase the compliance and quality of products, while simultaneously improving on


The strategies companies adopt to manage this expansion are diverse and can include captive centres, joint ventures with global outsourcing companies, expanded use of full-service clinical research organisations (CROs) and functional service providers (FSPs), use of diverse geographies, and any other creative approaches companies can envision – one example being a buildoperate-transfer, or BOT model. Through the increased use of external vendors for execution of such strategies, companies can focus and dedicate their internal staff and resources to their core business of developing biopharmaceutical products. The 3E Principle “The 3E Principle” considers the all important “whys” of doing business with partners - Effectiveness, Efficiency, and Economics. While every company has its own specific set of priorities, these principles can be broadly applied for effective decision-making when utilising and selecting an outsourcing vendor. In each case, the relative importance of these three principles also differs by the function that is being outsourced, i.e., safety vs writing vs statistics, etc.

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Effectiveness. Effectiveness comprises the delivery of quality and regulatory compliance in a manner that is consistent and reliable. This can often be a challenge for a sponsor company, due to the large volume, magnitude and variety of tasks and functions involved, together with the need to adapt processes constantly in a dynamic, global regulatory landscape. Selecting specialist partners, who focus on specific areas and continually learn and adopt, facilitates the desired level of effectiveness. Efficiency. Efficiency is defined as the ability to manage “peaks and troughs” in workload with minimal impact on productivity and cost. This includes streamlining processes and implementing LEAN methodology to drive process efficiencies, leading to gains that are then transferred to the sponsors. Specialised outsourcing partners provide just-intime resources in fully outsourced or hybrid models. Economics. Managing labour costs is an important reason for outsourcing and off-shoring, but it must be ensured that it is delivered without compromising quality and compliance. The goal is to select outsourcing partners who can absorb employee overhead and chase cost-effective geographies on an ongoing basis for access to an expanded talent pool. This provides scale and skill in a seamless manner, while maintaining the economic advantage.

Safety and Risk Management Within drug development and marketing, patient safety is the most important factor to consider. Regulatory reporting compliance is critical for each reportable adverse event and each aggregate safety report, as well as compliance with company standard operating procedures (SOPs) and all applicable regulations. The pharmacovigilance function tends to be most scrutinised by regulators, and any non-compliance can lead to serious consequences. Changes in the drug development process, globalisation and the dynamics of collaboration in the biopharmaceutical industry lead to evolving regulations for safety reporting in many regions of the world. Having the correct knowledge and expertise and keeping on top of a dynamic regulatory landscape is thus crucially required and 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

hence effectiveness - the first “E” - is the primary requirement of any outsourcing partner. When it comes to mid to large pharmaceutical companies with sizeable portfolios, the impact of volume fluctuations on resource needs is not high. Process and productivity improvements are expected on an ongoing basis given the nature of the business, and these are important. Overall, however, efficiency ranks lower than effectiveness as part of the decision to outsource and vendor selection. In many cases, cost reduction is a major consideration when mid to large pharma companies decide to outsource safety operations, especially post-marketing spontaneous reporting, given the high volumes to be processed. Increasingly, this has been achieved by outsourcing safety operations and retaining the strategy in-house. Though the entire area of safety and risk management (SRM) has been traditionally seen as a core function and hence retained in-house, with the sheer volume of reports to be processed, this method is seen as the most effective strategy. Risk is sometimes minimised by outsourcing only single-case processing while retaining aggregate safety reporting and safety surveillance in-house. Some companies may also choose to outsource to multiple providers and may outsource a subset of cases, for example literature cases, separately, where the risk and impact of failure are low. However, small companies tend to be highly risk-averse since they have much more riding on a handful of molecules or products under development. On the other hand, many also don’t have the ability or the resources to set up safety operations in-house. This leaves no option but to outsource, but they often do so to established near-shore providers rather than looking offshore. Another option is to use the same full-service CRO for safety that they use for clinical development. Cost reduction is not typically as important a consideration for such companies, but in recent years more have started to choose offshore partners. This is due to the increased prevalence of delivering safety services in a globally distributed model throughout the sector. For the risk management part of SRM and for other safety activities that, though resource-intensive, also require significant

domain expertise (e.g., writing periodic safety update reports and performing signal identification and analysis, running patient registries as part of risk management plans), effectiveness and efficiency feature higher than economics when outsourcing decisions are made. Though there was previously a tendency to consider these as core activities and keep them in-house, the growing volume of work in this area, due to the evolving regulatory requirements and availability of the right skills and expertise (e.g., with scientific process organisations (SPOs), who make it their business to deliver domain-intensive services in safety surveillance and risk management) has led to the outsourcing and offshoring of some of these activities as well. Scientific Writing Scientific writing can compromise many different areas, from safety writing (aggregate reports, etc), clinical writing (clinical study reports, protocols, investigator brochures etc.) and regulatory writing (sections of the common technical document (CTD) involving clinical and non-clinical overviews and integrated summaries of safety and efficacy) to the preparation of medico-marketing literature, such as product toolkits and manuscripts for publications. There are clear differences between these writing categories, but for scientific writing the main factor is having adequate time and resources available when they are required. Delivering on regulatory reporting compliance or meeting publishing schedules often requires working to very tight deadlines. Thus, efficiency is the main driver for outsourcing of scientific writing work and is a major criterion for partner selection. In today’s environment, economics comes in second, and effectiveness is the third principle that plays a role. Regulatory Affairs Due to an increasing industry focus on the gradually evolving and perhaps not welldefined local regulations in developing/ emerging markets, companies must have crucial access to intellectual property in regulatory affairs related to these markets and the specific countries in question. In this case, effectiveness, efficiency and economics are all crucial considerations, but perhaps are prioritised slightly differently depending on the activity.

Autumn 2014 Volume 6 Issue 3

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Regulatory & Marketplace the context of statistical services. The regulators come out with new guidance documents in order to provide direction to the industry about new statistical methodology required to make design and analysis more efficient. This implies that the statisticians performing the outsourced work have to keep abreast of all new guidelines on an ongoing basis and need to have good subject matter expertise. The volumes, and hence budgets, for outsourcing statistical work are typically low relative to the total clinical development expenditure. This prevents cost reduction Figure 1. The Relative Importance of the 3 Principles in from playing a major Partner Selection Decisions role when people are considering For example, in process-oriented outsourcing. Efficiency activities such as dossier compilation and effectiveness, therefore, remain as and submissions, together with product the most important drivers to consider. labelling, efficiency is most important, followed by effectiveness and then The primary consideration for economics. Alternatively, for small outsourcing domain-intensive efficacy companies, access to the required programming work is similar to that for expertise (for regulatory strategy) and outsourcing statistics work, so efficiency the required processes and technology is the most important principle that is (for dossier submission and product applied when the decision to outsource labelling) is the main requirement. Thus such work is made and vendors are effectiveness is most important, followed selected. However, the outsourcing by efficiency and then economics. budget for programming tends to be higher than for statistics, since the volume Statistics and Programming of work and number of resources required Although statistics and programming are are much higher. Thus, effectiveness and often grouped under the same umbrella, economics are equally important. the drivers for outsourcing these activities tend to be quite different. Here we define Understandably, mid- to large-size statistical services as comprising statistical companies have a higher volume of contribution to study design, planning, work involved in safety analysis and oversight and conduct of the statistical mapping data between standards than analysis of clinical trial and any other smaller companies. At the same time, related data. Programming, on the other they tend to have established libraries hand, refers to safety programming and of programmes and macros that can be mapping and efficacy programming. used repeatedly. Hence, economics tends to be the primary driver for the selection The requirement for statistical of a provider for outsourcing, followed resources has increased significantly by efficiency and, finally, effectiveness. alongside the growing demand on making trial designs more efficient. For small biopharmaceutical At the same time, due to acquisitions companies, there may not be much and portfolio rationalisation, both the differentiation between statistics, efficacy peaks and troughs get accentuated in programming and safety programming, 26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

since they typically have little in-house capability in these functions. Effectiveness thus ranks at the top for outsourcing decisions, with efficiency coming second, and economics in the third position. Summary When considering doing business with an outsourcing partner, applying “The 3E Principle” – Effectiveness, Efficiency, and Economics – gives companies the opportunity to properly evaluate the reasoning and priorities behind partner selection. These incentives will vary on the basis of the imperatives and strategy of the sponsor organisation, as well as what is desired to be outsourced. Only by completely understanding your own priorities will your company be able to properly evaluate a vendor’s ability to deliver these key elements against your company’s objectives and requirements. References 1. McKinsey & Company (2013). ‘Insights into pharmaceuticals and medical products – Generating value in generics: finding the next five years of growth.’ McKinsey & Company, published May 2013.

Chitra Lele is Chief Scientific Officer at Sciformix Corporation, with over 20 years of experience in the healthcare industry. She has been part of the company’s leadership from its inception and has been instrumental in establishing and growing the organisation. Prior to Sciformix, Chitra was Executive Director responsible for Indian operations of Pfizer Global R&D. With a PhD in Statistics from Stanford University, her prior experience includes work as a biostatistician in cancer epidemiology at both Stanford and University of California. Email: Autumn 2014 Volume 6 Issue 3

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Regulatory & Marketplace

Funding Options for R&D in the Life Sciences Sector With research and development (R&D) and growth being a crucial aspect for any business in the life sciences sector, it is essential to be aware of the various funding options that are available. Typically funding for R&D and business growth has been hard to secure over previous years due to the financial crisis. However, now that the financial uncertainty is passing, there is a definite sense of increased confidence in the economy with funding options returning and becoming more readily available and accessible to life sciences businesses. This article will discuss the various funding options available and the positive impacts and initiatives these have to businesses in the life sciences industry.

companies can access. • Horizon 2020 – Horizon 2020 is the largest EU Research and Innovation programme to ever exist. There is nearly €80 billion of funding available from 2014 to 2020. The aim of this scheme is to secure Europe’s global competitiveness by bringing innovative and ‘world first’ technology to market. The scheme aims to remove the previous ‘red tape’-type barriers to innovation and facilitate growth in the economy with the creation of jobs and commercialisation of these new technologies at an accelerated scale. Anyone can apply for funding and it is a relatively straightforward process, which is designed to ensure participants spend time on what is important – the development of innovative technologies.

Public and National Funding Initiatives Government and national development funding initiatives offer life sciences businesses another option to the traditional corporate venturing and private equity capital-raising processes and methods. There are several development funds which life sciences

• Wales Life Sciences Investment Fund – The Wales Life Sciences Investment Fund is a £100 million fund which opened in 2013. The fund is operated by Arthurian Life Sciences Limited, a new professional fund management company specifically formed to manage the fund. The fund was developed to invest in life sciences and


related medical, pharma and healthcare companies currently based in Wales. The fund is also available to companies from across the UK, Europe and internationally where investment will bring meaningful development and economic benefit to Wales. It will make initial investments of between £500,000 and £5,000,000, and will preserve capital to provide second round and subsequent follow-on investments. The fund is designed to focus on a small number of companies and will spread investment by risk, sub-sector, age or funding requirement. Any size company can apply, ranging from startups and spin-outs to mature companies. Many funds often focus on particular geographical areas with a primary focus to develop and facilitate economic growth in that area. For example, the Wales Life Science Investment fund is relevant to the development in Wales, whilst others include the Agri-Tech Growth Initiative, North East Growth Fund and the Mobius Life Sciences Fund. These funds are geographical-specific and focus on the North East, Midlands and Eastern

Autumn 2014 Volume 6 Issue 3

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Regulatory & Marketplace areas within the UK. Therefore, when researching funding options, it is always worth researching the schemes that are available in your area. • UK Government Biomedical Catalyst Programmes - The Biomedical Catalyst programmes are operated by the Medical Research Council and Technology Strategy Board. These programmes are designed to support early-stage, small and medium-sized life sciences and healthcare businesses. The funding has particular interest in businesses who aim to tackle healthcare issues and support businesses who are carrying out clinical trials. Therefore, this fund supports innovative ideas which are able to demonstrate the potential to provide significant positive healthcare and economic impact by providing up-to-date healthcare solutions and bridging the gap to commercialisation. There are three categories of grants – the confidence in concept award, the early-stage award and the late-stage award. The awards will be dependent on the stage of the

business. The Technology Strategy Board continually release funding competitions so it is important that specialist businesses keep an active eye on the funding movements of the catalyst programmes. Corporate Venturing Corporate venturing is a term used to describe a wide range of mutually beneficial business relationships between companies. Corporate venturing can take various forms, from an equity investment to joint venture arrangements between two or more companies. In each variation of structure, there will essentially be a financial investment made by a larger company into a smaller company in return for an equity stake in the smaller business or in a joint venture business between the companies. The life sciences, pharmaceutical and technology sectors have traditionally been an attractive market for corporate venturing due to their high growth track record and innovative technology. Larger companies are commonly interested in this investment structure

and method as they are able to gain access to innovative and progressive technologies and be involved in a more entrepreneurial culture. The larger business will also be able to furnish their R&D along with developing their existing skills and expertise. Similarly, this is an attractive option for smaller companies as it allows the company to raise capital to take their technology to the next stage of its development. Association with a larger player in the sector will increase the company’s market presence and status. It will also increase its profile and the company will benefit from a wider range of expertise and experience. In turn, this will often lead to further fundraising. Private Equity and Venture Capital Private equity and venture capital is another popular form of funding within the life sciences sector. These funding methods are private investments made usually to the spin-out and start-up technology business industry. Start-ups and spin-out companies are particularly recognising this method of funding as being essential for the development of their technology. Venture capital and private equity investments are similar to corporate venturing in the sense that finance is given in return for the investor taking an equity stake in the business. Private equity firms tend to invest capital in companies that have the potential for high growth and innovation, which can often be in underperforming companies. Once a company secures private equity, it is often the case that the private equity firm will introduce corporate disciplines to the business by working with the company’s management team and suggest ways to take the technology to the next stage in its development. Private equity and venture capital is often an advantageous option for spin-out and start-up companies, and additional strategic, financial and operational guidance is welcomed by the business to assist the progression of the company. Non-financial support also benefits the company in this respect by access to established marketing and distribution channels. By illustration of the venture capital investment activity in the market, in 2013 healthcare and pharmaceutical


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Regulatory & Marketplace giant GlaxoSmithKline released figures of their investments totalling £3.4 billion to develop new medicines, vaccines and consumer products. Even though venture capital and private equity investment is attractive to life science businesses, this method is often viewed as high risk to investors due to the nature and stage of the businesses seeking the investment. In order to counter this, investors are able to obtain certain tax relief benefits on their investments.

the company’s status profile, which could ultimately lead to institutional financial investment. This, in turn, will be valuable and provides the means to the evolution and development of the technology. Public admission also provides a way of attracting new talent and incentivising current employees.

It is important to research the various funding options and seek professional advice to find out which scheme best suits your business needs and strategy. It is also worth considering future funding options necessary for development, and so you are aware of all options for each of the stages of growth of the business.

Despite the benefits of going to the public markets, the process of preparation and application can often be time-consuming for the company’s senior team.

When you seek professional advice, ask how you should present your company to future investors, and what to do to make it more of a viable business to invest in. By having this knowledge, you should find that you are able to secure funding. With governments launching funding schemes specifically for the life sciences sector and more people looking for the right opportunity to invest in, life sciences companies are in a great position for securing that much-needed funding for R&D and commercialisation.

For example, the Venture Capital Trust (VCT) is a tax relief scheme, which is designed to encourage individuals to invest indirectly in a range of small higher-risk trading companies whose shares and securities are not listed on a recognised stock exchange. Tax benefits cover a wide range of reliefs including exemption from income tax on dividends from ordinary shares in VCTs (dividend relief).

In applying to float a company on the public markets, the company should consider various issues such as the timescales for admission, which can take up to four months to complete with a previous year of preparation, the constitution of the board and management team, its professional advisors, the commercial rationale driving the business and all business strategy and charging models.

Another tax relief scheme that is available to private equity and venture capital investments is the Enterprise Investment Scheme (EIS) and Seed Enterprise Investment Scheme (SEIS). Similar to VCTs, the EIS and SEIS schemes offer a range of tax reliefs to investors who purchase shares in smaller high-risk trading companies.

It is imperative that the business has its commercial rationale and profit path focussed so that the investors are attracted.

With the increase of schemes such as EIS, SEIS and VCTs, venture capital has become a popular source of funding for many life sciences companies, providing all eligibility criteria for the schemes are confirmed. Public Markets Over recent years, it has been difficult for companies floating on the AIM market or stock exchange to raise capital. Now, since the financial uncertainty is passing, there has been a significant upturn of raising funds on public markets, specifically in the life sciences sector. Whilst it is unlikely to be a viable option for start-up companies to float on the AIM market or London Stock Exchange given their lack of capital, it can be a particularly appealing method of fundraising for more developed life sciences companies. Floating a business allows the company to have global reach by showcasing their business and technology on the public market. Having public status increases 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Collaborative R&D Another popular choice of funding for life sciences companies is collaborative R&D. This involves the life sciences company teaming up with another business or with academia to co-fund projects. Collaborative R&D is a useful source of funding as it reduces financial risk and also encourages the exchange of knowledge, which can only benefit all parties involved. Conclusion There are several funding initiatives available to companies operating within the life sciences sector, in all stages – whether it be at clinical trial stages, startup or a more established company. This, coupled with the recent implementation of the patent box regime concerning the reduction of corporation tax payable on all registered patents and licensees using such patents, creates a notion of the life sciences sector becoming more prevalent and a progressive industry. In order to keep momentum continual development of life technology, funding rounds are milestones required for life businesses.

and the sciences essential sciences

Nigel Greenaway is the founder of Greenaway Scott. He is a corporate finance specialist, who has been recognised in both Chambers & Partners and the Legal 500. He has acted on a number of high-profile deals including the $76,000,000 USD disposal of Brecon Pharmaceuticals to AmerisourceBergen Corporation, the £21,000,000 acquisition of mass spectrometer business Markes International by Schauenberg GmbH and on the reverse takeover of AIM Listed Enfis PLC by Photonstar LED Group PLC. Laura Herdman is a Corporate Solicitor at Greenaway Scott. She specialises in mergers & acquisitions, disposals, corporate restructuring, fund-raising and investments and commercial contracts and IP. Laura’s experience includes advising on the acquisition of Seren Plus Pharmacy by AR Kowsor Limited and Designer Carbon Materials on the ISIS/ Oxford University Spin-out.

Autumn 2014 Volume 6 Issue 3

Regulatory & Marketplace

Global Tracking Regulations Present Challenges and Benefits Drug makers are facing an everincreasing challenge as more countries implement serialisation and tracking regulations and set compliance deadlines in an effort to ensure the safety and quality of prescription drugs being sold within their borders. Complying with regulations coming into effect will be a demanding task due to a lack of global harmonisation. The foundation of any tracking system is serialisation, which entails affixing to finished drugs a unique serial number and barcode or radiofrequency identification (RFID) that can be verified at the point of sale. But this basic step is fraught with complexities and variants. Some countries may require verification at each step of the supply chain; others may require it only when the drug

passes to the end user. Most countries require serialisation at the unit level. The numbering system a country chooses also adds to the challenges of compliance. For instance, countries such as Turkey and France are following GS1 standards, which include the GTIN (Global Trade Item Number), a unique numbering scheme, while China is imposing its own numbering system.1 In addition to the serial number, most countries want a barcode, either a two-dimensional (2D) matrix or a linear barcode. A second level of tracking involves aggregation, which entails putting a separate number and barcode on each bundling of the product so scanning will show the individual serial numbers of all the units included in that bundle, shipper box or pallet. Some countries do not require aggregation,

others require it up to a certain level and still others expect it throughout the supply chain. Another tracking requirement is an e-pedigree, an electronic document that moves through the supply chain with the drug, and records each sale, trade or purchase of the product. Currently, e-pedigrees are not required by the countries that have implemented a tracking system, but some, including the US, are proposing these. The level of detail and amount of data contained in an e-pedigree could vary greatly from country to country. An additional variant involves the point of origin for the document – whether it starts with the finished product or the active pharmaceutical ingredients (APIs). Regardless of which tracking elements a national scheme requires, a database is needed to tie them all together and to enable speedy verification of product authenticity at the point of sale. Different models are on the table, and many look towards the Turkish model, which has been operating for more than three years. Country Regulations, Deadlines Several countries, including China and the US, have been working on a tracking system for years, but Turkey took the lead in 2009 as the first to mandate serialisation at the unit level. The Turkish Ministry of Health (MOH) regulations require serialising and tracking, based on unique serial numbers and 2D data matrix barcodes, for all packs and all aggregated levels (i.e., bundles, shipper boxes and pallets) reimbursed by the government. The regulations extend to promotional samples, hospital packaged products, prescription drugs and overthe-counter drugs. Every entity in the Turkish supply chain – from the manufacturer to the wholesaler to the pharmacy – is required to send electronic serial number records to the national database in order for the product to pass to the next step of the supply chain and, eventually, for the pharmacy to obtain reimbursement from the MOH. China has had requirements for


Autumn 2014 Volume 6 Issue 3

Regulatory & Marketplace

serialisation and aggregation since 2008. A short list of essential drugs (EDL) must be marked with a unique serial number and a machine-readable linear barcode on the carton. In contrast to other markets, valid serial numbers for the Chinese market are issued by China’s Food and Drug Administration. In addition, aggregation of serial numbers and barcodes is required up to the shipper box level. The EDL has gradually been expanded and will, from 2015, include all pharmaceutical products sold in China. A little further out is the implementation of the European Medicines Association’s Falsified Medicines Directive (FMD). This directive – which will be adopted in the laws of the Member States – requires all drugs sold in the European Union (EU) – once it’s been adopted – to be serialised by 2018. The regulations to implement the directive are expected to be issued late this year or early in 2015 as delegated acts. The directive calls for serial numbers and 2D data matrix barcodes on individual packs of prescription drugs and other medicines at risk of being falsified. While it stops short of serialisation for APIs, the directive does require APIs imported into the European Union to be accompanied by written confirmation from the competent authority of the exporting country. The statements to be 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

issued for each manufacturing site and API ensure that the product was made in accordance with manufacturing, inspection and enforcement standards equivalent to those in the EU. Substances produced in non-EU countries with a regulatory framework deemed equivalent to that of the EU do not need the written confirmation.2 As the EU has yet to implement serial numbers and associated 2D barcodes, several Member States have proceeded with their own codification systems, which vary greatly. In 2005, Italy became one of the first EU members to implement a barcode-based system. Its “Bollini” label features an Italian product licence number with a sequential number. Belgium requires a sequential code that includes four different elements, and in France, the CIP13 requires printing a 2D data matrix containing product number, batch number and expiry date. Meanwhile, securPharm, a consortium of pharmaceutical trade associations in Germany, have conducted a pilot programme to give the EU directive a test run. The pilot involves manufacturers, wholesalers and retail pharmacies that will test an end-to-end authentication system using 2D barcodes. While it builds on an earlier pilot conducted by the European Federation of Pharmaceutical Industries and Associations, the new project includes two databases instead of

one centralised database. Manufacturers will store serialisation data on one database; pharmacies will use the other when they run authentication checks. The goal is a harmonised, EU-wide system.3 With the same goal in mind, a partnership of organisations involved in the EU pharmaceutical supply chain developed the European Stakeholder Model, which entails a 2D barcode system containing the product number, batch number, expiry date and serial number. Using this model, the manufacturer would submit the serial numbers of the shipped product packs to a national repository that would be checked by the pharmacist to validate a code when the drug is dispensed to a patient.4 Preparing for Serialisation Acquiring the necessary equipment and setting up a secure infrastructure to handle multiple sets of regulations is a big investment. Multinational companies will need to build flexible IT systems with codification templates for each market. Any system must be able to capture the information necessary to connect individual serial numbers, in keeping with each market scheme, to the drug unit, and then submit that serial number to the appropriate country database so it can be verified at the point of sale. In addition to the IT system, companies may have to install new cameras, printers and other equipment on their packaging Autumn 2014 Volume 6 Issue 3


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Regulatory & Marketplace

lines so serial numbers and barcodes can be properly placed on the product. Companies already have to run batches of drugs with different labels for each market. As more tracking regulations go into effect, they will have to ensure that the correct serialisation for each market matches the labelling. Most companies are contracting with external consultants to advise on the evolving regulatory requirements and to help develop a secure system that will ensure global compliance. Putting such a system together is likely to take more time than drug makers or regulators expect. Since everyone is trying to become compliant before the deadlines, the demand for consultants and equipment is outpacing the supply. The resulting bottleneck has created lead times of up to a year on selected equipment orders. It is likely to get worse as China’s deadline approaches. If companies do not want to be stuck in a queue in 2015, they 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

need to get their consultants on board and equipment ordered as quickly as possible. Drug makers that rely on contract manufacturers should make sure all their contractors are already working toward compliance with the various tracking requirements that are coming into effect. Even though the tracking systems will have to be installed at the manufacturer’s facility, the marketing authorisation holder, which most often is the actual drug maker, will be the one held accountable for compliance. If drugs are not properly serialised when a country’s deadline goes into effect, they will likely not be allowed in that market. Multiple Benefits Over time, drug makers should realise a number of benefits from serialisation. By ensuring that the correct drug gets to the patient, a good tracking system will reduce a company’s liability. It also will cut down on the volume of counterfeit and fake drugs on the market.

While counterfeit and fake drugs are a global health issue, the incidence varies by market and disease type. As an example, it is estimated that more than a third of malaria drugs available in SubSaharan Africa and Southeast Asia are thought to be counterfeit or substandard according to the US Food and Drug Administration (FDA).6 However, the World Health Organization (WHO) has found the incidence of counterfeit medicines is low – less than 1% of market value – in most industrialised countries with strong regulatory systems and market controls.7 Given the price of drugs in industrialised nations, the problem is likely to grow if precautions are not taken. Counterfeit Avastin, which lacked the active ingredient of the cancer medication, was used in at least 19 medical practices in the US in 2012 and early 2013. A year earlier, UK officials seized Truvada and Viread, HIV/AIDS Autumn 2014 Volume 6 Issue 3

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Regulatory & Marketplace

drugs, which had been diverted and were being sold in falsified packaging. The WHO also found that, in more than half the cases of pharmaceuticals purchased over the internet from illegal sites, the medicines were counterfeit.8 If the fake drugs were removed from the market, drug makers would inevitably see some of this revenue return to their books. Serialisation at the unit level, coupled with aggregation, will make a company’s supply chain more effective and improve its overall logistics. The tracking system will provide data on where a specific product is located at any given time. Such capabilities can enhance supply chain planning and enable leaner operations. Another benefit of unit-level serialisation is the ability to conduct a more targeted recall. Instead of having to recall entire lots when something goes wrong, a company could surgically recall only the problematic packs. Drug makers willing to go beyond the serialisation requirements could realise additional benefits by embedding more data in their barcodes. For instance, a barcode could contain useful patient information that could be read using a smartphone app. A company could also improve its pharmacovigilance by building a link to an adverse event form into the barcode. While serialisation generally will not be required for investigational drugs used in clinical trials, sponsors may find it a useful tool 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

for tracking the treatment of individual patients in a large trial as well. Other innovative uses for both regulators and the industry are sure to surface as the technology advances and people become more comfortable with its capabilities. References 1. GTIN (Global Trade Item Number). GS1 website. barcodes/technical/idkeys/gtin. Accessed 12 July 2013. 2. “Falsified medicines directive: imported active substances need written confirmation to guarantee GMP standards.” 2 July 2013. European Medicines Agency website. http://www.ema.europa. eu/ema/index.jsp?curl=pages/ news_and_events/news/2013/07/ news_detail_001840. jsp&mid=WC0b01ac058004d5c1. Accessed 7 July 2013. 3. securPharm – the German shield against counterfeit medicines. securPharm website. http://www. english.html. Accessed 13 July 2013. 4. About us. European Stakeholder Model website. html. Accessed 13 July 2013. 5. California’s E-Pedigree Law. California Board of Pharmacy website.

shtml. Accessed 13 July 2013. 6. “FDA Invention Fights Counterfeit Malaria Drugs.” 24 April 2013. Food and Drug Administration website. ForConsumers/ConsumerUpdates/ ucm349110.htm. Accessed 7 July 2013. 7. “Medicines: spurious/falselylabelled/falsified/counterfeit (SFFC) medicines.” May 2012. World Health Organization website. factsheets/fs275/en/. Accessed 7 July 2013. 8. Ibid.

Lars Hoejberg is the global serialization practice lead at NNIT, responsible for driving the development of NNIT’s Serialization and Track & Trace services. He started his career in the life sciences industry back in 1995 and has had numerous jobs – primarily in the Manufacturing and Supply Chain area – focusing on business and IT processes. Lars Hoejberg joined NNIT in 2012 – Email: Autumn 2014 Volume 6 Issue 3

The syriQ™ InJentle. The syringe with limited contact materials just like a vial. The syriQ™ InJentle offers a tungsten-free design, keeps the drug separated from adhesive or needle itself and offers a baked-on silicone to ensure less particles. The thin needle with no contact to the needle shield enables a safe and convenient injection. All in all you get a best in class solution for highly sensitive biotech drugs and sensitive application fields like e.g. ophtalmic. The best about it? syriQ™ InJentle with all of these special features can still be easily integrated in your process.

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Regulatory & Marketplace Get Ownership of your IP Right; Otherwise it can Turn into a Nightmare! When filing a patent application, there are lots of things to consider. Most of the attention is directed towards getting the disclosure of the invention right and ensuring that you have adequately covered your commercial product/ concept to prevent your competitors from entering the market space. Too often, little thought is given to who actually owns the invention. If you get this wrong, it can be incredibly difficult to rectify the situation at a later stage. The ownership of a patent is derived from the inventor(s). The first step, when determining the ownership of an invention, is to find out who the inventor is and then determine who owns the inventor’s rights in the invention. It is imperative that you get it right! Who is the Inventor? The short answer is that the inventor is


the actual devisor of the idea behind the invention and any person/party that contributed to the idea so that the invention can be fully enabled. Any person/party who merely contributes advice or other assistance once the invention has already been arrived at is not considered to be an inventor. Therefore, it is important to identify the “heart” of the invention and work out who contributed the information to enable the invention to be put into practice. There may be one inventor or a group of inventors. There are a few UK court decisions concerning ownership of patents and patent applications. One decision concerned an electrostatic trap for cockroaches. A university professor came up with the idea for the electrostatic trap. A specialist in magnetic powders then read about the invention and

realised that the electrostatically charged powders would lose their charge over time, especially in humid conditions, and wondered whether magnetic powders would work instead because they would not lose their “stickiness”. The university tested the idea, verified that it worked, and filed an application for the invention without referencing the specialist. The case went to the courts and it was decided that the specialist was the true inventor because he came up with the idea of using the magnetic powder, whilst the university only used routine experiments to determine that the invention worked. If it had been found that not all magnetic powders worked and the university had carried out experiments to arrive at a specific magnetic powder that had the desired function of trapping a cockroach, then the individuals who carried out

Autumn 2014 Volume 6 Issue 3

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Regulatory & Marketplace the work on behalf of the university would also have been considered to be inventors. This is because they would have contributed to the invention being fully enabled. Who is the Owner? The next question to be answered is: who is the owner of the invention? The answer to this question very much depends on the specific facts of the situation. For example, the inventor could be a nonemployed individual who will own his invention, an employee whose invention may belong to his employer depending on the circumstances, or a non-employed individual who has agreed to assign his rights in the invention elsewhere. Employee Inventions Whether or not the employee or employer owns an invention devised by the employee, i.e. the employee is the inventor, is dictated by UK statute. An employees’ contract of employment cannot circumvent the statute – their rights cannot be diminished! There are two scenarios: Scenario 1 If the invention was made by the employee as part of his/her normal course of duties or specifically assigned duties, and it would be reasonable to expect an invention to arise from those duties, the invention will belong to the employer. The best place to start is to look at the employment contract. For example, a researcher at a drug company is the inventor of a new antibacterial drug. If the researcher’s normal duties include carrying out research to find new drugs that treat bacteria, the drug company (the employer) will own the rights to the invention. In contrast, if the researcher devises a new tool for hanging wallpaper, and has devised the invention in his/her own time and using his/her own resources, then the invention (tool) will not be owned by the drug company. Scenario 2 If the employee has a senior position within the company, such as senior management, then the employee has a special obligation to further the employer’s interest. For this reason, the employer would own an invention when a senior manager is the inventor if it furthers the employer’s interest. 44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

For example, if a senior manager of a drug company’s main role is to oversee the research team then one would not expect the manager to devise an invention related to the drug research during his/her normal duties. However, if the senior manager devised a new assay, the invention would be owned by the drug company because of the manager’s special obligation to further the employer’s interest. Determining the correct owner of an invention can be a complicated process, especially if there is no clear documentation in place that outlines the duties that fall within an employee’s normal duties or specifically assigned duties. Therefore, it is important to keep records that list each employee’s duties and ensure that the list is kept up to date. Employee Compensation If an invention is found to be owned by the employer, but is considered to have “outstanding benefit” to the employer, then the employee can claim compensation. The employee can apply for compensation up until one year after a patent has ceased. It may also be possible for the employee to obtain compensation if they owned the invention yet assigned their rights to the employer. Compensation may be payable to the employee if the consideration received for the assignment of rights is not considered to be adequate in relation to the benefit derived by the employer from the invention and/or patent. Non-employee Inventions The question of who owns an invention when there is no employee/employer relationship can be harder to answer if there is no clear agreement in place when the invention is made. This is particularly true for people working at a university, or when there are a number of collaborating consultants. In such cases, ownership will depend upon the agreement between the collaborating parties. It is extremely important that an agreement dealing with IP ownership is in force when the invention is made to avoid the ownership nightmare! If no clear agreement is in place, it can be extremely messy to determine the ownership of an invention. It is also important that the agreement requires that information concerning the

invention is kept confidential. Joint Ownership In situations where there is joint ownership of an invention, it is important that the agreement between the owners not only outlines who owns what, but also the responsibilities of each party. For example, who is responsible for filing, prosecuting and maintaining a patent/ patent application and, importantly, who will pay for the patent prosecution and maintenance of the patents/patent applications. The agreement should also include details of whether one or both of the parties can decide not to go ahead with the patent/patent application. Universities The vast majority of UK and European patents/patent applications that have more than one owner/applicant include a university as one of the co-owners/ applicants. It is commonplace for universities to collaborate with industry to further the research or commercialise the invention. It is important that any agreement between the university and industry partner is clear on the issues of ownership and obligations associated with IP rights. From the industry partner’s perspective, it is also important to ensure that the ownership within the university has been fully determined and documented. Each individual university has different ownership policies in place for IP rights. Most universities have ownership rights for their fixed term and tenure staff, regardless of how a project is funded. This is in accordance with normal employee rights. However, there are some universities where staff have contracts that allow them to retain the IP they generate, but such contracts are becoming less common. Most universities waive their rights to the copyright of academic publications to ensure that researchers are not held back from publishing their work in scientific papers. However, this does not usually apply to the rights to a patentable invention. The ownership of inventions that have been derived from students is less clear cut. Students are not usually considered to be employees, so they do not have the same rights. Therefore, universities do not automatically own the IP generated by their students. Who owns the IP generated by a student will depend on the individual contract between the Autumn 2014 Volume 6 Issue 3

Pharmacy made simple. Life is complicated enough. So make it simpler — with the new solutions for process automation from Bürkert — designed with the needs of the pharmaceutical industry in mind. Featuring a hygienic design, easy cleaning and simple operation, they can also be sterilised and validated. A complex automation task can therefore become simplicity itself in a matter of seconds. Perfect for high process yields and your peace of mind. ELEMENT process valves: A highlight in our system. They simply keep everything under control. We make ideas flow.

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Regulatory & Marketplace Challenging Ownership! Challenging the ownership of a patent can be a complicated, time-consuming, and costly process. This is why it is important to ensure ownership is agreed at the very beginning before a patent is applied for. It is possible to challenge ownership of UK and foreign patent/patent applications. It is up to the national courts to determine ownership. If ownership of a European patent application is challenged, the issue will be determined by the national court in the appropriate designated European state. In the UK, ownership of a patent application can be challenged at any time and the ownership of a UK patent can be challenged up to two years after the grant of the patent. However, if it can be shown that the named owner knew that they were not entitled to the grant of the patent, the two years from grant deadline does not apply and the ownership can be challenged at any time.

student and the university. Different universities have different contracts with their students. Moreover, different types of students, such as undergraduates and post-graduates, often have different contracts with the universities to one another. Most contracts state that the university will own the rights to any inventions created by the student during the course of their studies. The agreement between the student and the university is becoming more and more important as students are encouraged to be involved in start-up companies based on their research, which usually involves working closely with the university’s technology transfer office. The ownership agreement between the start-up company and the university can be complex and place limitations on how the startup company can progress. Potential investors and industry collaborators can lose interest in a start-up company if the ownership within the university is not clear, or is overly complex. 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

In the UK, the onus is on the applicant or patent proprietor to prove that their ownership rights are derived from the deviser of the invention. To prove who devised the invention, it will be necessary to show laboratory notebooks and other evidence that shows when the invention was devised and by whom. It is also necessary to show any agreement or contract of employment to show how the applicant/patent proprietor derived the rights to the invention. Therefore, it is sensible to keep such documents for the life of a patent (up to 20 years), in the event that they are required during an ownership challenge. In the UK, the remedies for a successful challenge on ownership of a patent/ patent application are to be added as the sole or joint patent proprietor/applicant, to be granted a licence or to be given the option of refiling the application. The remedies available vary from country to country. Conclusions In conclusion, ownership should be determined by the time the invention is made to avoid complications in the future. The following general points should be considered when determining ownership: •

Determine the inventor(s) o Who devised the idea and contributed to it being fully

enabled? • Determine the owner o Is the inventor an employee?  If so, ensure that the employee’s duties are recorded and updated regularly o Is the inventor a non- employee?  Ensure any a g r e e m e n t s concerning ownership are in place prior to the invention being made • Is there more than one owner? o Ensure that there is an agreement between the owners stating the responsibilities of each party with regard to obtaining and maintaining IP rights • Retain all documents that provide the paper trail showing inventorship and ownership rights to the invention.

Jenny Donald graduated from the University of Leeds with a BSc (Hons) in biochemistry and genetics, and joined Forresters in 2001. Jenny specialises in patent prosecution in the UK, Europe and elsewhere. She mainly works in the fields of biotechnology, pharmaceuticals and medical devices. Jenny has particular experience of patent prosecution before the European Patent Office, including experience with opposition and appeal procedures. She also assists clients in obtaining Supplementary Protection Certificates and have comprehensive experience of the application of the transitional provisions of the Supplementary Protection Certificate Regulations by countries that have become member states of the European Patent Convention in recent years. Email:

Autumn 2014 Volume 6 Issue 3

Drug Discovery, Development & Delivery The Respiratory Drug Delivery Asia 2014 Scientific Conference will Bring the Respiratory World Together for the First Time in Asia The Respiratory Drug Delivery (RDD®) Asia 2014 scientific conference will welcome pulmonary and nasal drug delivery experts from all over the world to Goa, India from November 12-14, 2014. The joint organisers of the first edition of RDD Asia – Aptar Pharma and RDD Online – announce that the scientific programme and online registration are available at: rddasia2014. Bringing the Respiratory World Together for the First Time in Asia RDD scientific conferences are globally regarded as the premier venue for presenting the latest advances in pulmonary and nasal drug delivery. They take place in Europe (RDD Europe) and the United States (RDD US) in alternate years. After a successful RDD US 2014 held last month in Fajardo, Puerto Rico, the respiratory world is looking forward to the first RDD Asia meeting, which showcases one of the world’s most prominent emerging markets and a growing location for inhaler and nasal spray development.

RDD Asia 2014 seeks to link Asian regulators, industrial and academic scientists, clinicians and business professionals with their international counterparts, together working toward the goal of advancing inhaled and nasal drug therapy worldwide. RDD Asia, like its predecessors in the US and Europe, will feature lively, fresh and focused updates on respiratory drug delivery in Asia and the rest of the world. More than 200 delegates from Asia and beyond are expected to attend the conference which will be held at the Goa Marriott Resort & Spa in India. The meeting is jointly managed by RDD Online and Apta Pharma. A Two-day Scientific Symposium of the Highest Level in India The RDD Asia 2014 scientific conference will feature podium sessions, scientific poster sessions, a technology exhibition and workshop sessions focused on: • •

Global Regulation of Inhaled and Nasal Drug Products New Therapeutic Opportunities

• • •

Generic Product Development Advanced Drug Delivery Technologies Current Issues in Inhaled and Nasal Drug Product Testing

Expert speakers will address a blend of contemporary issues and essential background relating to pMDIs, DPIs, nebulisers, nasal sprays and emerging aerosol delivery platforms. RDD Asia 2014 offers sponsorship opportunities in order to maximise the visibility of organisations throughout the aerosol community months before the conference begins through the conference website and onsite during the event. In addition, conference sponsors can become exhibitors, providing a unique opportunity to display their devices, equipment and services, and to interact directly with conference participants. Various levels of sponsorship are available on the conference website ( as well as upon request at info@rddonline. com RDD Asia 2014 will also offer several networking opportunities, including a cocktail reception on November 12 and a gala dinner on November 13 sponsored by Aptar Pharma. RDD Asia Benefits from the Experience and Successes Gained During 25 Years of RDD US and RDD Europe Events Previous RDD Europe and RDD US events have sold out, therefore we recommend early registration to attend RDD Asia 2014. “With Aptar Pharma’s strong presence in India, and RDD Online’s extensive experience in organising high quality scientific conferences, there is so much to gain from the workshops, exhibitions and networking opportunities. We are proud to contribute to the advance of inhaled drug therapy in Asia and worldwide,” said Kanwal Tikoo, Vice President India and South Easth Asia, Aptar Pharma India.


Autumn 2014 Volume 6 Issue 3


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Poster Abstract Submission Deadline: June 30, 2014 For more information visit

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Drug Discovery, Development & Delivery

Device Design is Driving Innovation Devices are playing an increasingly important role in medicine. Medical devices offer innovative examination and treatment options and drug delivery devices permit precise, customised and intelligent therapies. New drugs with innovative active ingredients are being launched in conjunction with equally innovative delivery devices. They guarantee administration of the correct dosage, perform an important role in therapy management and improve patient commitment to a given therapy. Medical devices make innovative patient examination, therapy and rehabilitation processes possible. Both types of device deliver added value to the manufacturer or pharmacist, who can use them to distinctly brand the product within their brand universe. Novel active ingredients used to manufacture essential pharmaceuticals are associated with new packaging and administration challenges. Their vastly more complex molecules have to be packaged differently and dosed more precisely than their simple predecessors. That’s why the development of innovative drugs goes hand-in-hand with the development of equally innovative drug delivery devices that guarantee stability, optimise bioavailability and ensure the necessary precision of dosage. Although this trend emerged as a result of the development of innovative active ingredients, it is sustained because patients attach high value to individuality. Shrinking target groups and increasing diversification necessitate drug delivery systems that address differentiated patient types and dosage requirements. Intelligence, Customisation and Therapy Management Many innovative drug delivery device designs make the product more intelligent. For example, a conventional inhaler doesn’t provide the user with any reliable information about how many doses are left. Products with dose counters or residual content indicators not only offer reassurance, they also enable users to obtain a replacement well before they run out of their medication. Drug delivery devices can also perform important therapy management functions. Intelligent tablet dispensers remind the 50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

patient to take their medication and dispense the right tablet at the push of a button. Micro tablet dispensers offer additional scope for dose variation. They can be set to a dose that reflects the specific patient’s needs or varied as the treatment progresses. The number of micro tablets dispensed in place of a conventional-sized tablet is set on the dispenser, and the user then only has to push a button to dispense them. When a person is prescribed sensitive drugs that are associated with the risk of overdose or addiction, intelligent drug delivery devices can perform a control function. For example, morphinze dispensers with a lock-out function give the patient access to pain control medication as and when they need it, but only up to the maximum limit or at the dosage intervals defined by their doctor to rule out any risk of overdosing. Devices for Informed Patients The success of any particular therapy depends to some extent on the patient’s medication and to some extent on the patient’s cooperation. In an ideal world, doctors would be able to count on patient cooperation. Unfortunately, this isn’t always the case. 40% of all prescription drugs don’t have the intended therapeutic effect because they are taken at the wrong time of day, in the wrong dosage, or not taken at all. However, now that patients are assuming a more informed and responsible role in the doctor-patient relationship, progress is possible. Target group-specific drug delivery devices also offer vast potential for therapy optimisation. They support the process of self-medication, even if the user has sensory, mental or motor skill limitations or needs to take the medication in stressful situations. Dispensers with oversized buttons enhance convenience for patients with limited motor skills and actually increase the likelihood of the medication being taken. The aesthetic aspect of drug delivery devices also improves therapy commitment. Drug delivery devices such as injection pens and inhalers are an intrinsic aspect of the everyday lives of patients with a variety of health problems. So they have to fit into the patient’s home environment. Aesthetic design that reflects the user’s lifestyle definitely increases their acceptance of the therapy.

Design and Marketing Strategy Medical technology products are consumer goods and, as such, they have to be competitive and reflect the preferences of decision-makers and consumers. To make a product competitive, the manufacturer has to transform it from an anonymous object into a brand with its own unique personality and distinctive character. All consumer products are branded. In fact, companies that neglect brand building or, at the other extreme, companies that overstimulate consumers by offering an excessive range of products, don’t last long in the market. In the medical technology and pharmaceutical sectors a differentiation tends to be made between corporate and product branding. Many organisations spend vast amounts of money on developing a unique corporate identity with a distinctive look and linking it to values such as quality, reliability and trust. However, an astounding number of them fail to establish the same positioning for their products. Devices offer companies a range of opportunities to establish USPs for their products in their markets. Developing a design that reflects corporate identity is just the beginning. The complex interrelationships of form and function make it possible to develop designs that give consumers a first-hand experience of technical innovation, ergonomics, quality and sometimes even lifestyle aspects. Speeding Up the Design and Development Process The development of a new device - from the initial idea to a small production run for clinical tests - is a several-month process as a result of the complex technological, design and regulatory issues involved. Drug delivery devices in particular can be prone to development delays, especially when device development and drug licensing processes are ineffectively coordinated. In practice, the drug development and device design processes put considerable pressure of time on each other. Ideally, both processes should be better coordinated, interlinked and concurrent rather than sequential to reduce time to completion. It’s generally a good idea to get everyone involved in the design process together at the earliest possible stage of the project. The time required for development can Autumn 2014 Volume 6 Issue 3

Drug Discovery, Development & Delivery be further reduced by the use of platform concepts, and additional optimisation can be achieved at the end of the design process by carefully coordinating the validation and documentation processes. pHeton: From Scalpel to Device A product study conducted on behalf of Somatex Medical Technologies GmbH (Teltow, Germany) illustrates the device design process and the potential associated with it. This particular product study involves the development of a complex disposable gynaecological medical device. Perinatal asphyxia - the medical term for the baby being starved of oxygen during the birth process - is a high-risk complication that can cause severe brain damage to the newborn child. If there are indications of oxygen starvation during birth, the gynaecologist has to make a quick decision on whether to perform a caesarean section or not. Perinatal asphyxia is diagnosed on the basis of foetal blood pH value. The blood is taken from the baby’s scalp because this is the area that is visible and accessible during the birth. Usually, a scalpel is used to cut the scalp and a tube is used to draw up a small quantity of blood. Not only is this a relatively complex, several-stage process, the mother-to-be can also find it upsetting to see an array of surgical instruments in the labour room.

a much less complex and less threatening method of blood extraction. It involves suction being applied to a circular section of the scalp so that it bulges up and can be pricked to draw blood. The first step in the development process was proof of concept for the design and the testing of the blood extraction mechanism. Once it was evident that the extraction mechanism worked as intended, the pHeton's usability design was developed. First of all the designers conducted a comprehensive survey to identify the circumstances surrounding the blood extraction process. For instance, they needed to know details of the lighting situation and the positions of the motherto-be and birth helper in different scenarios, because birth bed and birth chair births pose different challenges to the person taking the blood. The survey results provided them with the information they needed to select a flat, knife-like handle.

The assembled pHeton

Devices are already key innovation drivers in the development of new therapies and pharmaceutical drugs. They optimise the physician-patient and drug-patient interfaces. The trend of increasingly complex medical technologies will increase the future significance of innovative devices. They also have considerable potential as brand ambassadors and differentiation factors that enhance competitiveness. Developing the pharmaceutical drug and the delivery device concurrently in an interlinked process will help to reduce time to market and development costs.

Detailed design: establishing final shape and function

Proof of concept: the blood extraction mechanism and practical tests

Usability design: development of the grip handle shape The product study for Somatex’s pHeton device revealed that the pHeton provided 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

In the detailed design phase, the ultimate shape and function of the product is established. The lancet that perforates the scalp has a fixed position so that it doesn’t come into contact with the skin until the suction action causes the skin to bulge. This prevents inadvertent injuries during the process of positioning the pHeton on the scalp. The suction mechanism is crucial to the product’s ergonomics. Pressing the blue button on the back of the product builds up the necessary vacuum before the pHeton is inserted in a separate piston. When the product has been correctly positioned, all the user has to do is pull back the blue valve lever on the top of the device. The skin is then suctioned, bulges up so that the lancet can prick it, and the blood is drawn up by a sample capillary. The redcoloured vent valve was integrated in the design to minimise air inclusions.

Peter Wallrabe graduated with a diploma in Industrial Design from the University of Applied Sciences in Krefeld in 1982. Subsequently he studied Mechanical Engineering at the Polytechnic University in Essen. Peter Wallrabe worked as director and later as partner in several companies in the field of product design and development. In 1999 he became a partner at WeLL Design Associates BV in Utrecht, Netherlands. In 2003 Peter Wallrabe founded item GmbH, a service provider for medical device design. In early 2012 he sold item to Gerresheimer Medical Plastic Systems, remaining at the company as managing director. Email: Autumn 2014 Volume 6 Issue 3

Drug Discovery, Development & Delivery

Improving Study Designs in Diabetes Drug Development Using Predictive Analytics Introduction Diabetes mellitus is a serious disease that has reached global epidemic proportions. As one country-specific example from the western world, the United States (US) National Diabetes Statistics Report, 2014,1 observed that in 2012, 29.1 million Americans (9.3%) had diabetes and that 86 million individuals aged 20 years and older had prediabetes: the respective figures for 2010 were 25.8 million (8.3%) and 79 million. As a regional example, consider the Southeast Asia region, where close to one-fifth of all adults with diabetes in the world live: the number of people with diabetes in this region is estimated to increase to 123 million by 2035 as the worldwide figure approaches 600 million.2 Complications of diabetes include heart disease and stroke, renal disease, blindness, nervous system damage, and lower-limb amputation. The cost of diabetes in the US in 2012 was estimated at $245 billion, with $176 billion consumed by direct medical costs and $69 billion resulting from reductions in productivity.3 Even more concerning from a global health perspective, most people with diabetes live in low- and middleincome countries, and these countries will also see the greatest increase over the next two decades.4 While concerted global efforts must encompass various strategies, including improving preventive care and education as well as adherence to medications already on the market and prescribed by physicians,5 development of new pharmacologic therapies for diabetes is of critical importance. As the European Medicines Agency's (EMA's) guideline addressing clinical investigation of medicinal products in the treatment or prevention of diabetes observes, "Glucose control in type 2 diabetes deteriorates progressively over time, and, after failure of diet and exercise alone, needs on average a new intervention with glucose-lowering agents every 3-4 years in order to obtain/retain good control."6 However, as discussed previously in the Journal for Clinical Studies, since the 54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

end of 2008, the development of such drugs has attracted additional regulatory interest and hurdles.7-9 The US Food and Drug Administration (FDA) Guidance for Industry that was released in final format in December 2008,10 and the EMA document already mentioned, released in final format in May 2012,6 require sponsors to demonstrate prospectively that a new agent does not have an unacceptable cardiovascular risk. To set the scene for the main discussions in this paper, i.e., how predictive analytics can facilitate more efficient study designs in development programmes for new antidiabetic drugs for type 2 diabetes mellitus (T2DM), the essentials of the FDA and EMA guidelines are briefly recapped in the following section: a more detailed account is provided by Turner and Strumph.9 A Brief Recap of the Guidance Documents In the FDA's Guidance for Industry, "Diabetes Mellitus Evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes," cardiovascular risk is operationalised in terms of an estimated relative risk ratio of cardiovascular events of interest occurring in the drug treatment group (the numerator in the ratio) in comparison with those occurring in the control treatment group (the denominator). A ratio of 1.0 would indicate that the number of events occurring in the two treatment groups is identical. The events of interest are cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke, which are the primary components of the Major Adverse Cardiovascular Events (MACE) composite endpoint typically used (it is possible to add other events to the composite endpoint, such as urgent revascularisation, at which point the term "MACE +" is often used). Independent adjudication of all events is required.11 A meta-analysis involving MACE data from Phase II and Phase III trials is conducted to yield the relative risk ratio point estimate. A two-sided 95%

confidence interval (CI) is then placed around this point estimate, and the threshold of regulatory focus is defined as an upper CI limit of 1.8 or greater for the estimated risk ratio for cardiovascular events: this threshold effectively translates to the statement that there is an 80% (or greater) likelihood of more MACE events occurring in the drug treatment group than in the control treatment group. Discharging this threshold (i.e., the actual upper CI limit must be less than 1.8, meaning that there is less than an 80% likelihood of more MACE events occurring in the drug treatment group than in the control treatment group) is necessary. Three scenarios are described in the guidance: •

If the upper limit of the CI is equal to or greater than 1.8, the drug would be deemed to have an unacceptable risk. In this case, “an additional single, large safety trial should be conducted that alone, or added to other trials, would be able to satisfy this upper bound before NDA/BLA submission.”10 If the upper limit is equal to or greater than 1.3 and also less than 1.8, and the overall benefit-risk analysis presented at submission supports marketing approval, “a postmarketing trial generally will be necessary to definitively show that the upper bound of the twosided 95 percent confidence interval for the estimated risk ratio is less than 1.3.”10 The post-marketing cardiovascular trial referred to is a large-scale cardiovascular outcomes trial (CVOT) focusing on MACE outcomes (see Joffe et al.12 for further discussion). If the upper limit is less than 1.3 and the overall benefit-risk analysis presented at submission supports marketing approval, “a postmarketing cardiovascular trial generally may not be necessary.”10

While it is true that, if the 1.3 threshold is discharged by a meta-analysis of Phase II and Phase III data, a post-marketing CVOT generally may not be necessary, this occurrence is not likely to be frequent. Therefore, data from a CVOT Autumn 2014 Volume 6 Issue 3

Corporate Profile Neuro-Sys, the preclinical CRO with a different approach Age-related neurodegenerative disorders currently affect millions of people worldwide and their prevalence is increasing at an alarming rate. Elucidating the basic biology and physiopathological mechanisms leading to neurodegeneration and treatments is a key challenge. Neurodegenerative disease research that blossomed in the last 40 to 50 years brought new technics and innovative methods in research. Based on these new technics, in-house automatized platforms and with the serious experience of its researchers and scientists, Neuro-Sys has standardized models of CNS diseases specifically on: • • • •

Alzheimer disease (AD); Parkinson disease (PD); Amyotrophic Lateral Sclerosis (ALS, Lou Gehrig's disease); and Demyelinating diseases.

What we do Neuro-Sys is an innovative company that provides the pharmaceutical and biotech industry with efficient and highly skilled cell-based preclinical modeling services: • • • • • • • • • •

Cortical neurons; Glial cells (astrocytes, oligodendrocytes); Hippocampal neurons; Mesencephalic neurons (dopa-, gabaergic neurons); Models of central and peripheral myelination; Motor neurons; Muscle cells; Nerve-muscle co-culture; Schwann cells; Sensitive neurons.

With a strong expertize and a hi-end laboratory equipment, Neuro-Sys develops and uses specific preclinical models of CNS diseases to achieve high-quality efficacy pharmacology and mode of action studies. We are dedicated to provide high-level technical expertise and preclinical services in a collaborative relationship with our clients. A team of experts Our operational and scientific team is composed of highlyskilled and experienced specialists such as pharmacologists, neuroscientists, neurologists, cell-biologists and phytochemists. Innovative models and automatized screening platforms Neuro-Sys invests a lot in R&D to continuously enhance its models of CNS bringing then the most advanced solutions to clients. Our high-content imaging platforms composed of the last cutting-edge equipment allows the highest screening quality. Moreover, assisted with a fully robotized system, our platforms including efficacy and mode of action testing can run on a 24/7 basis to provide the best results, faster. We have selected some of the best automation providers capable to design and setup such platforms.

The starting point Standard screening platforms on the market generally accept molecular compounds coming from the chemical industry that we also do perfectly. Uncommonly, our processes and platforms have been designed to be capable to receive other entities such as: • • •

natural products (plants, seaweed…); extracts from natural source; compounds from natural or chemical source.

Hence, before providing a full pharmacological and analytical profile of the initial entity, we apply a specific standardized process depending on the input source. The pharmaceutical and biotech industry as well as Governments are now really interested in this approach and the extended service coming from natural sources (more generally from plants) we propose to seize the potential on neurodegenerative diseases of natural products. Green-Extraction Natural products are processed into our “Green-extraction” laboratory where “green” stands for ecology. Extraction of natural products using standard methods is a truly polluting activity. Because reducing carbon footprint is important to us, Neuro-Sys also has a strong green policy regarding its activities and extraction which is a major activity. Our green-extraction laboratory composed of brand new extraction technologies (micro waves, ultrasounds, alternative solvents…) is handled by scientists, experts in eco-extraction technics and methods that provides similar or even better results than conventional extraction methods. Drug discovery programs Neuro-Sys also develops and uses its platforms to perform proper dedicated drug discovery programs. Sharing the same vision and determination, the IDVP (Institut de Développement Vietnam Pacifique) and Neuro-Sys setup an exclusive partnership to bring a new dynamic to neurodegenerative disease drug discovery researches. The IDVP was founded in 1989 in Nouméa, New Caledonia, to survey the medicinal flora of this rich archipelago, kept intact for 350 millions of years. From this privileged base, IDVP jumped to Vietnam and focused on medicinal plants with a traditional reputation for enhancing graceful aging. Such prevention derives from stimulating the immune system of natural defenses against oxidative stress created by free radicals. We are then proposing our clients brand new compounds with a proven efficacy and mode of action coming from medicinal plants selected by our scientific board. Key contact Yann Jaudouin, CEO Neuro-Sys 410 Chemin Departemental 60 13120 Gardanne France Email: Tel/Fax +33 4 13 41 51 71 / 72 Website:

Drug Discovery, Development & Delivery will typically be used, either alone or in addition to Phase II and Phase III data, to discharge the 1.3 threshold. Discharging this threshold (i.e., demonstrating that the upper bound of the CI is less than 1.3) effectively translates to a statement that there is less than a 30% likelihood of more MACE events occurring in the drug treatment group than in the control treatment group. When combined with compelling evidence of efficacy (and an acceptable general safety profile), this occurrence satisfies regulators that the drug has an acceptable cardiovascular safety profile (where "acceptable" is defined in the context of an acceptable benefit-risk balance).

landscape has changed within the last decade or so, consider a comparison of the clinical development programmes for sitagliptin13 and canagliflozin.14 Sitagliptin, a once-daily prescription medication that, along with diet and exercise, helps lower blood sugar levels in adults with T2DM, was approved by the FDA in 2006. Canagliflozin, which is similarly prescribed and

hence to patients very much in need of them. As noted by Caveney and Turner,7 many pharmaceutical companies of all sizes may have re-examined their diabetes pipelines and re-forecast their predicted return on investment. A critical question therefore becomes: While the regulatory landscape remains as encapsulated in these guidance documents, what approaches can be

indicated, received approval from the FDA in 2013. Their respective Phase III trials development programmes are summarised in Table 1.

taken to minimise the burden of running the appropriate trials while still ensuring the same degree of cardiovascular safety for clinical trial participants and, later, for patients prescribed the drug should it receive marketing approval? The answer presented in this paper is that, given the increasing complexity of study designs for diabetes trials, it is important to use predictive analytics tools to make a variety of choices, particularly the trial's inclusion/exclusion criteria, to facilitate more efficient trials that will lead to faster go/no-go decisions; this occurrence is not only beneficial to the sponsor, but, importantly, it is beneficial for patients at both the individual and public health levels.

The EMA guideline makes it clear that two strategies to prospectively excluding unacceptable cardiovascular risk are conceivable. The first is a meta-analytic strategy, which is similar in spirit to the one discussed in the FDA guidance, but which does not provide specific thresholds of regulatory concern. The second strategy is presented as follows: As an alternate approach or when there is suspicion of an adverse CV signal (from the database), a specific long-term controlled outcome study with at least 1824 months follow-up (depending on the characteristics of a drug and baseline risk of the studied population) would be expected as part of the clinical development program of new glucose lowering agents at the time of submission of the MAA.6 A second salient difference between the FDA and EMA approaches is that the EMA wishes to be fully satisfied at the time of granting marketing approval that there are no cardiovascular safety liabilities. This contrasts with the FDA's approach of sponsors satisfying a regulatory threshold of 1.8 at the time of granting marketing approval, and subsequently using postmarketing data to discharge the 1.3. (As noted previously, if the 1.3 threshold is discharged by a meta-analysis of Phase II and Phase III data, a post-marketing CVOT generally may not be necessary, but this occurrence is not likely to be frequent.) The Recent Evolution of Clinical Development Plans for Anti-Diabetes Drugs To illustrate how the drug development 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The total number of trials was three times greater in the canagliflozin programme than in the sitagliptin programme, the number of participants was more than four times greater, and the number of participants receiving the respective study drugs for at least 12 months was more than 10 times greater. It is also noteworthy that three of the nine Phase III trials for canagliflozin evaluated the drug in special populations with T2DM: the elderly, individuals with moderate renal impairment, and individuals at high risk for cardiovascular disease (CVD). As can readily be seen, therefore, the requirement to prospectively exclude unacceptable cardiovascular risk has added a considerable burden on sponsors wishing to bring new antidiabetic agents for type 2 diabetes to the market, and

The Usefulness of Predictive Analytics in Healthcare Settings Predictive analytics involves using data, and the inherent trends and patterns within data sets, to predict outcomes. In the healthcare setting, this manifests in the modelling of patients and their diseases to anticipate their progression Autumn 2014 Volume 6 Issue 3

Drug Discovery, Development & Delivery and the impact interventions can have on the course of their health and lives. In the absence of predictive analytics to predict event rates, the event rate for diabetes CVOT studies can sometimes be estimated based on observed event rates from a trial or trials in an earlier phase of the same development programme. An often utilised source of epidemiologic data for cardiovascular risk prediction is the Framingham study, which is a USbased population dataset.15 A caveat of event estimation models based on regionspecific population databases is that they do not represent global differences in terms of the risk profile for individuals of various races and socio-cultural backgrounds, or differences in local standards of care, including availability of different antidiabetic medications and other improvements in clinical care. For a more robust sample, one may review publication of long-term global studies of patients with diabetes and either established vascular disease or multiple risk factors.16 Analysis based on large global studies has the advantage of allowing a benchmark from studies with a similar disease profile and with participants from different regions. One downside of estimating event rates based upon published trials is that the combination of risk factors for populations enrolled in different studies may vary: consequently, predicting the event rates will not be a precise method, but rather an estimation. In addition, the endpoint definitions may differ between studies, including combinations of a number of hard cardiovascular endpoints such as cardiovascular death, non-fatal stroke, non-fatal MI, and hospitalisation for unstable angina, and occasionally other expanded definitions that include hospitalisation for heart failure or coronary revascularisation.17,18 A strength of using predictive analytics, therefore, is to base the event rate estimation on the real event rate of a large representative population which we can query based on different risk factors, and make simulations for the future according to the behaviour of their background conditions and treatments. Predicting Subject Eligibility and Event Rates: the Archimedes Model One predictive analytics tool in the healthcare area is the Archimedes Model, which was initially developed by Kaiser Permanente and is now offered by Evidera.19 Its proprietary technology,

the Archimedes Model, is a carefully validated and calibrated, full-scale, integrated simulation and mathematical model of human physiology, diseases, interventions, and healthcare systems. The highly detailed and clinically realistic model, which was awarded a patent in 2006, is designed to help people understand the implications of their decisions, and for the last 15 years it has been relied upon to answer complex, real-world questions for health plans, researchers, pharmaceutical companies, and other organisations. It enables decision-makers to understand likely outcomes of different treatment and administrative options. The Archimedes virtual patient population is based on the US National Health and Nutrition Examination Survey (NHANES) 1999-2008,20 including real population data from interviews and physical examinations (with extrapolation of missing values), and further validated against over 30 randomised controlled clinical trials. Dynamic physiology and disease processes are embedded in virtual patients that are built for experimentation with protocol/drug variations and for projecting their lives up to 20 years into the future, which enables more advanced clinical trial design and health economic queries. The simulations facilitate estimation of eligible population size and composition, quantification of baseline and control treatment arm event rates, estimation of the outcome of the trial based on assumptions about the anticipated effect of an intervention, and estimation of potential differences in outcomes based on specified modifications of the protocol. Predicting Achievement of Study Milestones: Endpoint Predictive Model Traditional randomised controlled trials in clinical research can be described as fixed-design/fixed-length studies. A study's protocol would state that a certain number of participants would be enrolled and randomised to the various treatment arms (for the sake of simplicity here, an investigational treatment arm and a control treatment arm), and the trial would proceed until that number of individuals had completed their participation. As another option, the concept of adaptive-design studies differs from the fixed-design concept in that interim assessments of data collected up to a given point in time (the analyses are conducted in strict and predetermined

ways that do not jeopardise the trial's integrity and validity) can influence how the rest of the trial is conducted. A variation of the fixed-length study, utilised more and more to comply with the EMA and FDA guidelines, is the time-to-event (TTE) design, in which milestones such as database lock, interim and final analysis, and potential regulatory submissions all hinge on the occurrence of a pre-defined number of events necessary to ensure the appropriate degree of power in the statistical analysis to be conducted. In the CVOTs of current interest, the MACE composite endpoint is typically employed. The event that completes the required number of events can be called the “Nth” outcome. For any given study, it cannot be known in advance exactly when the Nth event will occur, but, to optimise the planning and execution of the study, it is critical to make some prediction about its likely timing. Predicting the duration of TTE trials involves simultaneous consideration of many variables, including the event rate, enrolment timeline, drop-out rate, sample size (each arm), follow-up duration, and the relative risk ratio of regulatory interest (in the diabetes realm of interest here, 1.8 or 1.3). The authors' company has developed an Endpoint Predictive Model (EPM) to provide a sophisticated tool for eventdriven trials, which calculates how event rates and other factors, considered in tandem with participant flow in the trial, will impact the study milestones (see Anisimov21 for additional discussion). Stochastic process is accounted for in randomisation (participants entering the trial) and drop-out (participants leaving the trial/analysis) as well as events experienced: for trials concerned with the first occurrence of the events, once participants experience the targeted event they are no longer part of the pool eligible to experience events. Small differences in event rates, dropout, and the hazard ratio will impact endpoints and the EPM software provides both statisticians and nonstatisticians a straightforward way to predict event accrual, for better planning of study milestones such as interim analysis, database lock, and regulatory submission. The ability to more accurately estimate rates and related endpoints can prevent the “surprise” of a study that must INTERNATIONAL PHARMACEUTICAL INDUSTRY 57

Drug Discovery, Development & Delivery run longer (perhaps considerably longer) than initially expected to reach its final endpoint, and allow up-front decisions on the trade-offs between participant eligibility and event rate for optimal study execution. Cardiovascular Outcomes Trials in Diabetes Drug Development: A Case Study in the Use of Predictive Analytics Tools For CVOTs in development programmes for antidiabetic drugs for T2DM, it is now critical to ask the following questions at the protocol planning stage: What event rate might be expected for the patient population recruited for the trial? Are there modifications to participant eligibility criteria that would increase event rates without greatly reducing eligibility? With the predicted event rate, when will the trial achieve planned milestones? It is extremely helpful to have a data-driven benchmark, such as a virtual patient database (as in the Archimedes Model, for example), to test participant eligibility and event rate assumptions, as well as an advanced model that utilises these rates to predict trial endpoints. Access to and incorporation of tools like this can guard against overestimation of event rates and their effect given a certain flow of participants in and out of the trial, providing more accurate expectations. In the following sections of this paper, these tools are applied to a case study protocol to illustrate their application and

scenarios of inclusion/exclusion criteria: • • •

Trial datasets: databases from participants in previously conducted relevant clinical trials; Healthcare datasets: medical records (likely electronic medical records [EMRs]), from doctor visits; Population datasets: data collected from surveys of large population samples.

As each database represents information from a different participant sample, each has advantages and challenges: examples are presented in Table 3.

a clinical trial database in isolation to estimate the availability of participants within a specific HbA1c interval, for example, has the potential to be skewed. However, rather than seeing this purely as a disadvantage, it is potentially useful to question whether this information, when interpreted in conjunction with other data sources, would instead be a better indicator of potential screen failure rates than what is seen from the large population data, given that the clinical

Different datasets can have a high degree of agreement in most criteria, but may also differ, mostly due to how individuals are incorporated in each dataset. It is important to understand the differences between datasets because they provide specific individuals' information from different vantage points. When these differences are recognised, the level of risk is better understood, trial data best reflect the characteristics of populations more likely to be eligible for, and attracted to participate in, this type of trial.

utility in study planning and execution. The case study is a hypothetical protocol for a trial of a drug for T2DM: the key inclusion and exclusion criteria are presented in Table 2. Estimating Participant Eligibility There are several different types of patient datasets available that can help assess participant eligibility based on different 58 INTERNATIONAL PHARMACEUTICAL INDUSTRY

leading to more thoughtful risk mitigation plans. For example, clinical trials databases are influenced by the selection bias of the type of participants enrolled for the trials sampled. There may be a narrower range of age and HbA1c distribution for individuals in clinical trial databases compared with individuals in EMR databases or population-based samples. The use of

For the case study, analyses of subject eligibility and event rates were conducted using a population based data set, the Archimedes Model virtual patient database previously described, accessing the data through Archimedes’ ARCHeS Population Explorer tool. The percentages of those with T2DM meeting each of the eligibility criteria separately are shown in Figure 1. Although requiring previous cardiovascular history and protecting potential participants by restricting eligibility for those with previous heart failure eliminates a majority of otherwise eligible individuals with T2DM, these are the types of criteria whose employment the new guidelines require. When these key inclusion and exclusion criteria are considered together, 2.5% of those Autumn 2014 Volume 6 Issue 3

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with T2DM would meet key participant eligibility for the trial. Estimating Event Rates The Archimedes Model virtual patient database also provides a validated benchmark for estimating event rates for a defined population. An analysis was run for this case study showing how this population would naturally evolve over five years. In this exercise, there are no discontinuations or dropouts as occur in an actual trial, although participants are removed from the pool of participants via death. The denominator (i.e., participants at risk) changes each year based on death and whether the individual had an event. Kaplan-Meier MACE rates were analysed for cardiovascular outcomes. When receiving current standard of care, the Archimedes Model predicts a one-year 2.91% MACE rate for the trialeligible individuals, as shown in Figure 2.

Adjusting Participant Eligibility to Achieve Higher Event Rates Predictive analytics tools can also assist in determining ways to increase participant eligibility by adjusting inclusion and exclusion criteria. However, these changes shape the characteristics of the population to be included in a study, which in turn shapes the events they will experience. Therefore, these decisions are inseparable from considerations of the impact that these choices make on the expected outcomes of this population in the study; there is often a trade-off between subject eligibility and event rates for a specific trial.

of eligibility criteria required by the new guidelines. Additionally, individuals with previous cardiovascular events have a higher likelihood of future cardiovascular events, i.e. higher MACE rates. To examine the effects of increasing either participant eligibility or MACE rates, the case study protocol age and HbA1c criteria can be varied. Removing the upper restriction on age, leading to the revised criterion age ≼ 40, and lowering the HbA1c requirement, perhaps to ≼ 6.5%, greatly increases participant eligibility, as shown in Figure 3. However, the following consideration then becomes necessary: how does this affect event rates? The change in participant eligibility and event rates can be compared by analysing four possibilities: the protocol as originally planned; the protocol with only a change in age range; the protocol with only a change in HbA1c requirement; and the protocol with both changes incorporated. As can be seen in Table 4, when both HbA1c and age criteria are adjusted, these changes produce a large gain in participant eligibility, from 2.5% of type 2 diabetics to 12%, as well as a small but meaningful gain in MACE rate, from 2.91% for the original protocol to 3.33%. (Note: for readers who wish to pursue that level of detail, the sample size calculations conducted to compute the values shown in Table 4 are presented in the Appendix). Interestingly, it can be seen that changing the HbA1c criterion alone produces a fractionally higher MACE rate (3.35%) compared with

changing both HbA1c and age, but this is outweighed by the overall advantage of changing both HbA1c and age: changing both produces a larger gain in participant eligibility at very little cost to the MACE rate. Estimating Trial Endpoints Endpoint prediction is a key aspect of the new T2DM trial landscape. For the hypothetical case study presented here, EPM (which, as noted previously, provides the expected events accrual, i.e., expected endpoints, as well as probability confidence intervals based on assumptions on participant enrolment, dropout, and TTE) has been used to evaluate the effect of the difference in MACE of 2.91% for the original protocol case study compared with 3.33% after modifying eligibility criteria. In addition, the effect of varying the risk ratio from 1.0 to 0.9 can be considered. A risk ratio of less than 1.0 in this context indicates that there are likely to be fewer events in the drug treatment group than in the control treatment group, i.e., the drug is cardioprotective. If the upper limit of the CI also falls below 1.0, a statement of statistically significant cardioprotection can be made. The case study assumes an annual participant lost-to-follow-up (LTFU) rate of 0.1% (this figure does not include participants who discontinue study drug but remain in follow-up) and 4000 patients randomised into the study, with a 1:1 ratio of randomisation to treatment group and control group. In this model, during the 24-month recruitment period, it is assumed that participants enroll in the study evenly, with approximately 80 enrolling per month. (Note: for a more sophisticated analysis, EPM does allow participant randomisation to be input from an enrolment modelling tool to take into account either gradual or realitybased start-up assumptions; however, for

As noted previously, requiring previous cardiovascular history and restricting eligibility for heart failure are examples 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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this case study analysis a country/site strategy was not created.) Assumptions entered in the model are summarised below; enrolment and the participant LTFU rate are kept constant for the multiple scenarios predicted: • • • • •

Vary two event rates: 2.91% vs. 3.33% Vary hazard ratio: 1.0 vs. 0.9 Annual LTFU: 0.1% Non-inferiority margin of: 1.3 and 1.8 Randomise 4000 participants (2000 per treatment arm)


• •

2-year enrolment spread evenly 5-year follow-up

A subset of results from the EPM analyses is presented in Table 5. It takes approximately 27 months from the "first participant in" (FPI) to accrue 140 MACE events to ensure at least 90% power for a 1.8 estimated risk ratio margin with a 2.91% annual MACE event rate in the control group, with a true hazard ratio of 1.0. It takes approximately 24 months from the FPI to accrue 140 MACE events, if the annual MACE event rate is assumed to be 3.33% in the control treatment

group. With the same participant enrolment assumption, it takes about 48 months to accrue 320 MACE events to ensure at least 90% power for a 1.3 postmarketing estimated risk ratio margin under the assumption of a true hazard ratio of 0.9, with a 2.9% MACE event rate in the control group, while it will take 43 months from FPI to accrue 320 MACE events when the MACE event rate is 3.33% in the control treatment group. According to the FDA guidelines, to successfully discharge an unacceptable cardiovascular risk sponsors ultimately need to discharge the 1.3 non-inferiority margin; however, once the 1.8 margin is discharged they have the option to pursue regulatory approval for marketing of their drug, assuming that the efficacy endpoints are met and that there are no other safety concerns. In the case study presented in this paper, with a true hazard ratio of 1.0 the 1.8 margin would be reached three months earlier with the population selected for the higher MACE rate with the revised eligibility criteria. In a more restrictive scenario, if the true hazard ratio is 0.9, the 1.3 margin is reached five months earlier with the population with the higher MACE rate. These are the types of trade-offs and decisions that can be made during study Autumn 2014 Volume 6 Issue 3

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Drug Discovery, Development & Delivery planning when using predictive analytics tools. Concluding Comments The ability to correctly predict the event rate that is expected from a defined participant population and correctly interpret their effect on endpoints is critical for outcome-driven studies in diabetes drug development. Given the increasing complexity of the design and execution of diabetes trials in the current international regulatory landscapes, it is beneficial to use predictive analytics tools to choose smarter protocol inclusion and exclusion criteria: this will result in more efficient trials, faster go/no-go decisions, and bringing new diabetes drugs to market faster for patients who need them. References 1. National Diabetes Statistics Report, 2014. Available at: http://www.cdc. gov/diabetes/pubs/statsreport14/ national-diabetes-report-web.pdf (Accessed 18 July 2014) 2. International Diabetes Federation. IDF Diabetes Atlas, 6th Edition. Available at: sites/default/files/EN_6E_Atlas_ Full_0.pdf (Accessed 18 July 2014) 3. American Diabetes Association web site: Statistics About Diabetes. Available at: (Accessed 18 July 2014) 4. Whiting DR, Guariguata L, Weil C, Shaw J. IDF Diabetes Atlas: Global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract. 2011;94:311-321. 5. Turner JR, Strumph P. The moral imperative of improving patient adherence to pharmacotherapy for cardiodiabesity, Part I: A focus on type 2 diabetes mellitus. Journal for Patient Compliance. 2012;2(1):32-36. 6. European Medicines Agency. Guideline on the clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. Effective November 2012. Available at: docs/en_GB/document_library/ Scientific_guideline/2012/06/ WC500129256.pdf (Accessed 19 July 2014) 7. Caveney E, Turner JR. Regulatory landscapes for future antidiabetic drug development (Part I): FDA guidance on assessment of cardiovascular risks. Journal for Clinical Studies. 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

2010; January issue:34-36. 8. Turner JR, Caveney S. Regulatory landscapes for future antidiabetic drug development (Part II): EMA guidance on assessment of cardiovascular risks. Journal for Clinical Studies. 2010; March issue:38-40. 9. Turner JR, Strumph P. 2012. FDA and EMA actions regarding the cardiovascular safety of drugs for type 2 diabetes mellitus, 2007-2012: An overview of respective regulatory landscapes. Journal for Clinical Studies. 2012:(3):22-24. 10. FDA. Guidance for Industry. Diabetes Mellitus—Evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Effective December 2008. Available at: http:// GuidanceComplianceRegulatoryInformation/Guidances/ucm071627. pdf (Accessed 19 July 2014) 11. Turner JR, Somaratne R, Cabell CH, Tyner CA. Centralised endpoint adjudication in cardiovascular outcomes studies: Composite endpoints, risk ratios, and clinical endpoint committees. Journal for Clinical Studies. 2011;3:46-49. 12. Joffe HV, Parks MH, Temple R. Impact of cardiovascular outcomes on the development and approval of medications for the treatment of diabetes mellitus. Rev Endocr Metab Disord. 2010;11:21-30. 13. h t t p : / / w w w . a c c e s s d a t a . nda/2006/021995s000_StatR.pdf 14. advisor ycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm334550.pdf 15. Framingham Heart Study website. Available at (Accessed 29 July 2014) 16. Scirica BM, Bhatt DL, Braunwald E, et al. The design and rationale of the saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus-thrombolysis in myocardial infarction (SAVOR-TIMI) 53 study. Am Heart J. 2011;162:818825.e6. 17. Menon V, Lincoff MA. Cardiovascular safety evaluation in the development of new drugs for diabetes mellitus. Circulation. 2014;129:2705-2713. 18. Yang F, Ye J, Pomerantz K, Stewart M. Potential modification of the UKPDS risk engine and evaluation of

macrovascular event rates in controlled clinical trials. Diabetes Metab Syndr Obes. 2013;6:247-56. 19. The Archimedes Model website. Available at (Accessed 29 July 2014) 20. Centers for Disease Control and Prevention. National Health and Nutrition Examination Survey. Available at: (Accessed 19 July 2014) 21. Anisimov V. Predictive event modeling in multicentre clinical trials with waiting time to response. Pharm Stat. 2011,10:517-522. 22. Addplan. Version 6.0.8. Cologne: Addplan GmbH; 2013.

Denise F. Messer, MA, is Senior Project Manager, Clinical Analytics and Simulations, Quintiles. She supports metabolic and cardiovascular projects via her expertise in clinical data mining, country/site strategy development, and probability enrollment modeling. Prior to joining Quintiles, she had a 16-year research career at Duke University Medical Center. Email: Claudia De Oliveira, MD, PhD, MPH; Xiaoqiang Xue, MS, J. Rick Turner, PhD Dr. Erica Caveney is Quintiles’ Global Therapeutic Strategic Lead for Diabetes, and chairs Quintiles’ Diabetes Center of Excellence. She is Board Certified in E n d o c r i n o l o g y, Diabetes, and Metabolism. Her areas of special interest are type 1 and type 2 diabetes, obesity, metabolic syndrome, and cardiovascular outcome studies. Email:

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Drug Discovery, Development & Delivery

How Can Pharma Develop Paediatric Medicine? Paediatric Healthcare Landscape The European Paediatric Regulation came into force in the European Union (EU) in January 2007, with the key objective of improving children’s healthcare. The key goals of the Regulation are to facilitate the development and availability of medicines amongst children and young people, ensure that medicines used in children are of a high quality, are ethically researched and appropriately authorised, and engage with pharmaceutical and healthcare stakeholders to improve the availability of information relating to the use of medicines for children 1. The introduction of the European Paediatric Regulation was a major milestone for paediatric medicine, recognising the historical paucity of information relating specifically to medicines in young people, and taking steps to minimise the use of unlicensed medicines, doses or formulations when treating children. The challenge in applying adult-licensed medications to young people has long been an issue in paediatrics, with dose and formulation choices based upon peer usage and limited clinical trial data part of daily standard clinical practice throughout Europe2. A five-year report of the impact of the European Paediatric Regulation concludes that paediatric clinical development is notably becoming an integral part of the overall development of medicinal products in the EU, and provides supporting evidence that the Regulation is enabling significant changes in improving the clinical healthcare landscape for young patients3. The Paediatric Regulation is just one example demonstrating the rapidly accelerating paradigm shift in paediatric medicine – children are no longer being considered clinically as ‘small adults’. Recognition of specific and complex medical differences, not just between adults and children but also between children at different ages and developmental stages, is a major driving factor for rapid advancement in treatment patterns for young people. Throughout history, the pharmaceutical 66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

industry has played a critical role in developing and shaping the healthcare landscape. From leading innovation through clinical research and development (R&D), to enabling major advances in productivity and progress in healthcare and treatment systems, the role of the pharmaceutical industry in providing clinically-justifiable treatment options to healthcare professionals has enabled the establishment of an industry that now contributes more than £8billion per annum to the UK economy alone4. Over recent decades, the evolving nature of the healthcare landscape has had a significant impact upon the expectations and perceived responsibilities of the pharmaceutical industry. The long-running discussion around how the industry should be relating to and conducting business with healthcare professionals, and ultimately patients, is one of the most extensive and exciting conversations of modern times, and one that is leading to huge new advances in patient experiences of healthcare. Clinical R&D lies at the heart of the pharmaceutical industry, which invests more in the continued development of the field than any other industrial sector in the UK5. However, an increased level of patient engagement with healthcare than ever before means the historical ‘doctor knows best’ legacy and approach to treatment is no longer applicable to modern medicine. The number of stakeholders involved in patients’ experiences of healthcare and medicine has increased exponentially as adult patients are becoming fully enabled and supported in claiming their rights for access to information, choice in healthcare and inclusion in decisionmaking. The field of medicine in adults is rapidly evolving to include a huge range of new factors beyond just the clinical characteristics of a specific treatment, and in doing so is creating a whole new range of challenges for clinicians and the pharmaceutical industry to balance a focus on clinical expertise and innovation with a truly patient-focussed approach to improving healthcare experiences.

In paediatric medicine, this evolution is not currently being explored to the same extent. Despite evidence that communicating directly with children improves compliance and health outcomes6, studies suggest that children currently contribute as little as 5% to a paediatric clinical consultation7, and that less than 15% of the medical information discussed is directed to the child8. One of the key challenges in paediatric medicine moving forwards will be to ensure that positive steps to empower patients in being involved in their own healthcare are consistently and appropriately applied to young people. Patient-centricity As a concept, ‘patient-centricity’- the process of designing a service or solution around the patient – is an objective that has been enthusiastically embraced by leading pharmaceutical organisations, such as AstraZeneca (‘Science and patients are at the heart of everything we do’9, Sanofi (‘a global integrated healthcare leader focused on patients' needs’10 and UCB (‘inspired by patients, driven by science’11). In reality, however, a considerable number of the current advances towards patient-centricity remain predominantly focussed on adult patients, who represent the largest patient population in business terms and are the stakeholders most effective at communicating their needs. Children often have acute, shortterm illnesses such as upper respiratory tract or ear infections, gastrointestinal illness with vomiting and diarrhoea, or injury-related problems. Some children additionally develop chronic illnesses, lasting for years or even a lifetime, due to inherited conditions, environmental factors, or a combination of these and other factors. Although the paediatric population with chronic illnesses may be relatively small when compared to the adult cohort, epidemiological studies suggest that up to 30% of young people are affected by one or more chronic condition(s)12 13, a significant proportion of which will require ongoing treatment for months, years or even an entire lifetime. An effective initial approach to Autumn 2014 Volume 6 Issue 3

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Drug Discovery, Development & Delivery involve young people in the management of their own healthcare from the point of diagnosis and treatment initiation has the potential to establish a consistent attitude and approach amongst affected children to their condition, which can be maintained throughout an entire lifetime of treatment, thereby significantly contributing to improved health outcomes. Explaining complex medical concepts to young people can be extremely difficult; children assimilate information in different ways and may make assumptions that could have been avoided, had the information been presented in a simple and engaging way. Conversations around the medical basis of conditions, various treatment approaches and the impact upon the lifestyle of a young person can be especially challenging during times of high anxiety and stress among families, particularly around the point of diagnosis. Currently, in many disease areas there are also very limited resources and tools tailored specifically to support healthcare professionals in helping children understand and cope with the realities of medical conditions during what is often an incredibly challenging time for patients and their families. Dr Columba Quigley, Chief Medical Editor at Medikidz (previously Consultant and Senior Lecturer in Palliative Medicine at Hammersmith Hospitals Trust), explains: “When communicating with children about medicine, it is absolutely key that they are part of the conversation right from the point of diagnosis and throughout the whole process of their treatment. Effective communication involves not only starting those conversations early, but discussing the issues with young people in a simple, engaging way that clearly explains the relevant information at a level that is appropriate for children. Helping children to understand their own bodies and medical conditions is an incredibly valuable approach to ensure consistent engagement of children with their health, and can also contribute to overall health outcomes through improved adherence with treatment. Understanding what is happening can also help young people cope with an often frightening situation, and can support them in managing their own condition and the effect that it could have upon their lives both in the short and long term.”


So what are the key challenges that clinicians face in providing accurate, appropriate and engaging medical information to young people? Patient Engagement The first challenge faced by clinicians as part of their standard daily practice, is initiating productive conversations with young people in the first place! In paediatrics, the traditional doctor-patient relationship seen in other medical fields is shifted into a discussion with multiple stakeholders, most often including doctors, parents and the patient themselves. Studies suggest that in a clinical consultation, children contribute to less than 5% of the discussion, with the main focus of communications with young people being around information-gathering (rather than decision-making), and in discussion of social and psychosocial issues as opposed to explanatory medical issues7, 8. Only a small proportion of the medical information shared as part of these discussions is typically directed at children 8, and many clinicians feel that the resources currently available for sharing with young patients are either limited in many disease areas, or may not be suitable for the age or educational level of the individual child. Clinicians may therefore instead choose to defer to parents and provide them with all of the relevant medical information, to be passed down to the child at a level deemed appropriate by the parent, which can introduce a whole new range of challenges in assuring that the parents fully understand the medical information to explain to their children. Provision of a suitable range of educational tools to enable clinicians to initiate effective conversations directly with young people with a wide range of educational requirements needs to be a key feature of paediatric medicine. Engaging children with their own health issues using specific child-focussed resources will additionally support families and facilitate a wider child-centric discussion. Patient Education Patient education is a key objective throughout the medical profession, and paediatric medicine is no exception. The paediatric population contains an extremely wide range of educational needs that can make patient education extremely challenging for clinicians. However, the benefits of working with patients and their families to promote

a clear understanding of medical issues strongly outweigh any perceived challenges to clinicians in communicating the information. Studies have shown that communicating directly with children improves adherence with treatment and satisfaction6 14. Furthermore, a thorough understanding of the underlying condition and the justification behind treatment options has the potential to be valuable when discussing why adherence with treatment regimes is key, despite potential side-effect profiles which may otherwise lead to non-adherence. In addition to improving the patient illness experiences, removing some of the fears and anxieties associated with lack of understanding through education can also lead to improved adherence patterns in patients and contribute to significantly improved health outcomes. “Adherence to medication is a challenge at any age but particularly for young people who are establishing their independence. Experts in adolescent medicine advise that understanding your chronic medical condition improves adherence. This is certainly our experience with our young people with HIV. Our clinical nurse specialists find that using appropriate resources with young people has helped them to talk about the issues and improved their understanding”, explains the Patient Support Lead from Children with HIV Association. Patient Empowerment Beyond the direct clinical benefits of engaging children with medical education, patient empowerment is an incredibly important factor amongst young people that can have a dramatic effect upon their healthcare experience. Long-term or chronic illness can be extremely frightening for young people, and providing them with age-appropriate information in a suitable format that they can understand can be a major factor in empowering children to be proactively involved in managing their condition. By helping children to understand what is happening in their bodies, clinicians can provide patients and their families with valuable tools to promote discussion and engagement of young people with medicine. Suitable education can additionally empower young people to feel confident and comfortable talking about health issues with others - perhaps their teacher, peers or extended family, to explain a condition that may affect Autumn 2014 Volume 6 Issue 3

Drug Discovery, Development & Delivery

their life and that of those around them, and assist in removing some of the fear or stigma that they may experience as a result of their diagnosis. Role of the Pharmaceutical Industry In the evolving healthcare landscape, the key areas of patient engagement, education and empowerment are only just starting to be scrutinised in paediatric medicine. There are many as-yet unexplored opportunities for the pharmaceutical industry to become established leaders in driving innovation in these areas; from tailoring traditional educational materials to focus on children, to championing novel approaches across a wide range of digital platforms, a focus on improved health outcomes through effective patient engagement is becoming an essential part of paediatric medicine. With a history of driving innovation through new approaches, the pharmaceutical industry is ideally placed to support healthcare professionals with new initiatives to provide engaging and appropriate educational tools for use with young patients. “The industry needs to realise that modern paediatrics is about so much more than just clinical treatment choices, and that education needs to be at the heart of the service. Enabling young people to access 69 INTERNATIONAL PHARMACEUTICAL INDUSTRY

information in their language in whatever format is most appropriate – be it print, digital, web, or video – will undoubtedly help improve adherence,” Dr Quigley says. “In paediatrics, there are myriad opportunities for pharma to lead the charge in new engagement approaches and to demonstrate a real commitment to improving the patient experience for children.”   References 1. European Medicines Agency. Science Medicines Health. [Online] index.jsp?curl=pages/regulation/ document_listing/document_ listing_000068.jsp. 2. Working with the pharmaceutical industry in relation to paediatric clinical trials. A British perspective. O Dewit, R Tiner. 4, s.l. : Paediatric and Perinatal Drug Therapy, 2008, Vol. 8. 3. Paediatric Committee, European Medicines Agency. 5-year Report to the European Commission- General report on the experience acquired as a result of the application of the Paediatric Regulation. 2012. 4. ABPI. The pharmaceutical industry and market in the UK. [Online]

Pages/uk-industry-market.aspx. 5. ABPI. Research and development: innovation and investment. [Online] Pages/default.aspx. 6. Educating young children about asthma: comparing the effectiveness of a developmentally appropriate asthma education video tape and picture book. Holzheimer, L Mohay, H, Masters IB. 1, s.l. : Child Care Health Dev, 1998, Vol. 24. 85-99. 7. How do paediatricians communicate with children and parents? Wassmer, E Minaar, G Abdel Aal N, Atkinson M, Gupta E, Yuen S, Rylance G. 11, s.l. : Acta Paediatr., 2004, Vol. 93. 1501-6. 8. Children's contributions to pediatric outpatient encounters. van Dulmen, AM. 3 Pt 1, s.l. : Paediatrics, 1998, Vol. 102. 563-8. 9. AstraZeneca. [Online] http://www. 10. Sanofi. [Online] com. 11. UCB. [Online] 12. CHRONIC ILLNESS IN CHILDHOOD: PSYCHOSOCIAL ADAPTATION AND NURSING SUPPORT FOR THE CHILD AND FAMILY. Theofanidis, D. 2, s.l. : Health Science Journal - International Journal of Nursing Research and Review, 2007, Vol. 1. 13. Welfare, Australian Institute of Health and. Australia's Health 2010. 2010. 298. 14. No57, NICE Clinical Guidelines -. Atopic Eczema in Children: Management of Atopic Eczema in Children from Birth up to the Age of 12 Years. National Collaborating Centre for Women's and Children's Health (UK).

Dr Kate Hersov, UK CEO and Co-Founder of Medikidz, the medical education company specifically for children, discusses the application of a patient-centric philosophy in paediatric medicine, and how the pharmaceutical industry can contribute to the engagement of young people with medical education to improve adherence, health outcomes and patient experiences of healthcare. Email: Autumn 2014 Volume 6 Issue 3


Drug Discovery, Development & Delivery

Smart Pills for Oral Drug Delivery

A smart pill is an ingestible capsule with miniaturised micro-electronics. A smart pill for drug delivery may be used in a wide range of applications from use as a smart tool in drug development to a key element in a smart connected care environment. This emerging technology presents significant opportunity for the pharma industry to exploit modern digital innovations and take a lead position in the future of healthcare. Introduction It seems that there are smart products of one sort or another everywhere we look, with new devices and models constantly being introduced. One industry that has seemingly resisted the pull of “smart� products is the pharmaceutical industry. To be fair, the industry is an extremely smart one with a very high level of technological prowess. Yet products based on smart digital devices or application interfaces are few and far between. For the most part, the industry thinks in production of white powders and innovation strictly means discovering and developing new chemical entities. With increasing competition, reimbursement concerns, and expiry of blockbuster patents comes great pressure on the pharma industry to transform from entrenched business practices. With this pressure also comes opportunity to embrace new approaches and technologies that are transforming society. Making smart use of modern digital innovations promises to bring a revolution in healthcare. One direction that pharma has necessarily embraced is a shift in focus from pills to outcomes. That is a move from the goal of pushing a drug through


the approval stage, to creating therapies that improve health and offer a clear improvement over current practice. In this move to improved outcomes, there is recognition of the role of the many factors beyond the direct action of the drug. Two areas to consider are devices and technology. Those companies that can successfully combine the elements of drug, device, and technology to bring about better outcomes will be rewarded (Figure 1). Trends also to be considered are personalisation of healthcare, greater ownership by the individual, digital management of data, and drive to reduce overall cost. Examples of the integration of a drug with devices and technology are growing. An application area that illustrates well the merging of these elements is the programmable insulin pump for diabetes care. Products include the Medtronic MiniMed, Insulet Omnipod, and Animas OneTouch Ping. These systems combine elements of a drug reservoir, insulin pump, blood glucose monitor, and handheld management device. Delivery of insulin is adapted to the patient’s current blood glucose level and may be delivered on demand by the patient, for example at mealtime. Similar is the emerging area of wearable bolus injection devices1. These devices serve a need to enable delivery of an injectable drug while freeing an individual from the care setting and reducing the overall cost of administration. While the present use of digital electronics is modest, the path towards greater exploitation of digital technology solutions is clear. A prime area for development is a smart pill. The oral route of administration is by far the most preferred and meshes well with the need to have greater ownership of health management in the hands of the individual at home. While the concept of smart pills has existed for decades, only recently has the technology advanced enough to make an oral smart drug delivery pill feasible. Due to the many technical, business, and human factor issues present, the development path for the smart pill is challenging. Early products may use only a small

part of the potential of smart systems but this will grow with increased experience and familiarity with such devices. As the technology matures, we will see a move from the smart pill as a smart tool in drug development, to smart devices for novel therapies, to a smart connected healthcare environment. Smart Pills A smart pill can be defined as an ingestible capsule with miniaturised micro-electronics. This is an area that is old in concept, established in some areas, yet nascent. A report from marketsandmarkets gives an overview of the smart pills technology market2. The report cites a fast emerging cross-platform technology market growing from $442 million in 2012 to an estimated $965 million by 2017. Capsule endoscopy is an established market for diagnosis of intestinal conditions. A capsule endoscope is a swallowed camera pill that captures images within the body and transmits data wirelessly to a recorder for later review by a physician. Capsule endoscopy was introduced into the market in 2001 with the PillCam by Given Imaging. This was a breakthrough product allowing for the first time convenient and accurate visualisation of the small bowel. Entering into the drug arena, there are a number of early examples from parties ranging from university research groups to start-up companies and large established device or technology companies. One development bridging the monitoring and drug markets is the Helius system from Proteus Digital Health. This system embeds a tiny ingestible sensor into an otherwise standard oral drug product. The sensor responds to body conditions and reports information to a data capture unit worn by the patient. A primary application is to monitor the compliance or adherence of a patient to a prescribed drug regimen. The adherence pattern may be reported to and analysed by the physician, care giver, patient, or others. Drug delivery directly from a smart pill brings many advantages Autumn 2014 Volume 6 Issue 3

Drug Discovery, Development & Delivery and opportunities for improved drug effectiveness, personalisation, and better management of disease and health. Past examples are largely mechanicalbased solutions or research prototypes exploring system construction. An example of an electronics-based product is the IntelliCap system from Medimetrics3. Smart Drug Development A smart drug delivery pill is controlled by electronics and has great flexibility and precise control in delivery location, release rate, and dose. At the same time it can monitor the local GI environment, report measurements in real time, and be commanded by an operator to perform an action on demand. This type of performance is impossible with conventional oral drug forms. While there are myriad therapeutic implications, the system can also be viewed from the direction of a smart tool that can be employed to great advantage in drug development of more conventional oral drug products.

Figure 2a

Figure 2b To understand the utility as a smart tool, the construction and functionality of the IntelliCap system is examined. The capsule incorporates a microprocessor, battery, pH sensor, temperature sensor, RF wireless transceiver, delivery actuator and drug reservoir. The pH data, in addition to being an important environmental parameter, is used to locate the capsule individually during transit. Transit events of gastric emptying and entry into the colon are readily determined from the pH data. There are two versions of the

capsule that share the same electronics core but differ in the nature of the drug reservoir and delivery method (Figure 2). The IntelliCap CR is constructed for a fluid payload and dispenses drug in small increments under control of the microprocessor. This allows the creation of practically any delivery profile. The IntelliCap FR is constructed for practically any payload type (powder, particles, solid, fluid) and dispenses drug as a single fast-release event. The IntelliCap system has the capability to house a drug formulation, protect it from the gut environment, and release it in a targeted location with a bolus release or extended release pattern. Such is essentially the target of modified release (MR) technology. With conventional formulation approaches, the performance in vivo often does not meet the desired target and is at the same time highly variable. This ends up in failed studies, re-formulation attempts, costly delays, and abandonment of projects. Often there is a lack of full understanding of the behaviour in specific regions of the GI tract and a lack of ability to release drug as desired. To address these difficulties we can apply the smart pill to act as a smart tool. This tool in turn is used to craft a smart drug development process, saving time, putting resources to more efficient use, and uncovering novel products. Since experiments can be designed and performed quickly, a more systematic approach may be employed, creating a deeper understanding of the drug properties. This is typically explored within a pharmacokinetic (PK) study where a delivery profile is designed to determine the bioavailability in specific regions. The resulting data leads to a better model, so that the delivery target and formulation may be improved, thus resulting in optimised performance. One of the basic questions for extended release development is whether the compound has sufficient absorption in the colon. This can be quickly determined with a regional delivery study. The IntelliCap FR system may be used to house the drug, track transit until the capsule reaches the colon, and then release contents. An example from such a study is shown in Figure 3. The advantage of using the smart tool is that the release location in each subject is reliable despite a wide variation in GI transit time. Another common question is whether the drug has an absorption

Figure 3 window. Or, related to this, what is the absorption throughout the entire GI tract. This may be determined with an absorption window mapping study. For example, the IntelliCap CR system may be used to create an extended zeroorder delivery profile starting from the duodenum and extending throughout the small bowel and into the colon. The regional transit times from each subject are measured and this information is used to further analyse the data. PK and transit data are incorporated into a modelling program such as GastroPlus or SimCyp, to de-convolve the data and determine absorption at a finer level. An example is shown in Figure 4. The advantage of this approach is that the entire GI tract can be probed in a single

Figure 4a

Figure 4b study and a more sophisticated model created. Armed with knowledge of the regional absorption behaviour and a detailed simulation model, an optimised release profile is determined. In a process of rapid formulation prototyping, a smart pill system is used to program a desired release profile for testing in vivo before undertaking more lengthy formulation development4.


Drug Discovery, Development & Delivery

It is clear that the use of enteric delivery has application beyond the traditional goal of modified release products intended to reduce dosing frequency. It has long been a goal to achieve oral delivery of larger molecule drugs such as proteins, peptides, antibodies, or vaccines. The oral route of administration is by far the most preferred due to convenience, cost, and patient acceptance. There are various strategies to enable oral delivery of macromolecules such as micro-particle formation, permeation enhancers, encapsulation, receptor targeting, and uptake by antigen sampling cells. The solutions are typically a combination of advanced formulation and location targeted delivery to the small bowel or colon. The smart pill provides a ready solution to test and prove concepts quickly through accurate and repeatable delivery of the test formulation to the target site in the intestinal tract. Thus delivery concepts can be validated early before undertaking more complex dosage form development. In a similar way, concepts to improve solubility of compounds may be tested and validated in vivo. A large fraction of compounds in development today face solubility problems and significant effort is applied to enhancing the bioavailability of these compounds. Typically the local pH and release concentration at the site of absorption are critical elements. Thus, it is just a matter of time before controlled release dosage forms for compounds requiring solubilisation become important5. Smart Healthcare While the smart pill is put to effective use today as a tool for smart drug development, the full potential of the technology may be realised in creating innovative new therapies and as a key element in a smart connected care environment. The combination of functions 74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

available from a smart pill enables therapies not possible by conventional means. For example, targeted topical drug delivery has advantages for the treatment of locally active disease of the gut, such as inflammatory bowel disease (IBD), intestinal cancers, and irritable bowel syndrome. Topical delivery only to the region of involvement can reduce toxicity from systemic exposure. The region of involvement can vary from patient to patient, and within a patient over time. The programmable nature of an electronic pill allows the target site and dose to be personalised. Going beyond intestinal diseases, the unique features of an electronic delivery pill may be used more widely. Delivery based on time of day can be beneficial. For hypertension or Parkinson’s disease, there is benefit to establishing a base level in the morning, for example, by starting delivery one hour before waking. In areas such as pain or oncology, individual titration and delivery upon user demand can be put to effective use. The combination of a drug with a device is by definition a combination product as viewed by regulatory authorities. A combination product must be considered separately as a drug, as a device, and in combination. The primary mode of action determines which area takes the lead in review and approval. While there are added difficulties in bringing a new combination product to market, the pioneer will enjoy a strategic advantage by defining the space and the regulatory path. Pharma, as opposed to the device industry, is well positioned to lead as the primary mode of action is usually due to the drug. Furthermore, a new combination product provides opportunities for extended patent

Figure 5 protection of a compound as well as a creating a barrier to competitors that do not have access to the required device technology.

So far, we have focused primarily on the delivery capabilities of the pill itself. But a smart pill has the ability to perform much more broadly and become a key element of a larger connected care environment (Figure 5). Consider the use of on-board sensors for measurement of biomarker levels where data is transmitted wirelessly and integrated automatically into the patient’s health record for reporting, diagnostics, and management of long-term treatment. The innovative use of technology and connected devices promises to improve outcomes, empower the patient, and lower healthcare costs. As outlined well by Eric Topol, “The near future of health care will be revolutionized by two important critical factors, technology and consumerism”6. Pharma is well-positioned to become a key player and stands to benefit greatly by defining and executing a digital strategy in this emerging area. Herein lies an opportunity for the industry to move towards the centre of patient care and become a key interface to the patient. Let the era of smart healthcare begin. References 1. Injectable Delivery: Wearable Bolus Injectors. ONdrugDelivery 51, entire issue (2014). 2. Smart Pills Technologies Market (2012 – 2017) (Diagnostic Imaging, Patient Monitoring, Drug Delivery). MarketsandMarkets, PH1303 (2012). 3. van der Schaar, P.J. et al., Gastrointest Endosc 78(3), 520-528 (2013). 4. Becker, D. et al., AAPS PharmSciTech, epub ahead of print (2014). 5. Selier, C. The Chemical Engineer 877(78), 39-42 (2014). 6. Topol, E. The Creative Destruction of Medicine, Basic Books, New York (2012). Jeff Shimizu is a pioneer of the IntelliCap drug delivery system, cofounder and CTO of Medimetrics. Prior to Medimetrics, Jeff had been with Philips Research for over 20 years in systems research and development. After creation of the IntelliCap system, Medimetrics was formed to bring this technology to the market. Email: Autumn 2014 Volume 6 Issue 3

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Clinical & Medical Research

Key Considerations for Conducting Clinical Trials in Idiopathic Pulmonary Fibrosis Introduction Idiopathic pulmonary fibrosis (IPF) is a form of chronic, progressive fibrosing interstitial pneumonia that is of unknown cause, occurring primarily in older adults, limited to the lungs, and associated with the histopathologic and/ or radiologic pattern of usual interstitial pneumonia.1 Over time, the lung tissue becomes thickened, stiff, and scarred and the damage is irreversible.2 IPF is a rare disease affecting 132,000200,000 individuals in the United States, and 37,000-40,000 in the European Union;3 the condition has been estimated to affect as many as 5 million persons worldwide.4 However, these estimates vary in the literature, as a uniform diagnostic definition of the disease has only been introduced fairly recently. The prognosis is extremely poor, with an average survival of two to three years following diagnosis. The annual mortality due to IPF is estimated to be 40,000 in the United States (US). Respiratory failure is the most common cause of death.5 IPF affects more men than women, and occurs primarily between the ages of 50 and 70 years with a prevalence peak at 65 to 79 years.6

trials, focusing on country and site identification, feasibility, and study design. Approaches for mitigating these challenges will also be described. Current Treatments and Implications for Clinical Trials As noted, IPF is a rare but inevitably progressive and fatal lung disease, and it has a prognosis that can be worse than that for many forms of cancer. There have been several important advances in this field over the past two years, which have increased understanding of how IPF can be managed, and this has brought new hope for patients with this devastating disease.8 There have been a few studies investigating the effect of thalidomide in IPF patients, indicating improvement of cough and respiratory quality of life, but until recently there were no pharmacological treatments approved for IPF.

A major advance in 2011 was the European Medicines Agency (EMA) approval of the antifibrotic agent, pirfenidone (trade names Esbriet速 and Pirespa速), for treatment of adults with mild to moderate IPF in all 28 European Union member countries. The approval was based on the results of two pivotal Phase III, double-blind, randomised, placebocontrolled clinical trials demonstrating the efficacy and safety of pirfenidone. These two studies were supported by two additional Japanese clinical trials. Those studies were based on the primary endpoint of disease progression, measured by the difference between pirfenidone and placebo in the change in forced vital capacity (FVC) from baseline to treatment week 72. The product is also approved for marketing in Norway and Iceland. In 2012, pirfenidone was approved for IPF in Canada; it is also approved for this indication in Japan,

The number of individuals diagnosed with IPF is forecast to continue to increase, due to an increase in life expectancy, an improved clinical understanding of this condition, and earlier and more accurate diagnosis.7 There is no cure for IPF. Limited therapeutic options are available for patients with mild-to-moderate IPF in the European Union (EU), Canada, and Asia, and there is substantial off-label use of medications. Currently, there are no therapies approved by the US Food and Drug Administration (FDA). However, many patients are able to purchase a drug online, but there is no proof that the drug is identical to that marketed in other countries, and/or that it has not been altered. While the number of clinical trials in this area has increased in recent years, there remains an urgent and unmet need for new therapies. This article aims to identify key methodological, practical, and ethical issues involved in IPF clinical 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2014 Volume 6 Issue 3

Clinical & Medical Research South Korea, China, India, Argentina and Mexico. Pirfenidone is not approved for sale in the United States; the FDA has requested supplemental data as one of the pivotal studies failed to meet the primary endpoint. This Phase III study was recently completed, with results announced in February 2014, and demonstrated positive efficacy results.10 Pirfenidone is currently marketed in 16 countries for IPF, and its availability must be considered when selecting countries to be involved in a clinical trial. There are both advantages and disadvantages for involving countries where this drug is marketed and reimbursed. Inclusion of a positive control for Phase III studies should be considered due to the fact that if the study design allowed pirfenidone as a background therapy, the studies would be more appealing to sites and patients, and this would increase the likelihood of the trial being approved by ethics committees and regulatory authorities. There is now a growing body of evidence regarding the use of pirfenidone in clinical practice, which

influences clinical decisions for disease management, including the role of earlier diagnosis, expected clinical outcomes with pirfenidone in the real-world setting, and the role of multidisciplinary teams for diagnosis and treatment of this disease. Prior to approval of this drug, there was little impetus to diagnose a patient with IPF, as there was no treatment available that demonstrated clinically relevant improvement. These advances were reflected in the fact that the 2013 European Respiratory Society (ERS) Annual Congress included a focus on IPF, along with a review of interstitial lung disease (ILD), and discussion of the ongoing revision of the guidelines for the diagnosis and management of IPF issued jointly by the American Thoracic Society, the European Respiratory Society, the Japanese Respiratory Society, and the Latin American Thoracic Society (ATS/ ERS/JRS/ALAT).11

mechanisms of action, although many of these clinical trials failed to demonstrate a statistically significant treatment effect, as recently reported in two reviews published by Cottin12 and Antoniou et al.13 This historical lack of positive results is due to the fact that, originally, IPF was viewed as an inflammation-driven process. However, mainly due to the lack of efficacy of the anti-inflammatory treatment approach, there was a shift to the current view that IPF is an epithelialdriven and fibroblast-activated process, in which inflammation is a secondary event. A review of protocol designs indicates how the definition of IPF, and thus clinical trial entry criteria, have become more specific. However, study design considerations still remain a challenge as there is a continued debate on what constitutes a clinically meaningful endpoint.14 While all-cause mortality and all-cause non-elective hospitalisations have been proposed as the best choices,15 measuring these outcomes could be prohibitive, requiring the

The search for effective treatments for IPF has involved numerous multicentre, randomised, placebo-controlled trials investigating agents with different

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Clinical & Medical Research enrolment of a large number of patients to be followed over an extensive period of time. Others have proposed that the widely adopted primary endpoint16 of pulmonary function, specifically FVC, is in fact clinically relevant and is an acceptable surrogate. Some authors have proposed definite and suspected acute exacerbations of IPF as separate outcome measures or as a combined idiopathic acute worsening endpoint. The concept of IPF as a neo-proliferative disorder of the lung may help in meeting the urgent need for a better understanding of the pathogenesis of IPF by taking advantage of learnings from cancer biology.17 The identification of common pathogenic pathways between the two diseases may stimulate new clinical trials with cancer drugs and with different combinations or types of drugs, as has been intensively explored in cancer. Furthermore, clinical trials in IPF could take advantage of the experience of oncologists, following the cancer model of trials of new treatments by using progression-free survival as a reasonable, if not ideal, logical and clinically meaningful endpoint.

use as outcomes in IPF trials. New IPFspecific PROs in relation to disease progression, and to measure the impact of investigations aimed to improve patient quality of life, are needed. SGRQ-I, an IPF-specific variation of SGRQ, has been developed.21 Another published tool to assess quality of life in IPF is ATAQ-IPF: future research to validate the use of ATAQ-IPF in IPF trials is planned.22 Due to the low prevalence, short duration from diagnosis to death, the high mortality rate of IPF, and the competitive nature of the clinical trial landscape, it is important to design clinical trials that are relevant and interesting to investigators and patients. Factors such as currently available therapies, country and site selection, and study design issues must be taken into account. Ongoing Clinical Trials As of April, 2014, there were 54 ongoing global IPF studies (with 'ongoing' being defined as recruiting or not yet recruiting), as outlined in Figure 1. An identical search in early 2012 identified only 40 ongoing studies at that time.

The vast majority of ongoing clinical trials for IPF are located in the US (63%). This figure is followed by the EU (39%), where most studies for this disease are being conducted in the United Kingdom (UK) (48%); as a result, the UK currently appears to be at capacity for such trials. Potential regions/countries to conduct IPF studies with little to no competition are Latin America, Central Eastern Europe, India, Canada, Australia, and China. Table 1 provides a review of Clinicaltrials. gov23 statistics for IPF studies over last five years. Current Treatments and Implications for Clinical Trials Evidence-based guidelines for the diagnosis and management of IPF issued jointly by the ATS/ERS/JRS/ALAT do not give a positive recommendation for any pharmacological treatment, and the guidelines recommend that IPF patients be treated within a clinical trial, if possible. IPF patients are mainly treated with corticosteroids such as prednisone, oxygen therapy, and a variety of other

Published literature has identified a number of endpoints as predictors of survival outcome: FVC, diffusion capacity for carbon monoxide (DLCO), the 6-minute-walk test (6MWT), dyspnea, and high-resolution computed tomography (HRCT). The FVC18 and 6MWT19 are considered the best predictors of mortality and can be viewed as the best marker of chronic disease progression. Analysis of the data from the largest trial in IPF (INSPIRE; effect of interferon Îł-1b on survival in patients with idiopathic pulmonary fibrosis) has confirmed the high reliability of the 6-minute-walk test (6MWT) as an endpoint in IPF clinical trials.20 Although there are no FDA-qualified patient-reported outcomes (PROs) for IPF to date, and PROs were not used as a primary endpoint in therapeutic trials in IPF, there is a growing interest in PROs in IPF studies. There are limited research data that support the validity of the Baseline Dyspnea Index/Transition Dyspnea Index (BDI/TDI), the University of California San Diego Shortness of Breath Questionnaire (UCSD), the St. George Respiratory Questionnaire (SGRQ), and the Medical Outcomes Study 36-Item Instrument (SF-36) for 78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2014 Volume 6 Issue 3

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Clinical & Medical Research agents, including n-acetylcysteine, azathioprine, cyclosporine, and cyclophosphamide. Based on feedback from global clinical sites, oral corticosteroids are often used for IPF treatment, in spite of the lack of evidencebased data confirming efficacy. The dose range is fairly wide, with little apparent variability between countries. No barriers are anticipated to stopping these medications prior to enrolment in a study. Additional classes of drugs routinely used for the treatment of this patient population include immunosuppressive agents and antifibrotic agents, such as pirfenidone.24,25 It is important that the study design of these trials is consistent with the ATS/ERS/ JRS/ALAT guidelines and incorporates key elements from these guidelines, such as diagnostic criteria, standard of care, and assessments to monitor the progress of the disease.

patients. Table 2 outlines investigators with IPF experience by region, based on a proprietary investigator database at the authors' company. IPF Study Metrics The following metrics come from BioPharm Clinical’s Study Advisor tool, based on 30 IPF studies (26 sponsors; 27 interventional/3 observational studies; Phase I or I/II = 6; Phase II or II/III = 12; Phase III = 6): •

Study length: average duration of an IPF study is 31 months, 23.3 patients per site, dosing mean of 28 days/patient Enrolment: 70 patients/study, recruitment of 21.6 months, recruitment rate (RR) of 3.25 patients/site/month (p/s/m).

The mean enrolment per site is extremely variable based on the study

design and study phase. In an attempt to better quantify the enrolment per site, completed studies with metrics available were reviewed and are summarised in Table 3. Based on the Quintiles’ investigator database, enrolment metrics for several principal investigators who participated in IPF studies are shown in Table 4. All sites are located in Latin America (Argentina, Brazil, Chile and Mexico). The mean recruitment rate was 1.04 p/s/m (range: 0.68-2.08 p/s/m). This variability was most likely due to study-specific entry criteria and required procedures. For IPF trials, the most promising countries are North America, Latin America (Argentina, Brazil, Chile, and Mexico), Eastern and Western Europe (Belgium, Bulgaria, the Czech Republic, France, Germany, Greece, Hungary, Ireland, Italy, the Netherlands, Portugal, Russia, South Africa, Spain, and the UK), the Middle East, and possibly Asia, depending how many sites are needed and whether certain ethnic populations need to be studied for registration purposes. Recruitment and Retention An interesting strategy would be to focus initially on the ability of sites to conduct all protocol-specific procedures, with access to required equipment, and to provide tools to help sites identify and recruit suitable patients from within their own patient population. Patients who suffer from IPF are typically established within the healthcare system and well known to the sites. It is at the site level where the highest number of patients

Methodological Considerations Global Site Identification In the US, pulmonary specialists are largely responsible for managing IPF patients, although such patients may briefly come under the care of other specialists, such as thoracic surgeons at the time of their lung biopsy. They may also be seen by pulmonologists in private practice and at academic hospital-based centres. Outside the US, this pattern is replicated, but with variations depending on the availability of pulmonologists or other types of respiratory specialists. IPF clinical trials typically involve collaboration with major university hospitals, research clinics, and academic centres with experience in managing such 80 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Clinical & Medical Research for seriously ill patients. One approach would be to use a trial design with a treatment-to-placebo ratio such that more participants receive the active drug (or active comparator) than placebo. An open label extension of long duration would also be advantageous both for approval and enrolment.

can be informed of the studies. Once site databases are depleted, a study-specific outreach campaign should be carried out, directly targeting referral healthcare providers and patients via support groups, health fairs, publications, and websites (including social media) geared towards IPF patients. Liaising with various regional or international patient advocacy organisations and registries is vital. Other methods for successful recruitment and retention include webinars, study-specific


branding, leaflets, and online advertising and search engine optimisation. Other Study Design Considerations A placebo arm in IPF clinical trials could potentially pose ethical concerns in some countries. This is common to indications when “standard� therapies have been established, with or without an evidence base, making it appear that participants are being denied potentially beneficial treatments.26,27 This is a particular issue

A second consideration for study entry criteria is the fact that clinical trials subjects are required to have an IPF diagnosis less than five years prior to randomisation (with or without a lung biopsy), according to the 2011 ATS/ERS/JRS/ALAT joint guidelines, including the 2013 revised guidelines, which suggest that a lung biopsy is not necessary for the diagnosis.28 Inclusion of newly diagnosed individuals as well as patients who have had the diagnosis for several years is also an important consideration due to the short median survival time post-diagnosis. A third consideration is whether to mandate that the diagnosis of IPF is confirmed by central reading of highresolution computed tomography (HRCT) and central review of lung biopsy specimens, if performed. A median of 65% of patients are diagnosed by HRCT alone, with a median of 35% of patients

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Clinical & Medical Research being diagnosed by HRCT plus lung biopsy.29 Elements to take into account include: •

If the HRCT criterion is included, a vendor should be selected with global experience and the ability to analyse data from different types of scanners, in addition to experience with providing phantoms (used for validation of the scanner) worldwide. A diagnostic challenge is that IPF histology shows striking variation from one region to the next, with temporal and spatial heterogeneity. It is not unusual to find areas of normal lung next to areas with severe thickening of alveolar walls. Therefore, findings from bronchoscopic or percutaneous lung biopsy are difficult to interpret. Open lung biopsy and video-assisted thoracoscopic lung biopsy are the preferred methods. The variability in diagnosis of IPF comes from the inter-observer variability of radiographers and pathologists for interpretation of images.

Additionally, HRCT images should already be available in digital format. The challenge may be for sites to be able to provide digital images of lung biopsies. Other study design factors such as treatment duration will be based on study objectives, e.g., to delay or prevent exacerbations, reduce pulmonary decline, improve patient-reported outcomes, and/or improve survival time. Finally here, blood biomarkers for IPF should be considered due to their easy accessibility and reported association with survival or pathogenesis of the disease and consideration needs to be given to the mechanism of action of the investigational product. Examples of common biomarkers included in IPF studies are as follows: • • •

Disease progression biomarkers: CCL-18, KL-6, SP-A, SP-D Fibrosis biomarkers: MMP-1, MMP7, circulating collagen fragments Th2-related cytokines and associated signature: IL-4, IL-13, YKL40, Ig E, eotaxin, CCL18, YKL-40, vascular cell adhesion molecule-1 (VCAM-


1), intracellular adhesion molecule-1 (ICAM-1). Concluding Comments While there have been significant advances in the understanding of the pathophysiology of IPF over the past decade, the mechanisms underlying this disease are still relatively poorly understood. To date, only one therapeutic agent has been approved for IPF worldwide. This leaves an urgent unmet need for new treatment modalities. Based on our experience providing clinical services for more than a dozen

IPF trials involving nearly 1000 patients in 20 countries worldwide, there is room for optimism that new, effective treatment options will be developed in the foreseeable future for this severe and fatal disease. References 1. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK. An Official ATS/ ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management. Am J Respir Crit Care Med. Mar 15 2011;183(6):788-824. [Medline]. Cited in [http://emedicine.medscape. Autumn 2014 Volume 6 Issue 3

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Clinical & Medical Research






7. 8.





com/article/301226-overview] Pulmonary Fibrosis Foundation press release. Pulmonary Fibrosis Foundation Expands with Two New Leadership Positions, February 4, 2014. [http://www. pulmonar] Pulmonary Fibrosis Foundation Messages for Global Pulmonary Fibrosis Awareness Day 2013 Messages for Social Media, September 7, 2013 [http://] Meltzer EB, Noble PW. Idiopathic pulmonary fibrosis. Orphanet Journal of Rare Diseases 2008, 3:8 doi:10.1186/1750-1172-3-8. [http://] Martinez FJ, Safrin S, Weycker D, Starko KM, Bradford WZ, King TE Jr, Flaherty KR, Schwartz DA, Noble PW, Raghu G, Brown KK; IPF Study Group. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med. 2005 Jun 21;142(12 Pt 1):963-7. [http://www.] Coultas DB, Zumwalt RE, Black WC, Sobonya RE. The epidemiology of interstitial lung diseases. Am J Respir Crit Care Med. 1994 Oct;150(4):967-72. [] Pulmonary Fibrosis Foundation website [ Prevalence] Poletti V. Evolvement of best practice in diagnosis and management of idiopathic pulmonary fibrosis. Eur Respir Rev 2014; 23: 3–4. [http://err.ersjournals. com/content/23/131/3.full.pdf] Horton MR, Santopietro V, Mathew L, Horton KM, Polito AJ, Liu MC, Danoff SK, Lechtzin N. Thalidomide for the treatment of cough in idiopathic pulmonary fibrosis: a randomized trial. Ann Intern Med. 2012 Sep 18;157(6):398406. doi: 10.7326/0003-4819-157-6201209180-00003. [http://www.ncbi.] InterMune press release. InterMune Reports Phase 3 ASCEND Trial Results of Pirfenidone in Idiopathic Pulmonary Fibrosis (IPF), February 25, 2014. [] Raghu G, et al. An Official ATS/ERS/ JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management. American Thoracic Society Documents. Am J Respir Crit Care Med. 2011, 183: 788–824, 2011. DOI: 10.1164/ rccm.2009-040GL. [] Cottin V. Changing the idiopathic pulmonary fibrosis treatment approach and improving patient outcomes. Eur Respir













Rev 2012; 21: 161–167. [http://err. short?related-urls=yes&legid=errev;21/124/161] Antoniou KM, Margaritopoulos GA, Siafakas NM. Pharmacological treatment of idiopathic pulmonary fibrosis: from the past to the future. Eur Respir Rev 2013; 22: 281–291. [http://err.ersjournals. com/content/22/129/281.full] Rafii R, Juarez MM, Albertson TE, Chan AL. A review of current and novel therapies for idiopathic pulmonary fibrosis. J Thorac Dis 2013;5(1):4873. [] Raghu G, Collard HR, Anstrom KJ, Flaherty KR, Fleming TR, King TE Jr, Martinez FJ, Brown KK. Idiopathic pulmonary fibrosis: clinically meaningful primary endpoints in phase 3 clinical trials. Am J Respir Crit Care Med. 2012 May 15;185(10):1044-8. doi: 10.1164/ rccm.201201-0006PP. Epub 2012 Apr 13. [] Collard HR, Yow E, Richeldi L, Anstrom KJ, Glazer C; IPFnet investigators. Suspected acute exacerbation of idiopathic pulmonary fibrosis as an outcome measure in clinical trials. Respir Res. 2013 Jul 13;14:73. doi: 10.1186/1465-992114-73. Vancheri C. Common pathways in idiopathic pulmonary fibrosis and cancer. Eur Respir Rev September 1, 2013; 22(129): 265-272.doi: 10.1183/09059180.00003613. [ h t t p : / / e r r. e r s j o u r n a l s . c o m / c o n tent/22/129/265.short?rss=1] King TE Jr., Safrin S, Starko KM et al. Analyses of efficacy end points in a controlled trial of interferon-γ1b for idiopathic pulmonary fibrosis. Chest 2005; 127: 171–177. Caminati A, Bianchi A, Cassandro R et al. Walking distance on 6-MWT is a prognostic factor in idiopathic pulmonary fibrosis. Respir Med 2009; 103: 117–123. du Bois RM, Weycker D, Albera C et al. Six minute-walk test in idiopathic pulmonary fibrosis: test validation and minimal clinically important difference. Am J Respir Crit Care Med 2011; 183: 1231–1237. Yorke J, Jones PW, Swigris JJ. Development and validity testing of an IPF-specific version of the St George’s Respiratory Questionnaire. Thorax. 2010;65(10):921-926 Swigris JJ, Wilson SR, Green KE, Sprunger DB, Brown KK, Wamboldt FS. Development of the ATAQ-IPF: a tool to assess quality of life in IPF. Health Qual Life Outcomes. 2010;877. web site [http://

Search] 24. Raghu G et al. An Official ATS/ERS/JRS/ ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management. American Thoracic Society Documents. Am J Respir Crit Care Med. 2011;183: 788–824. DOI: 10.1164/rccm.2009-040GL. [ resources/interstitial-lung-disease/ ipf0311.pdf] 25. Rafii R, Juarez MM, Albertson TE, Chan AL. A review of current and novel therapies for idiopathic pulmonary fibrosis. J Thorac Dis 2013;5(1):4873. [ pubmed/23372951][http://www.] 26. Short PM, Harani N (2012). The treatment of idiopathic pulmonary fibrosis: an unmet clinical need. Scottish Universities Medical Journal. 1(2). P 199203. [ uploads/volume2/sumjv1i2p.199-203. pdf] (2012) 27. Swigris JJ et al. Idiopathic Pulmonary Fibrosis: Challenges and opportunities for the clinician and investigator. Chest, 2005. 127(1): 275-283 [http://journal. 28. Wells AU. The revised ATS/ERS/JRS/ ALAT diagnostic criteria for idiopathic pulmonary fibrosis (IPF) - practical implications. Respiratory Research 2013, 14(Suppl 1):S2 doi:10.1186/14659921-14-S1-S2 ( 29. Source: Quintiles internal feasibility report, conducted in March 2013

Acknowledgement The authors would like to thank Jill Dawson, Ph.D., Consultant to Quintiles Corporate Communications, for medical writing assistance. Vikki Brandi, PA, DHSc, Therapeutic Strategy Lead, Allergy & Respiratory Center of Excellence, Quintiles, 4820 Emperor Blvd, Durham, NC 27703, USA. Tel: +1 305.757.2027; Fax: +1 305.921.0697; E-mail:

Juan Gispert, MD, Senior Medical Director and Chair, Allergy & Respiratory Center of Excellence, Quintiles, Via Poblados 3, Edif 7, 5 Planta, 28033 Madrid, Spain. Tel: + 34 690 888 374; Fax: + 34 91 414 87 83; E-mail:

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Labs & Logistics

Clinical Trial Logistics – Meeting the Needs of an Evolving Pharmaceutical Industry The pharmaceutical industry, and its approach to outsourcing clinical supply chain activities, has evolved rapidly over the past two decades. Early outsourcing by major pharma was typically a tactical exercise, aimed at alleviating short-term peaks in demand on internal resources. Outsourcing was often prescriptive and aimed at specific tasks – for example packaging and labelling of clinical supplies. Big pharma generally possessed internal capacity and expertise, and service providers simply delivered services based on specific instructions provided by these clients. Conversely, the emerging biotech sector took a different approach. These companies mostly operated under virtual models, with the majority of development services outsourced. Biotech companies typically did not have large clinical supply departments or experience internally, and largely relied on input from service providers to help design and implement clinical supply strategies. Over the past 20 years, these two approaches have moved closer together. As a result of downsizing, many big pharma companies have shed their internal capacity, and a focus on core competencies has resulted in a reduction in experienced in-house clinical supply managers. While there are still exceptions, it is reasonable to conclude that both types of company are seeking true strategic partnership with their service providers, with the latter having greater input not only into execution of tasks, but also into the planning process. This is especially true in the management of clinical trial logistics, which has changed dramatically over the years. This paper will discuss where we have come from, how this service has developed, and drivers for some of this change. Clinical Trial Distribution – Origins Two decades ago, shipments of clinical trial supplies typically shared the same supply chain as commercial product. Clinical supplies would be packaged centrally (either in-house or by a vendor) and shipped to the company’s own incountry distribution facilities in territories where the trial was taking place. In88 INTERNATIONAL PHARMACEUTICAL INDUSTRY

country depots would then ship to clinical trial sites within each country. With the exception of couriers, most of the tasks in the supply chain were performed by each company’s own assets. Based on the design of the clinical supply chain at that time, this strategy made sense. • •

Costs were minimised, as companies were using existing infrastructure and import/export expertise. Clinical supplies were often supplied to study sites as a statistical ‘block’ of medication for several patients (block = minimum number of randomised kits required for each site to have an equal number of kits for each treatment arm without unblinding a study). Sites were also supplied with all potential doses for each patient for the entire duration of the study, so additional shipments were not required even if a patient titrated from a low to a high dose. Since the size of the block often exceeded the number of patients enrolled at a clinical trial site, repeat shipments were limited. As a result, the additional clinical trial workload did not over-burden the commercial supply chain. Shipping a single large international shipment, followed by multiple short-distance local shipments is more cost-effective than multiple international shipments.

This model had some advantages: 33 Lower freight costs than shipping direct-to-site from a single central depot. 33 Consistent processes and visibility (one company, one IT system). 33 Under block-based clinical supply strategy, low burden as few shipments/site. However, it also had disadvantages, which would grow as clinical supply strategies evolved: 33 Higher overage requirements increasing drug costs – safety stock at each depot, an issue that increased with the growth of biopharmaceuticals and associated increases in drug values/dose. 33 Lack of scalability. Can this model be maintained without increasing fixed costs if there is a significant uplift in shipping frequency? What investment would need to be made if additional storage conditions are required across the entire network? The above approach is used by very few companies today. Changes in clinical supply strategy as a result of technologies such as IRT, globalisation of clinical trials, an increase in the number of temperaturesensitive products in development, an increase in product value, downsizing, increased regulation, and the need for more improved cost control, have led

Figure 1: Distribution Using Existing Commercial Infrastructure – Local Depot in Each Country Autumn 2014 Volume 6 Issue 3

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Labs & Logistics to the development of new distribution management models. The Impact of Interactive Response Technology (IRT) on Distribution Strategy As mentioned above, clinical supplies were traditionally delivered to study sites as blocks of medication, including every possible dose a patient could need. This is potentially very wasteful – supplying a site with eight patients’ medication if they subsequently enrol only one patient would waste seven patients’ supply of drug. Similarly, if a patient discontinued in the trial, the patient-specific nature of clinical packaging at that time meant that their drug was wasted – it could not be reassigned. Finally, providing all possible doses to a patient was also wasteful. IRT systems removed the need for ‘patient kits’ and patient-specific labelling of packs. Instead of providing the site with a full block of medication to cover every patient for the entire trial duration, sites could be provided with a small quantity of visit kits covering each dose level for each treatment arm. Since drug was assigned by the IRT system during dispensing visits, there was no longer any need to use patient-specific labelling – if a patient withdrew from the trial or changed dose, medication could simply be assigned to other patients. As sites dispensed drug to patients and inventory was used up, resupplies were automatically ordered by the IRT system once pre-determined trigger levels were hit. As a result of this, inventory could be stored centrally, labelled for multiple countries, and only shipped to site in small quantities as and when required. While this has a dramatic effect on reducing drug overages and the costs associated with this, switching from supplying each site with multiple smaller resupplies rather than a single ‘full study’ supply dramatically increased the volume of drug shipments required to support each trial. This, in turn, impacted on the costs and workload associated with the clinical supply chain. While some companies persevered with the model of shipping through their commercial local depot network, many companies sought alternatives. As a result of the increased burden on the commercial supply chain, many companies centralised distribution at a regional level where possible, and contracted all, or surplus, storage and

distribution to clinical supply specialists. The EU single market allows shipments to be made easily to other member states from a single EU depot. Also, the EU Clinical Trials Directive made it mandatory for clinical supplies imported from outside of the EU to be released by an EU Qualified Person. Importing through a single EU hub and shipping directly to clinical sites from there reduced the burden of multiple EU imports and releases associated with shipping to multiple EU sites.

Many new clinical trial destinations were not served by companies’ existing commercial distribution networks. Local import regulations made it difficult to supply directly to patient sites from outside of each country, and the costs and distances involved in shipping from a central global hub made this an

Figure 2: Use of a Contracted Depot for Centralised EU Distribution Globalisation of Clinical Trials Two decades ago, clinical trials typically enrolled patients in the industry’s main markets of Europe and the US. However, competitive enrolment rates and large treatment-naïve populations have encouraged the industry to broaden the global clinical trial footprint to include new territories in Eastern Europe, Asia, Latin America, the Middle East and Africa.

expensive option. As a result of this, pharma companies set up relationships with local distribution depots. Initially this was done independently by local study teams in each country. This approach created some difficulties – separate contracts meant that pharma companies could not maximise volume discounts on service pricing. Also, a decentralised

Figure 3: Global Distribution Using In-Country Depots Where Appropriate – Multiple Partners


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Labs & Logistics

approach to depot management led to inconsistent service delivery in each country. As each depot provider operated different IT systems, getting real-time visibility of global inventory and distribution activities was impossible. This model has the following advantages: • Allows access to emerging clinical trial territories. • Hybrid of hubs covering multiple countries, local depots where necessary provides a balance of lower inventory requirements, and lower distribution fees. • Use of depots in countries with complex import requirements helps reduce administrative burden of shipping to these countries (import licence application) and the number of times the supply chain is impacted by customs delays. • Use of local depot providers gives local knowledge, which central HQ may not possess. • However, there are some disadvantages: • Multiple providers of depot services reduce the potential for volume discounts. • Multiple providers with inconsistent 92 INTERNATIONAL PHARMACEUTICAL INDUSTRY

processes can introduce quality risks into the supply chain. It can be difficult to get a full ‘global’ picture of inventory.

Setting up global teams and owned facilities to improve this situation was contrary to the industry’s strategy to reduce fixed costs and focus on core competencies. Pharma instead turned to their clinical supplies and logistics outsourcing partners to help determine global distribution strategy, and to manage global depot networks on their behalf. Changes in the Nature of Pipeline Products and Regulations Biopharmaceuticals are making up an increasing proportion of the industry’s development pipeline. Global sales of biopharmaceuticals have risen 353% to $163bn between 2001 and 20121. Similar growth has been seen in the development pipeline, with the number of biopharmaceuticals in development increasing from 355 in 2001, to 907 in 2012 . Biopharmaceuticals are sensitive to changes in temperature, and as a result are typically shipped under refrigerated conditions in insulated

shipping systems. The large cost and weight of these systems compared with standard uncontrolled ambient shipments has vastly increased shipping costs. Also, the expertise required to manage these shipments has increased the skill set required in distribution teams, again driving increased outsourcing to specialist service providers. Storage facilities for temperature-sensitive products require major capital investments and running costs. The growth in temperature-controlled shipping costs looks set to continue to increase as older biopharmaceutical patents expire and generic versions of these (biosimilars) enter development. New GDP regulations, and the need to demonstrate adequate temperature control even for products traditionally shipped under lower-cost ambient conditions, look set to further increase distribution costs in the future. Industry forecasts estimate that clinical trial logistics spend will reach $2.99 billion in 2014, rising to $3.16 billion in 2018.2 Finally, as pharma companies increase their focus on rare diseases, and the number of orphan drugs entering pipelines increase, further increases in Autumn 2014 Volume 6 Issue 3

Labs & Logistics logistics costs are expected. For example, if a rare disease only affects a few thousand patients globally, recruiting sufficient patients in a short timeframe to support a global clinical trial is likely to require patient enrolment from a wide range of countries, further adding to pharma’s rising logistics bill. It has been estimated that the cost per patient for an orphan drug trial can be more than 25-times greater than that for a more common condition3. Industry Response None of the above factors look likely to change in the coming years. Pharma will still use IRT technology to control overages and waste in clinical studies, which is becoming more critical as unit dose costs for new drugs continues to rise. In fact, the advent of mobile technology and lower-cost fully-configurable IRT systems is likely to increase the number of trials employing this technology. There is no sign that biopharmaceutical development will slow down – new biosimilar regulations in key markets are likely to continue to increase the growth of these compounds. Clinical trials will continue to globalise – especially as markets such as China become increasingly important to the global industry, necessitating trials on local populations. To control increased costs and risks associated with these developments, pharma needs to choose between investing in expertise and assets internally, or working strategically with external partners to ensure the supply chain is efficiently maintained. While a handful of companies continue to work in-house and outsource tactically when required, the majority have now chosen to work with a small number of external global partners to benefit from their expertise, asset investments, and volumebased pricing.

Figure 4: Entire Distribution Network Managed by 1-2 Clinical Supply Partners The model below illustrates the direction most large pharma companies seem to be taking, in which 1-2 partners are contracted to manage the depot network. It is important to highlight the word manage and point out that it is not necessary for the partners to own their own facilities. No clinical supply company has a depot in every country. Similarly, performance varies geographically even for large global couriers. A multiple provider model managed by a single partner can be very successful – provided partners take responsibility for the quality and performance of any depots they manage. The partner managing the network should also work to ensure that, even if multiple depots are used, the sponsor is able to access supply chain information (e.g. global inventory) from a single source by integrating subcontractor systems and reports with their own, either by rolling a single IT system out across the entire network, or by integrating third-party IT systems with their own. The management of clinical trial distribution has changed over the past two decades, very much as a result of changes in the wider pharmaceutical industry. While management of the clinical supply chain is a critical part of drug development, it can be viewed as a highcost (technology, assets and headcount), low-value-adding component of drug development for a pharma company to take on single-handed. External clinical supply specialists, by spreading this cost over multiple sponsors, have been able to invest in improving distribution models to provide a truly global clinical trial supply chain.

References 1. edsilverman/2013/11/18/biotechmeds-are-swelling-those-pharmapipelines/ 2. h t t p : / / w w w . index.php?pg=latest_news&article id=27174&keyword=Sourcebooklogistics-cold%20chain-biopharmaBasta 3. h t t p : / / w w w . o r p h a n - d r u g s . org/2013/10/07/strategicallymanaging-logistics-costs-raredisease-clinical-trials/#sthash. ZSVdkIPD.dpbs

Martin Lamb has worked in the clinical trial supplies industry since 1996. Prior to joining Biotec Services International (now Packaging Co-ordinators Inc) as Commercial Director in June 2014, he spent more than 17 years with Almac Clinical Services, the majority of which were as a member of the senior leadership team. His previous publications include papers on patient compliance in clinical trials, novel blinding technologies and global clinical trial logistics. Martin studied Pharmacology at the University of Leeds, which he supplemented with postgraduate qualifications in Marketing (Chartered Institute of Marketing). The author can be contacted on martin. INTERNATIONAL PHARMACEUTICAL INDUSTRY 93

Labs & Logistics

Thermal Packaging and Good Distribution Practice: A Natural Fit? Introduction It’s reasonable to assume that, when confronted with the latest GDP guidelines, most manufacturers of thermal packaging will have allowed themselves a wry smile, since their products have largely been developed over time to compensate for the absence of such guidelines. From the perspective of the thermal packager it has always been best to assume that whatever can go wrong will go wrong, and that however simple and user-proof the packaging, people will still find a way to do something bizarre with it. The advent of the new guidelines is therefore to be welcomed, since they place a very considerable onus on all parties to comply with what are largely well-thought-out and sensible provisions. Beyond this, potentially, they spell an end to a period of significant frustration. Everyone said that key market drivers, in particular globalisation and greater regulation, would pose great challenges to providers of thermal packaging. Longer compliance times, less predictable and wider ambient temperatures and a rigorous audit trail requirement would all send thermal packagers back to their R&D labs to seek new methodologies. If those challenges weren’t enough then the coming economic slowdown would demand lighter and more space-efficient configurations. In theory, then, a nightmare scenario for the packaging suppliers, and it is certainly true that recent years have seen new ideas being introduced to better address some of these issues but, excepting the odd scare story, and perhaps ruling out the most challenging destinations, it’s reasonable to suggest that the cold-chain element of the pharmaceutical supply chain actually functions pretty well. This is despite most packaging solutions needing to be designed down to a price. Some while ago I recruited a packaging engineer from a well-known maker of disposable products, and when he arrived another colleague asked him why he was leaving such a well-established company to join our then-newly-formed enterprise. He said that he was fed up with designing to a 94 INTERNATIONAL PHARMACEUTICAL INDUSTRY

brief defined by a pharma customer, only then to be told that his solution was too expensive, and he needed to ‘engineer out’ a certain amount of cost. He therefore wanted to work within the reusable packaging market, where high quality can be designed and built in, and which can be amortised over years rather than one trip. I recount this story not to be disparaging about the highlycommoditised disposable packaging market but to illustrate the delicate balance of risk versus cost that this sector deals with on a daily basis. What effect GDP guidelines will ultimately have upon cost is uncertain right now, but I think it’s realistic to suggest that costs will rise, but that this increase will be counterbalanced by the reduced level of write-offs due to non-compliance. What is certainly true is that the GDP provisions will have been greeted with considerably less panic by thermal packaging providers than they have been by some other players in the cold chain. This is because, as I suggested at the start, for years they’d been designing solutions that needed to compensate for the absence of commonly-agreed practices. When things go wrong in the pharma supply chain the packaging provider is a very easy scapegoat, and it’s far too easy to attribute sloppy practice elsewhere to a failure of the packaging. If the issue is simple, such as somebody forgetting to connect a powered, active, device to the mains when it comes off the plane, then that’s equally simple to address. However, if the problem relates to an unforeseen temperature excursion which could derive from faulty packaging, but in our experience is more likely to reflect incorrect use of such packaging, or a departure from the agreed shipment plan, then this is much more complex to unravel post-shipment. Thus the provision of an internationally-agreed set of guidelines by which all can abide is greatly to be welcomed. So what do the new guidelines say about thermal packaging, and what should we make of them?

Quality Management If we accept the premise that thermal packaging solutions have been laboratory tested to a certain level of performance, then we should also note that the highly-pressured, rough-andtumble freight environment is a world away from that ideal development scenario. Solution providers therefore adopt highly-disciplined ISO-type quality management systems so that customers can replicate best practice every time that they use the products. Because English is so widely accepted this places extra responsibility upon those creating written instructions and procedures: in a world so dependent upon accuracy it is startling to discover the numbers of words and terms that are susceptible of alternative interpretation, with potentially alarming consequences. This might matter less if the only changes in thermal packaging were between various types of disposable products, where the main principles are consistent and where terminologies are wellestablished and understood. The issue now is that there are more and more different packaging methodologies: simple disposables are accompanied now by semi-reusables, capable of being used several times; reusable solutions may be active or passive, and with each of these options come another set of instructions and new expressions. Phase-change materials, for example, have been employed in this market for many years, and yet it is surprising how many people within the pharma supply chain are ignorant about their use and how they work. The emphasis therefore falls back onto the need for high-quality instructional materials and high-quality training because, as I observed earlier, if something can go wrong, it will, and whether that problem is overcome with zero consequence, or whether it leads to many thousands of dollars of product being lost, is entirely down to the actions of people on the ground, hopefully being able to fall back on good training and good supporting information.

Autumn 2014 Volume 6 Issue 3


Diabetics do it better

What if we only hired diabetics to work in the active cold chain? Would they take more care handling healthcare products? We think they would. They know what happens if they don’t get insulin. Of course we don’t just employ diabetics. But we do share their understanding of the value of what we ship in our containers. We educate the members of the active cold-chain on the difference they make to the lives of diabetics and others who rely on healthcare products. Because people do a better job when they understand the importance of why they are doing it. Gunay Hadjimehmed is a diabetic. And his son Mehmet works for us.

Labs & Logistics Transportation I wrote earlier about the difficulties of attributing ‘blame’ when something doesn’t go according to plan. I’m thinking not so much about the need to identify who should bear any financial compensation that is necessary, but perhaps more importantly the idea of ensuring that whatever did go wrong can’t happen again. GDP calls for a ‘risk-based’ approach when planning transportation and Fig. 1 illustrates why this makes sense. In this case we are assisted by the dataloggers built into TOWER’s range of KryoTrans containers, which record both internal and ambient temperature, and so the jagged inflection that appears on the product temperature line after around 130 hours (where the phasechange materials react to a major shift in

ambient temperature in order to control the internal temperature) can be seen to be caused by a huge ambient spike. The instructions for this shipment, from France to California, called for the container to be moved straight from the aircraft to a controlled-temperature warehouse facility, but when the audit trail was downloaded it revealed a startling spike of over two hours in which ambient temperature reached over 60°C. Although the ground handling company initially denied that there had been any failure to comply with the agreed instructions, when confronted by the evidence they conceded that the container had been transferred to an ambient vehicle and then left out in the sun and forgotten for two hours. I recount this story not to promote the way in which

Fig. 1, from France to the US West Coast, with more Californian sunshine than was expected x-axis shows transit hours, y-axis shows degrees Celsius

Fig. 2, a Middle East road trip with an unscheduled blip Katie Friday, TOWER Cold Chain Solutions, September 2014


the KryoTrans container dealt with the problem, nor to exemplify the way that the datalogger records both internal and ambient temperatures, but to show how, even with well-set-out and properly communicated instructions in place, somebody’s thoughtlessness can still have the potential to wreck the best-laid plans. I guess it is such circumstances that prompt the authors of the GDP guidelines to call for a ‘risk-based’ approach! A similar situation arose after a roaddistribution job that one of our containers undertook in the Middle East (Fig. 2). In this graph you’ll see a spike in the internal temperature at around 48 hours and, not unreasonably, the client needed some explanation. Because the container features a proximity sensor that records occasions upon which the door is opened, it was possible to correlate the time records and show that, for some unaccountable reason, the driver had decided to investigate the contents of the container in his truck. No harm came of it but, as direct evidence of the strange things that can happen, it is instructive. The bottom line is that all participants in the pharma cold-chain are charged with the very considerable responsibility of ensuring that life-saving, life-changing, life-prolonging medicines reach patients in perfect order, at the right time. Until recently the various participants in this process have been obliged to develop products and procedures that have been designed to overcome the fact that other links in the chain may not be quite so strong. Now we have a set of sensible guidelines that are there for all parties to be measured against, for new entrants to aspire to and which will undoubtedly lead to a harmonising of effort.

Katie Friday has been part of the TOWER & KryoTrans team for several years, her background is in the specialist pharmalogistics courier sector. Katie's role at TOWER encompasses technical sales support and marketing. Autumn 2014 Volume 6 Issue 3

Sept 2014


Tailor-Made Product Attributes Tailor-Made Product Attributes Fluid-bed technology opens up an enormous range of possibilities for optimising products – from better solubility, dust reduction, easier tabletting and fortification with vitamins to microencapsulation of active ingredients. Very gentle handling of the products and the diversity of the possible applications have made fluid-bed processing one of the most important formulation methods in the food and pharmaceutical industries. Fluid-bed technology is a formative drying process enabling a specific influence on the physical properties of solid and liquid products and their possible applications. Depending on the customer’s requirements, the process results in agglomerates, instantised granulates and coated or microencapsulated particles which are easier to use and have better functional properties. More Than Just Hot Air In the fluid bed the product is dried in a controlled environment, which permits optimum adjustment and standardisation of its attributes. Warm, filtered air is sucked into the product container of the unit through a fluidised bed. A distribution plate ensures that the current of air has defined flow characteristics. In this way the starting materials are mixed intensively, creating a fluid bed. Practically the whole surface of the individual particles is exposed to the relevant medium – whether air for drying or sprayed-in suspensions or emulsions. The liquid is introduced either from top to bottom or from the bottom upwards. The particles can now be dried to the desired final moisture. Since drying can be carried out in a low and therefore gentle temperature range, the product is usually subjected to only moderate heat between 30 and 50°C. No thermal damage occurs. The method is therefore especially suitable for processing heatsensitive ingredients such as enzymes, flavourings, vitamins and microorganisms. Besides the gentle drying process, granulation, agglomeration, coating and microencapsulation can be carried out in the fluidised bed with a saving in time and cost. 98 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Gentle Drying by Spray Granulation Spray granulation is used for transforming liquids into powders. Fluidbed drying has a number of advantages over conventional spray-drying. The process is not intended just to remove the moisture from a product. The main purpose of the method is to obtain dry products with precisely defined structures and parameters. It is possible, for instance, to produce a dustless powder or a free-flowing granulate with a defined particle size that disperses extremely well in liquids. Applications include the drying of enzymes. The liquid enzyme is sprayed onto a carrier and gently dried. The resulting granulate of the active substance has optimum characteristics for further processing. Vitamins can be applied to carriers in the same way. Agglomeration for Readily Soluble Instantised Powders Moreover, the fluid bed is an ideal blender. Several powdered substances can be mixed in the processor and agglomerated in the same step. If the surface of the particles is moistened and simultaneously dried, the powder particles stick together to form freeflowing agglomerates. Among other things, this influences the instantising properties of the powder. Compared with the fine powders that result from spraydrying, the products from the fluidised bed dissolve and disperse much more readily in liquids. This also facilitates handling

of the goods, because the agglomerates thus produced contain much less dust, are more suitable for tabletting, and are easier to dose because of their superior flow properties. Agglomeration also prevents the individual components from separating again when processed. In the case of pharmaceutical products and also food supplements, a very high degree of homogeneity is essential – every tablet, capsule or portion must contain exactly the same amount of the active ingredient. In the fluid-bed processor, even minute amounts of the substances are firmly bound in the agglomerate; this ensures homogeneity and prevents any separation. Coating: Functional Surfaces or Protective Films Whereas the purpose of agglomeration is to achieve specific modification of the particle size distribution, coating covers the individual particles with a layer that gives the product a defined functionality. In the coating process, particles are wetted and covered with a liquid in a current of air. A thin, even shell of melted fats, sugar dissolved in water or functional polymer mixtures, for example, then protects the solid material against external influences such as light, oxygen or moisture. Particles can also be coated to enhance their appearance, mask an unpleasant taste or prolong their

Autumn 2014 Volume 6 Issue 3


shelf-life. One of the applications of the method is tablet production, in which a functional surface is applied in order to shield sensitive substances from the gastric juices. In the case of hygroscopic substances, a coating can reduce the absorption of atmospheric moisture and thus prevent the formation of lumps. Microencapsulated Granulates Microencapsulation differs from coating in that solid or liquid active substances are bound homogeneously into a carrier material. It results in particles which are in a precisely defined state and resistant to external influences. Microencapsulation effectively protects enclosed droplets of liquid such as omega-3 fish oils against oxidation, and can thus prolong the shelf-life of the product. Moreover, the method permits the specific or delayed release of pharmaceutical substances through “controlled release” or “slow release” mechanisms that act as the powder formulation dissolves. Even volatile substances like flavourings can be stabilised by microencapsulation. Outsourcing Production Fluid-bed technology has a great diversity of applications. The pharmaceutical and food manufacturers who use it are optimally set up for the more and more complex products on the market. But for small companies and manufacturers with a quickly changing range, it is a challenge to install expensive plant or constantly bring their equipment up to date. So it may be a sensible solution to outsource production. SternMaid, 100 INTERNATIONAL PHARMACEUTICAL INDUSTRY

a leading contract manufacturer of both foods and food ingredients in powder form and pharmaceutical active substances and excipients, owns state-ofthe-art equipment. In 2012 the company invested some 5 million EUR in a fluid-bed processor and is therefore in an excellent position to offer flexible and efficient production of functional ingredients or end products. Moreover, eight separate blending lines are available to meet all manner of different requirements. The Wittenburg company’s modern countercurrent container blending line – ideal for blending vitamin compounds – has been qualified retrospectively and certified officially according to Part II of the EU GMP Guide. It permits blending, processing and filling of active pharmaceutical ingredients and excipients according to strict regulations. [Box-Text:] Specific Enhancement of Product Attributes The fluid-bed processor makes it possible to achieve or influence the following product attributes: Agglomeration • Instantisation of powders • Enhanced flow properties • Less tendency to separate • Smaller proportion of fine dust • Easier tabletting • Low bulk density Spray Granulation • Very good dispersibility in liquids • No separation of the individual components

• • •

Very little fine dust Narrow range of particle sizes High bulk density

Coating • Inertisation of the surface, e.g. to mask an unpleasant taste • Protection of the core against moisture, acids (gastric juices), oxidation etc. • Application of colours or varnishes to design the surface Microencapsulation • Longer shelf-life • Stabilisation of volatile substances • Protection against chemical reactions, oxygen, light or moisture • Depot effect

Mark Riemer completed his training as an industrial mechanic, specialising in process technology, in 1994. From 1994 to 1998 he worked for the SternWywiol Gruppe in Marketing and Assistance, also starting a university course in automotive engineering. In 1998 the new SternMaid production facility was built in Wittenburg. Mark Riemer has been employed as its Commercial Director since 1999. Autumn 2014 Volume 6 Issue 3


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Manufacturing Accelerating the Development of Generic Pharmaceuticals: Developing an Analytical Toolkit Suitable for De-formulating Complex Reference Products In its report ‘Critical Path Opportunities for Generic Drugs’, the FDA emphasises the need for advances in the field of analytical sciences in order to accelerate the development of generic products1. Here, Gurfateh Singh and Paul Kippax highlight techniques that are especially helpful in the de-formulation of complex reference products, focusing on triple detection Size Exclusion Chromatography (SEC) and Morphologically-Directed Raman Spectroscopy (MDRS). The FDA’s report ‘Critical Path Opportunities for Generic Drugs’, published in May 2007, identifies a number of areas for improvement in generic formulation development. It emphasises the need to upgrade the science underpinning the application of quality by design (QbD) for example, and to improve the efficiency of current methods used to assess bioequivalence (BE) for systemically acting, topical and inhaled drugs. In addition, the guidance underlines the increasing requirement to advance the analytical technology used in characterising drug substances and products, most especially those products that involve complex and novel drug delivery technology1. While the development pathways for generic and innovator drugs have much in common, there are also some important distinctions. One critical difference is that commercialisation of a generic begins with de-formulation, the unpicking and rationalisation of those characteristics of the reference listed drug (RLD) that deliver its performance. As pharmaceutical products become more sophisticated, de-formulation becomes more difficult, an issue reflected in the FDA observation that “In the characterization stage, some generic products are challenging to develop because of the complexity of the reference product.”2. With a complex dosage form the de-formulation and product development stage can fail directly because of an inability to identify the critical quality attributes (CQAs) of the RLD. Mapping analytical requirements on to the workflow for de-formulation is helpful in identifying those techniques that 102 INTERNATIONAL PHARMACEUTICAL INDUSTRY

are the most productive and efficient in generating the required information. This is increasingly important as regulatory guidance now points to the application of QbD for abbreviated new drug applications (ANDAs). Understanding and controlling all the variables that have an impact on product and process behaviour is essential for the application of QbD and intensifies the need to thoroughly explore the product design space, this being the combination of characteristics that define and safeguard clinical efficacy3. In this article, triple detection SEC and MDRS are considered within the context of characterising complex drug formulations, with specific case studies and results illustrating their application. The Growing Challenge of Deformulation As innovators push back the boundaries of pharmaceutical product engineering, tablets, inhalers and topical creams are being precisely formulated to give closely controlled clinical performance. For the resulting complex products, deformulation and generic development may be made difficult by the presence of “drug substances with many

potentially active molecules”2. However, replication of the behaviour of the active pharmaceutical ingredient(s) (API) is just one challenge. For example, the performance of dry powder inhalers (DPIs) is the result of complex interaction between device and formulation. In many cases these products are breath-actuated, which means that any generic DPI must be engineered to perform equivalently to the reference product, over the full range of flow rates exhibited by the target patient group2. Achieving this level of equivalence relies on knowing and developing a thorough understanding of those features of the reference device and formulation that give rise to the observed performance. Another example of the complexities of de-formulation is highlighted by recent concerns about the interaction of modified release oral dose formulations with alcohol consumed by a patient. These interactions have the potential to cause ‘dose dumping’, where the dose is released over a much shorter timescale than the design intent, causing severe adverse effects4. This concern has led to the identification of a new, potentially CQA, for generic controlled

Figure 1: The de-formulation work flow for oral solid dosage forms Autumn 2014 Volume 6 Issue 3

Manufacturing release oral dose formulations, and has made it essential to characterise the polymers used in the RLD to ensure the desired control release effect, under all circumstances. Clearly, rigorous de-formulation and bioequivalence testing is essential for regulatory approval and for building the confidence of healthcare providers, patients and the public in generic drugs, in their safety and equivalence to innovator products. With complex RLDs, this may mean that formulation scientists working on generics now need even better characterisation technology than was used for the innovator product. Introducing the De-formulation Workflow Dr Arvind K Bansal, Professor and Head of the Department of Pharmaceutics at the National Institute of Pharmaceutical Education and Research (NIPER), India, describes a general approach to the process of de-formulation (see Figure 1). The described de-formulation process consists of two main activities: identification of the CQAs of any excipients present, which dictate the RLD’s target performance profile, and de-coding of the characteristics of the API. Both activities involve understanding the chemical and physical forms of the materials used in the formulation by applying a combination of analytical techniques. De-formulation typically begins with identifying the CQAs of the various excipients present. Excipients used as stabilisers and surface active agents directly control the rate of dissolution of a product. Polymer excipients are especially challenging in generic development because of the complex relationship between minor changes in their structures and the effect this may have on bioavailability. Separating such components from other excipients present to enable closer analysis without interference from other ingredients is therefore helpful. Reverse phase chromatography and SEC are valuable techniques for separating excipients, but the information gathered about the separated components is highly dependent on the detectors used. Refractive index (RI), ultraviolet light (UV) and light scattering detectors, viscometry and mass spectrometry, can all be applied to generate useful information about individual components of the formulation. For example, SEC, 104 INTERNATIONAL PHARMACEUTICAL INDUSTRY

when used in combination with an optimal triple detector array, may prove effective for quantification of release modifying polymers. The solid state characterisation of the API and excipients is the second critical part of the process. An innovator product is usually developed with the most stable polymorphic form to avoid polymorph transformation-related complications during processing and storage. For a generic manufacturer, identifying and using the same polymorphic form helps to avoid complications with bioequivalence. The techniques commonly used at this stage are: imaging, spectroscopy, X-ray powder diffraction, differential scanning calorimetry and thermogravimetric analysis. Dr Bansal also describes microscopy as an effective tool in differentiating API and excipients, but this is an area where MDRS can bring speed and efficiency. In addition to processability, the manufacturing technique can also affect drug stability and performance. The de-formulation workflow therefore concludes with the identification and establishment of a manufacturing process for a generic product which is similar to the manufacturing approach adopted in production of the RLD. The following case studies provide some illustrative examples of how certain techniques can bring value within this defined workflow. These case studies highlight the effectiveness of triple detector SEC for efficient determination of the absolute molecular weight of polymeric excipients used in controlled release oral dose formulations. They also indicate the use of MDRS to measure componentspecific particle size distribution, in a multicomponent RLD. Case Study 1: Decoding the Molecular Weight and Grade of Polymers Commonly Used to Modify Release of API in an Oral Solid Dose Formulation Hypromellose (hydroxypropyl methylcellulose, HPMC) and its derivatives are commonly used for controlling the rate at which an API is released from a formulation during use. These polymers are considered to be challenging to work with, because of their high glass transition temperature, low degradation temperature and high viscosity. Hypromellose acetate succinate (HPMCAS) is a specific derivative of the HPMC widely used as a cellulosic enteric

coating agent5. The grade of the polymer used directly affects the release profile of the API, making it a CQA for achieving a target product performance profile and bioequivalence. SEC is used routinely across the pharmaceutical and biopharmaceutical industries to gather molecular weight information for polymers, proteins and macromolecules. It involves passing a dissolved sample through a column containing a micro-porous packing material to produce a size fractionated eluent stream. Larger molecules elute from the column first as they are sizeexcluded from the smaller pores in the packing; the smallest molecules can access all of the pore volume and elute last. With conventional SEC, a single detector, most commonly an RI detector, is used to measure the concentration of polymer in the eluting sample. The conventional SEC set-up relies on the use of polymer reference calibration standards to establish a correlation between molecular weight and the elution volume from the column. The molecular weight data reported are therefore relative to the calibration standard, rather than absolute. If the relationship between size and molecular weight differs for the sample and the standard, for example because of conformational or structural differences, then the molecular weight information generated will be inaccurate. In contrast, triple detection SEC systems, such as the Viscotek TDAmax (Malvern Instruments Ltd), incorporate additional detectors to analyse the eluting fraction in more detail and, most especially, to provide absolute molecular weight without any requirement for a relevant calibration standard. A common triple detection array includes a light scattering detector and a viscometer, alongside an RI or UV concentration detector. In combination, the results gathered enable calculation of the absolute molecular weight and molecular weight distribution of the sample and quantification of the structural characteristics of any polymer present, such as degree of branching. Figure 2 shows the molecular weight distributions of a series of HPMC and HPMCAS grades measured using a Viscotek triple detection system6. Measuring absolute molecular weight, rather than applying conventional calibration (see Table 1), successfully Autumn 2014 Volume 6 Issue 3

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Figure 2: Molecular weight distributions of HPMC and HPMCAS samples measured using triple detection GPC/SEC. [Reproduced with the author’s permission from reference 7]

differentiates the different grades of HPMCAS and correctly reveals all the grades to be of higher rather than lower molecular weight than the HPMC. In fact, the absolute molecular weights of the first two samples of HPMCAS are shown to be around double the relative molecular weights reported by the conventional calibration technique; the absolute molecular weight of the third sample is five times higher than the figure suggested by conventional SEC. Since molecular weight directly impacts the release profile of the formulation, accurate measurement is essential when it comes to de-formulation. Furthermore, in addition to accurate molecular weight information, triple detection also provides molecular size and intrinsic viscosity data to differentiate between different grades of a polymer that have similar molecular weight but different structures. This ability makes triple detection SEC an essential tool for ensuring the accurate characterisation of the polymer used in an RLD.

other characteristics such as shape can be advantageous. In addition, during de-formulation it is often necessary to gather size and shape data for specific components within a formulation, most usually the API, rather than averaged data for the formulation as a whole. The techniques commonly employed for this task are microscopy, spectroscopy and X-ray diffraction as described in the deformulation workflow above. MDRS is a relatively new technique that can provide component-specific particle size and shape information effectively and rapidly. Introducing the Morphologi G3-ID The Morphologi G3-ID combines advanced optics for automated static imaging with Raman spectroscopy to enable the measurement of componentspecific particle size and particle shape distributions. The system provides size, shape and chemical analysis information for particles in the size range 0.5 µm – 1000 µm and is employed for a variety of sample types in the development of a

range of pharmaceutical products, including dry powders, liquids and creams. It operates by scanning an automatically dispersed particle sample, using advanced optics to capture images of individual particles. Selected particles can then be analysed using Raman spectroscopy, to enable the chemical identification of discrete populations within a multicomponent mixture. Automation, from sample dispersion through to measurement, delivers substantial improvements in accuracy and measurement times relative to manual microscopy, which, in contrast, is labour-intensive and can exhibit operator-dependent results. In order to show the capabilities of MDRS, a commercially-available branded cold and flu remedy (sold as a powder) was analysed alongside a generic formulation using the Morphologi G3-ID system (Malvern Instruments). Both the generic and commercial remedies contained a significant number of components, including an API. To investigate the composition of the two products in detail, Raman spectra were gathered to identify the components present and their relative amounts within each product. By comparing the spectra obtained with reference Raman spectra from a commercial database, 11 components were identified in both products. The percentage of each component was consequently quantified (see Figure 3). The three most common components in both formulations were 1, 2 and 11. The commercial product was found to contain more of component 1 than the generic product, whereas the generic contained more of compound 2. From reference

Case Study 2: Focusing on Characterisation of the API The functionality of an API is directly attributable to particle characteristics such as particle size distribution, particle shape, morphic form and crystal habit. These parameters influence a number of pharmacological properties, including drug release and uptake within the body, a critical component of clinical efficacy. Laser diffraction is the standard technique for particle size distribution measurement within the pharmaceutical industry. However, when it comes to closer scrutiny of the API, the measurement of 106 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 3: Raman spectroscopy efficiently detects the amount of each ingredient present in a commercial (green) and generic (red) cold and flow remedy. Autumn 2014 Volume 6 Issue 3

The Smart Excipient

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Triple Detector Array (TDA) Mw <Rg>w <Rh>w ()w (Da) (nm) (nm) (dL/g) 88,100 18.54 14.24 2.493 162,300 13.49 10.36 0.87 167,500 13.5 10.36 0.882 360,900 15.95 12.25 0.792

a 1.016 0.689 0.688 0.667

Conventional Results Mw (Da) 98,100 83,400 74700 72500

Table 1: Results for the analysis of HPMC and HPMCAS samples using conventional and triple detection GPC/SEC from reference [6]. Measuring absolute molecular weight with a triple detector correctly reveals that the HPMCAS samples have a higher molecular weight than HPMC. spectra, component 2 was successfully identified as the API, acetominophen (paracetamol), while components 1 and 11 were both revealed to be different forms of sucrose, an excipient. The spectroscopic capability of the imaging system makes it possible to generate component-specific particle size distribution data, an exercise that can provide further insight into the characteristics of the API. In this case component 2 was targeted to investigate differences between the particle size and shape of the API in the two products. Figure 4 shows overlaid componentspecific volume-based circular equivalent diameter (CED) size distributions for the particles classed as acetominophen in each sample, along with example particle images. The particle size of this API is revealed to be larger within the generic product compared to the branded product. This may affect the bioavailability of the API. These data illustrate how spectroscopy

and imaging, in combination, enable identification of the components present in a formulation and the discrete determination of physical characteristics of the API particles, such as size and shape that will influence in vivo performance. Looking Ahead As the de-formulation workflow becomes well-established, the associated analytical toolkit is being refined. The creation of a successful generic product requires formulators to identify the components present and the features of those components that confer established clinical performance. The optimal application of analytical techniques is essential to gather the required information in an efficient manner. The case studies presented show how techniques such as triple detection SEC and MDRS can be applied to accelerate ANDA submissions to a successful conclusion.

Figure 4: A comparison of the particle size distribution of the API in a commercial (green) and generic (red) cold and flu remedy shows that the API is present as larger particles in the generic. 108 INTERNATIONAL PHARMACEUTICAL INDUSTRY

References 1. FDA, “Critical Path Opportunities for Generic Drugs May 2007”, criticalpath/reports/generic.html. 2. Robert A. Lionberger, “FDA Critical Path Initiatives: Opportunities for Generic Drug Development” The AAPS Journal, Vol.10, No 1, March 2008 (Review Article) DOI: 10.1208/ s12248-008-9010-2 3. Robert A. Lionberger, Sau Lawrence Lee, LaiMing Lee, Andre Raw and Lawrence X. Yu, “Quality by Design: Concepts for ANDAs” (Review Article) The AAPS Journal, Vol. 10, No.2, June 2008 DOI:10.1208/s12248-0089026-7 4. Meyer R., “Clinical relevance of acoholinduced dose dumping. Advisory Committee for Pharmaceutical Science Oct 2005. ohrms/dockets/ac/05/slides/20054187S2_01_Meyer.ppt 5. Tanno F, Nishiyama Y, Kokubo H, Obara S., “Evaluation of hypromellose acetate succinate (HPMCAS) as a carrier in solid dispersions” Drug Dev Ind Pharm, 2004 Jan;30(1):9-17. 6. Chen R., “Characterization of Hypromellose Acetate Succinate by Size Exclusion Chromatography (SEC) Using Viscotek Triple Detector”, International Journal of Polymer Analysis and Characterisation,14:7,617-630

Dr Paul Kippax is Product Group Manager at Malvern Instruments. A chemist and colloid scientist by background, he has long experience and in-depth understanding of particle characterization techniques, and specific expertise in the application of laser diffraction and analytical imaging to pharmaceutical industry challenges. Email:

Autumn 2014 Volume 6 Issue 3

Manufacturing When Two is Better than One: The Benefits of Two-floor Production Facilities for Future-proof Manufacturing Capability The impact of batch transfer methods on the ‘Lean success’ of a plant is starting to be recognised earlier in the plant design process. Before deciding on building and process room heights, proper attention must be given to materials handling processes.

The working areas can become crowded and require significant efforts in housekeeping.

In the past, inter-process transfer had low priority in terms of building design and process equipment selection. Consequently, sub-optimal systems existed to overcome room height restrictions or floor layout obstacles. It is only recently that the positive impact of batch-transfer methods on the Lean success of a facility has been recognised. That is why nowadays, from day one, plant design engineers bear in mind handling practices.

The Power of Gravity A better alternative is to use gravity feed with a Matcon IBC and Discharge Station. This provides closed, automatic transfers and protects against segregation.

Also, during transfer, the blended powders risk becoming segregated, affecting the quality of the final product.

increased capital expenditure in turning such a vast area into a cleanroom, and also in its further maintenance and cleaning. More is Not Always Better A multiple-floor approach enables a separation of process areas and equipment from materials handling floors. With a Matcon IBC system, this means that the materials handling floors can have a lower area classification as the system is dust-tight and enclosed,

All over the world, wherever new solid dosage facilities are being built, fundamental choices are being made between building a single-floor or a multifloor plant. When land is expensive it makes sense to look at building upwards, rather than outwards with a larger footprint. A new facility is often being built for capacities that are educated guesses at best, so should be laid out for ‘future needs’. But this requires balancing the need for high investment costs now versus a high modification cost later, should demand grow. A single-floor facility design is simply not flexible enough, and a multiple-floor plant could well be too expensive. A twofloor facility is a good compromise as it provides good agility for future demands with a modest investment requirement. The following article looks at the pros and cons of these different facility designs, exploring the benefits to the future requirements of the business. Vacuum Transfer On a single-floor facility, transferring a batch into a process machine is often conducted via vacuum transfer. However, this has inherent problems in that the manually operated process uses ‘open’ connections and transfers with consequent risk to operators and GMP standards. 110 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Pillar-lift mounted Matcon IBC feeding to Tablet Press However, it means placing the IBC above the process machine with a pillar lift. Using pillar lifts can in itself add to complexity as well as increasing the initial capital cost, not to mention the need to maintain and clean them. They also limit the size of IBC that can be used due to ceiling height clearance, and further add to the crowded GMP production area. Although most single-floor designs are limited in ceiling height, in a newbuild, heights of 6m can be constructed. Whilst this will accommodate larger IBCs it consequently creates problems of

saving cost on finishing and maintaining environmental standards. In addition, IBCs can be moved around with AGVs (automatic guided vehicles), removing the need for operators on these floors. However, the capital cost of building such a multi-floor facility is substantial and largely out of reach of most. Compromise at Two Floors A two-floor facility is a suitable middleground. Whilst it is a higher cost than a single-floor facility, it is obviously substantially less than a multiple-floor design, but still provides the separation of materials and processing, as well as Autumn 2014 Volume 6 Issue 3

Manufacturing gravity feeding. The top floor can be dedicated to materials handling and blending, with tableting and packing taking place on the lower floor. The process rooms can have standard height ceilings as the IBCs do not need to be raised up, but are discharged from floor-mounted discharge stations, thereby limiting the cost of the cleanroom requirements. The discharge stations can be laid out in an ergonomic design and are easily accessed and cleaned. The risk of contamination between such points is avoided as the discharge stations remain closed when not in use and provide a dust-tight transfer of powder. This means that housekeeping requirements are kept to a minimum without shut-down for cleaning. When Bigger is Better Although of a standard ceiling height, these rooms can now accommodate larger IBCs as they are floor-mounted. This means that production ‘lots’ can be consolidated into larger batch sizes for

Model of a two-floor installation showing the powder processing steps

Model of a two-floor installation showing the tablet handling steps

SOLUTIONS FOR BIOTECH/PHARMA Protein Production Bacterial and mammalian production - from process development to purified product.

From Active Compound To Administration Drug characterization, analysis and formulation development.

Immune Models In vitro models for prediction of immunoregulatory effects of compounds.

Biomarkers Identification, validation and documentation of disease relevant biomarkers.

Molecular Histology Service In situ detection of microRNA. Image analysis - quantitative ISH. Combined IHC and ISH service.

Stem Cell Technology Adult – and pluripotent stem cell characterization. Stem cell models for regenerative medicine. Cell (stem) motility models.

Bioneer A/S INTERNATIONAL PHARMACEUTICAL INDUSTRY 111 Kogle Allé 2 t +45 45 16 04 44 e DK- 2970 Hørsholm f +45 45 16 04 55 w


Matcon IBCs can be achieved, with a resultant high blending throughput. Furthermore, there is no risk of room contamination, so the blender can be part of an opendesign materials handling floor and does not require its own dedicated, costly, cleanroom. The unique cone Matcon IBCs feeding through-floor in fully contained process valve technology within each of the a more Lean approach to manufacturing Matcon IBCs ensures that these large and to accommodate an increase in IBCs can still discharge their contents in production demand. a controlled fashion and protect against segregation. The cone valve promotes Matcon supply a range of sizes of mass-flow and overcomes other notorious IBCs from 300L to 3100L. The use of problems of ‘bridging’ and ‘blocking’. large IBCs means that a number of This continuous, automated feed ensures process savings can be made through that the tablet presses or downstream needing fewer IBCs, a reduced number process are steadily fed, allowing them of IBC movements, less cleaning, and a to work most effectively. reduction in quality testing cycles, not to mention the manpower saved. The Matcon IBC Blender can easily accommodate these larger IBCs, achieving successful blend homogeneity. Because the powder is mixed within the IBC itself there is no product contact with the blender, so changeovers can be instantaneous. Thereby much higher OEE (overall equipment effectiveness) rates 112 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Tablet transfer can also be performed successfully across the floors by use of a ‘gentle transfer chute’ which protects against damage as the tablets travel between floors. Conclusion We hope that we have demonstrated

how a two-floor facility is a good compromise, balancing a modest capital building investment, whilst protecting the future throughput capacities. If you would like to discuss how Matcon systems could improve the capability and profitability of your manufacturing processes, please contact Wim Spook at or visit www. for further information. Benefits of a two-floor facility: • Operational cost savings in cleaning time as processes separated • Reduced HVAC utility consumption with smaller cleanrooms • Ergonomic layout of equipment • Ability to use larger IBCs and reduce processing costs • Minimised capital investment • Future capacity expansion possible

Wim Spook (BSc Engineering) is a professional powder handling specialist with extensive experience working in hygiene business environments for many years. He joined Matcon Ltd in 1997 as Sales Manager for Holland and Belgium, focusing on the food and pharmaceutical industries. In 2009, he became Pharmaceutical Business Development Director of Matcon Ltd UK.Email:

Autumn 2014 Volume 6 Issue 3


Meet us at CPhI 2014, stand 6P45

A new study proves that more than half of the population – regardless of age or gender – has problems swallowing tablets and capsules. From breaking and dissolving to not taking them at all, people invent their own strategies to cope with tablets – unfortunately, this may reduce efficacy and treatment success. We at HERMES PHARMA have over 40 years of experience in developing and manufacturing pharmaceuticals that are effective and easier to take than conventional tablets and capsules. Be sure to visit us at CPhI 2014 for more details on the market study – and discover the alternatives that will make your products more user-friendly.

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Small Changes To Tablet Shape Bring Big Results Despite being integral to production success, tablet shape is generally given the most consideration as new products are branded by marketing departments, whereas whole campaigns have been built around a tablet’s colour or shape. However, it’s important to consider how small adjustments to tablet shape can influence everything from production efficiency to consumer acceptance. An improper tablet design can cost millions in lost production and possibly lead to a disastrous product launch. While most companies complete their due diligence when designing a tablet, unfortunately some don’t understand how greatly tablet shape can influence production – particularly the efficiency of the tableting operation. Experienced tooling manufacturers are often asked to assist in finding a solution to a tablet or tooling issue. We’re often asked, “Why that tablet shape?” after submitting tablet design suggestions that will greatly improve the tableting process. It’s been our experience that small design changes that are hardly visible to the naked eye can have dramatic results. Why Tablet Design is Important Usually, the marketing department in a company drives the tablet design process. Some companies hope to maintain consumer loyalty by designing unique tablets that will encourage a certain level of consumer recognition. Tablets are also designed considering the end user, for example, a “breakeasy” bisect design offers functionality and versatility if dosage is adjustable, and a child’s three-dimensional animalshaped multi-vitamin encourages acceptance. However, manufacturing efficiency is sometimes most important, with some companies desiring a tablet shape engineered to provide easy and unobstructed production - such as a simple standard round. All of these issues need to be kept in mind when designing a tablet, as ease of production is too often overlooked during the process. Certain tablet shapes simply play havoc with tooling 114 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and press function - adding significant costs to the unit dose. The same can be said regarding packaging issues, as an incorrect tablet design can chip, clog or produce an unacceptable level of dust at the bottom of the bottle. It is for all of these reasons, and more, that tablet shape should be carefully considered and engineered during the initial design phase. Even if the tablet is desired to be a particular shape, it is possible to add features into the design that will reduce production issues – therefore reducing cost. Consumer Ease of Use The FDA has issued guidance regarding tablet shape, size and other attributes that encourages thoughtful design in regard to patient acceptance and swallowability. As certain end users, such as paediatric and geriatric patients, tend to find it more difficult to swallow tablets, it’s important to consider the medication’s use and target demographic. For example, it’s been documented that patients find it difficult to swallow tablets more than 8mm in diameter. Tablets with smaller cross-sectional areas are easier to swallow and are less likely to present a choking hazard than thick, wide or more spherical designs. Physical characteristics need to be considered so as to provide the safest and most comfortable experience for the patient, as this will help to facilitate patient compliance. Certain shapes, such as ovals, are easier to swallow and have faster esophageal transit times. The FDA recommends that drug applicants design and develop drugs with these considerations in mind.1 Tablet design also plays an important role in generic production of reference listed drugs (RLDs), also known as branded products. There are many reasons to consider tablet shape during brand duplication. Generally, generic tablets are designed to closely resemble the RLD. It increases patient compliance and acceptance of the medication, and can also reduce errors in dispensing. However, the FDA has recommended that

when tablet shape can be improved from the branded product to make it easier to swallow, then changes to the design should be made in the generic. All of these considerations aid in product success. Other factors such as friability, tablet weight, transit time, and dissolution time are also necessary to consider when designing the tablet. Once these parameters are established for the tablet, the tablet production and packaging departments should be encouraged to be involved to ensure that the design can be produced without encountering issues such as chipping, picking or sticking. Additionally, the FDA advises that it has received reports of tablets being too friable to be pushed through blister packs. It’s important that any recommendations or concerns from other departments are addressed properly. Keeping all departments involved in the development process will allow the tablet design to be modified for success in the marketplace as well as in production. When a tablet can be easily produced, it reduces operating cost and eliminates operators from wasting time troubleshooting. Branded or generic, small and sometimes imperceptible design changes can yield significant results in improving the patient experience, as well as providing cost savings to the manufacturer. For example, we’ve worked with a well-known calcium supplement manufacturer who was having significant issues with producing their tablets. The tablet was originally developed and marketed to women as an oval shape that was not intimidating to swallow – a good first step as it meets suggested guidelines. However, as the tablet moved into production, the manufacturer experienced costly issues with its tooling and tablet presses. The tablet design was causing excess ejection force, which was creating excessive punch head wear, and in turn was causing premature wear on parts of the press. This chain reaction was all a result of tablet design. With a Autumn 2014 Volume 6 Issue 3

LYOCONTRACT GmbH - Your reliable partner for development and manufacture of liquid and freeze-dried drugs in vials

LYOCONTRACT GmbH, a new and future oriented pharmaceutical company, started manufacturing in 2012 after receiving its manufacturing license according to § 13 of the German Drug Law (AMG) and GMP certification. The core business is the development and GMP conform manufacture of parenterals according to customers orders. A filling line from Bosch and a freeze-dryer from HOF Sonderanlagenbau for the manufacture of parenterals in liquid or freeze-dried forms are the main focal point of the production facility. LYOCONTRACT possesses extensive professional knowledge and years of experience in contract manufacturing and can offer its worldwide customers the highest degree of quality in the manufacture of products. The Story: The owners of LYOCONTRACT GmbH, Dr. med. Milan Č. Pešić - physician, and Ms. Ruth Barg - MBA, both from Bad Harzburg, Germany have more than 30 years of practical experience in sterile filling and freeze-drying. They were very successful in pharmaceutical contract manufacturing with the internationally recognized company THYMOORGAN in Vienenburg, Germany until they sold it in 2006. Dr. Pešić and Ms. Barg have used their extensive knowledge and competence in the manufacture of sterile and freeze-dried drugs to build a new, highly modern manufacturing plant.

The Construction Phase: High value was placed on quality German work and GMP conformity during the construction of the new company. The most prestigious manufacturers of pharmaceutical equipment and production lines were contracted. During the conceptualization of the building, future expansion of the space and media for two additional freeze-dryers was already planned. The increasing requests for lyophilization capacity have lead to the fact that, exactly one year after the start of production, an order for another freeze-dryer with the same size and capacity as the current freeze-dryer was given to HOF Sonderanlagenbau.

up to 24,000 vials per hour (2R vials), has the latest Bosch technology. During the design of the system, the possibility of using dedicated and disposable equipment was taken into consideration. The automatic loading and unloading system from Motus Engineering is also located under the RABS system and ensures a person-independent loading of the freeze-dryer. The freeze-dryer has an ice capacity of 400 kg and a total shelf area of 29m²; it is possible to freeze-dry up to 126,000 vials (2R) in one freezedrying cycle. The vials are crimped in the high-performance closing machine by groninger. The labeling is done with the labeling machine by Bausch + Ströbel.

Building a team of qualified and motivated employees was important in order to create conditions for a highquality production site with competent and highly trained personnel.

The Future: In addition to product and process development, the research and development department offers the optimization of freeze-drying programs in their own development lyophilizer. LYOCONTRACT GmbH is an independent, family business. Dr. Milan Č. Pešić has appointed his successor early on by naming his daughter Dr. Katrin Pešić as general manager. With their high quality products, extensive knowledge and years of experience it is the goal of LYOCONTRACT to establish themselves as a leading contract manufacturer on the pharmaceutical market through flexibility and by meeting deadlines as a reliable and competent partner.

Production Process: The preparation of the formulated solution is done under a laminar flow from Ziel. Mixing containers are available in sizes up to 500 liters. The filling and freezedrying process are fully automated and under a RABS system (restricted access barrier system) in a clean room. The filling machine, with a volume of

LYOCONTRACT GmbH Volker Kobbert Buiness Manager/ Authorized Representative Dr. Michael Schön Head of Production Pulverwiese 1, 38871 Ilsenburg, Germany Tel: +49 (0) 39452/48 29-0 Fax: +49 (0) 39452/48 29-199 E-Mail: Visit our website: 97 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Spring 2014 Volume 6 Issue 1

Manufacturing redesign that kept the look of the original shape but took some of the volume out of the band of the tablet, the manufacturer was able to reduce all of their efficiency issues and still present a tablet that was appealing to consumers. Clearly, changes to a tablet shape can reduce costs during production. In addition to reducing excess ejection force, adjusting the shape can reduce issues such as heat and friction during tableting – two things that can cause considerable problems for a tablet press. Reducing these issues will significantly reduce parts wear, tooling and other operating costs – all of which add up quickly. What Kind of Design Changes can Help Increase Efficiency? One of the simple tablet shape changes that can be made and will bring positive results is to consider switching from a bevel edge to a radius edge when producing uncoated flat bevelled tablets. This is an improvement that doesn’t affect the overall tablet shape, but can greatly help to ensure smooth tablet production. Understandably, companies do what they can to limit expenditures throughout the development process. A common and ill-advised practice is for companies to attempt to replicate or duplicate an existing tablet with an inherently weak or problematic design. This often happens when companies reproduce designs already in their portfolio. One of the oldest tablet designs, the flat-face (FF) design, has been commonly used to produce tablets. As commercial tablet manufacturing took off, the industry found it needed to rectify edge attrition in flat-faced tablets. Edge attrition occurred as the flat-face tool entered into the compression cycle and pushed powder to the outside perimeter of the punch tip and towards the die wall, which in turn extruded through the punch and die clearance. Increase Strength by Increasing Bevel to Flat Radius











On an FF punch tip, there was virtually no cup or cup depth – it was simply flat; so there was no cup limiting compression force. Pressure limits were determined by the punch tip size. To combat this issue, the flat-face bevel edge, or FFBE, configuration was developed as an alternative. This design is one of the oldest and most commonly reproduced designs – yet it presents many manufacturing challenges. The FFBE design proved to be beneficial for reducing soft edges by guiding the powder back into the tablet; however the design presented a new issue - punch weakness. A necessary lack of cup depth in this design caused a limit on compression force in order to avoid tip bending and distortion. So although the FFBE corrected edge attrition, it presented new manufacturing issues such as substantially limiting compression force and difficulty in achieving desired hardness when compressing certain powders.

Detail DWG Forces. design advantages that improve patient acceptance. By eliminating the bevel edge and replacing it with a radius edge, the FFRE design allows maximum compression forces in many cases to almost double, allowing additional pressure to alleviate conditions such as sticking in the corner

Max Force Chart S7 In order to combat these problems, another design evolved. This alternative design, the flat-face radius edge, or FFRE, is a much more robust design that allows for a significantly higher compression force to be applied without causing punch tip damage when producing flatfaced tablets with a shallow cup depth. The FFRE design should be considered when producing flat-faced bevelled edge tablets because it provides several manufacturing improvements as well as

junction of the bevel and the flat. The radius edge is simply stronger. Increasing the radius by even a fraction dramatically increases the strength. The FFRE produces better uniform tablet hardness as well, which provides for a highly desired uniform dissolution rate. In this design, the powder has a natural flow across the radius, which will reduce hot spots and or discolouration to the perimeter of the top of the tablet. Autumn 2014 Volume 6 Issue 3


Clearly, the FFRE shape has advantages during tablet production and can eliminate many headaches when powder needs high compression force. Using an FFRE design instead of an FFBE design is a very simple change that can bring big results. We’ve observed that companies experiencing a tool breaking issue can change the radius by even 20 thousandths of an inch and eradicate certain problems. Reducing downtime by keeping tablet presses running and eliminating tool breakage can add up to significant cost savings. The FFRE design can also improve product acceptance among consumers. Tablets produced on tooling with a radius edge design can have a softer look and better mouth feel, which is highly desirable. Although the difference between the FFBE and FFRE designs typically is visually unnoticeable, a more appealing tablet can cause consumer acceptance and compliance to skyrocket. The FFRE tablet design presents enough advantages over the FFBE design that it should be considered for all new flat-face designs applied to non-coated tablets, which may someday make the FFBE design obsolete. Concave bevel edge, or CCBE, tablets

suffer from a similar legacy to the FFBE design. The CCBE is a design commonly used on both round and shaped tablets to assist in reducing edge attrition during the coating process. This design would also benefit from the addition of a radius edge. As with the issues encountered with the FFBE, applying a radius edge to this tablet would make a better and more robust design, which would generally allow an increase in maximum compression force. In effect, replacing the bevel with a radius creates a compound cup design, which is much more desirable than the CCBE design. These often imperceptible changes can bring tangible results. As mentioned, small adjustments to the tablet’s shape can positively impact issues that arise during production as well as improve the consumer experience in using tablets. Many considerations should be borne in mind when tablets are designed. To design a tablet with a high degree of success, it’s important to get all departments involved in the process. Even if the marketing department drives the design process, other departments from production to packaging should be given the opportunity to comment, as they too should have a stake in the product’s success. Be sure to involve your tooling supplier as well, as they should

have experience in tablet design and will be able to provide guidance that will help to head off possible problems before they occur. Keeping all responsible parties included in the design process will ensure a successful and timely launch. It’s in everyone’s best interest to provide a product that succeeds in the marketplace and provides a great experience for the consumer. References 1. Food and Drug Administration. Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules. Draft Guidance. (2013)

Dale Natoli is president of Natoli Engineering Company, Inc., and has over 35 years of worldwide experience in the tablet compression industry. He has published articles for major pharmaceutical publications and authored chapters in three books, including the Tablet Specification Manual, sponsored by the American Pharmaceutical Association. He presents lectures for universities, pharmaceutical associations and tablet manufacturers worldwide. Email:



Gentlewing: The Name Says It All Implementing innovations in the pharmaceutical market is an ambitious task. In an industry that requires precise and reproducible results, changes to current systems always involve certain challenges. An external study can provide certainty, which was the case with the uniquely shaped 'Gentlewing' mixing device from Hüttlin GmbH, a subsidiary of Bosch Packaging Technology, based in Schopfheim, Germany. A study conducted by the University of Mainz, Germany, confirms that the special design of the device offers several advantages to users – while achieving the same processing results as a conventional mixer. High-shear granulation is a highly complex process where different parameters exert significant influence on the final product. The mixing device constitutes an integral part of this process. Bosch Packaging Technology equips all its high-shear mixer granulators with the patented Hüttlin Gentlewing. In contrast to conventional three-blade mixers, the high-shear mixer granulator only employs two blades and runs at lower speeds. The


specific rounded z-shaped blades offer several practical benefits. However, the success of an innovation largely depends on its application results. For this reason, Bosch commissioned a study designed to answer the following questions: How does the Hüttlin Gentlewing influence granular quality? Which additional parameters have an impact on the granule? The Department of Biopharmaceutics and Pharmaceutical Technology at the University of Mainz conducted the study in partnership with the Bosch subsidiary Hüttlin GmbH between February and August 2011. Both partners had previously worked together in a number of PhD programmes. Screening for Test Design The formulation was initially developed in a two-stage screening phase. “The process had to encompass a certain degree of susceptibility. A robust formulation that is always effective would not have delivered significant results,” explained Dr Marcus Knöll, head of the Pharma Service department at Hüttlin.

Amlodipine, an antihypertensive calcium channel blocker, was selected as the active ingredient. Together with further excipients, it constituted the formulation for the study. The second phase of the screening indicated which factors have the potential to influence the granulation process. It also showed what levels these factors were allowed to achieve during the planned tests to span the largest possible design space. Based on the screening results and with the help of MODDE9 (Umetrics) software, the scientists set up a statistical Design of Experiments (DoE) with five factors. To identify the extent of the factors’ influence, each factor had to be examined at different levels. This resulted in a total of 36 trials, during which any possible combination of these factors was tested with high, medium and low settings. In addition to other process parameters, the device parameter “geometrics” of the mixing device was examined to compare the Hüttlin Gentlewing with conventional

Autumn 2014 Volume 6 Issue 3

The safe choice for Pharma labelling UPM Raflatac supplies a range of pressure sensitive materials to meet the strictest requirements in pharmaceutical labelling. Whether you need a non-migration adhesive or an ultra-clear luminescent adhesive for missing label detection; think safe, think UPM Raflatac. UPM Raflatac has always been defined by engineering expertise and service excellence. Our customer promise Engineered with Raflatouch captures them both.


impellers. “We tested the following factors for their influence on final product quality: impeller type, premixing time, impeller speed during granulation, spray rate of granulation liquid and granulation time,” said Sarah Kindgen from the University of Mainz. The test procedure was divided into several stages. Initially, the core ingredients were blended in the highshear mixer granulator. In the second step, the actual granulation process was performed by adding the granulation liquid. The product was then wet-milled, dried, dry-milled and compressed. During the final phase, Bosch and the University of Mainz tested the granular quality for particle size, mass, density, compressibility and flowability. Apart from the granule properties, the trials also focused on the tabletting characteristics and the distribution of active ingredients in the tablet. “Ultimately, it is the tablet that counts,” Dr Knöll emphasised. The results served to create models that reliably describe how the different factors affect the final product. Convincing Results The study provided conclusive results. At a lower impeller speed, granulation using the Gentlewing leads to a more homogeneous distribution of the active ingredient compared to the conventional mixer. “We saw significantly higher 120 INTERNATIONAL PHARMACEUTICAL INDUSTRY

content uniformity in tablets,” Sarah Kindgen confirmed, while Dr Knöll commented, “The Gentlewing provides improved homogeneity at a lower energy input level. With respect to granule properties such as particle size, density, compressibility and flowability, we achieved the same results as conventional impellers. This means that it is safe to change from a traditional mixer to Gentlewing.” When comparing both types of impellers, the only parameter that significantly influenced both granular quality and the tablet itself was impeller speed. Gentlewing achieved its best results at a lower impeller speed, while traditional three-blade impellers required higher speeds. Besides, the relative standard deviation (RSD) of Gentlewing was below the level of the conventional mixing device. The ability to run processes at lower speeds shows advantages in terms of both active ingredient distribution and granular quality. A lower speed always guarantees less shear stress for the product. A First-class High-shear Mixer Granulator Tabletting characteristics are not influenced by the impeller’s shape but by its speed. With its two wings and container-optimised shape, Gentlewing is able to run effectively at these low

speeds. This prevents mechanical stress and local heat generation, which is especially beneficial for the processing of sensitive ingredients or formulations that are prone to develop sticky characteristics at high temperatures. In addition, the rounded z-shaped blades of the mixing device offer significant practical advantages. They enable thorough emptying. Moreover, products do not adhere to the container walls thanks to the narrow clearance between container and impeller. The study has confirmed that the Hüttlin Gentlewing is well-named. Not only does its unique shape come without risk, it also offers tangible advantages. The recent scientific study has provided substantial evidence that the Hüttlin Gentlewing is truly a first-class high-shear mixer granulator, in spite of – or perhaps even because of – its lower speed. Dr Marcus Knöll is a pharmacist and graduated from Philipps-Universität Marburg/Germany. He accomplished his doctoral thesis “Entericcoated Mucoadhesive Micropellets in Rotary Agglomeration Process for Wet Spheronization” (20022005). He is Head of Pharma Service at BOSCH Hüttlin, Schopheim, Germany since 2005 with four coworkers. Email: Autumn 2014 Volume 6 Issue 3


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Packaging Impact of Sterilisation Method on Packaging Component Machinability Performance: Steam vs. Gamma Evaluation of the 1mL Long Plunger Pharmaceutical manufacturers are faced with numerous challenges during production, filling, packing and transport of pharmaceutical products to patients and caregivers. Common concerns for all pharmaceutical manufacturers include meeting targeted timelines to guard against drug shortages and ensure speed to market to generate revenue. Manufacturing delays can result from the stopping of filling lines, product/ component line clearances and pending investigations, which can lead to reduced output of finished product. Maximising filling line operating speeds and minimising line downtime are essential to handling these issues and facilitating manufacturing efficiencies for the benefit of all stakeholders. The capability of parenteral packaging components (containers, elastomeric components and caps) to efficiently flow and effectively be processed on drug manufacture filling lines is commonly known as the machinability. The machinability of parenteral packaging components is recognised to have a significant influence on productivity of the drug product manufacturing process. In this case study, elastomeric components, intended for aseptic processing are considered with respect to machinability on a lab-scale filling line. Parenteral packaging components used in aseptic drug manufacturing are required to be clean and sterile when intended for drug products for human use. 21 CFR 211.94(c) states that “Drug product containers and closures shall be clean and, where indicated by the nature of the drug, sterilised and processed to remove pyrogenic properties to assure that they are suitable for their intended use.” There are various processes that can be used for washing and sterilising elastomers for aseptic fill, and depending on conditions of processing, the physical and functional characteristics of the component will be altered to some degree. The two most common means of sterilising elastomeric parenteral packaging components are steam autoclave and gamma irradiation. When appropriately validated, both processes are very effective at eliminating microbial 122 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 1: Machine Setup contamination of components used for container closure of sterile liquid, lyophilised or powder drug products. Despite the ability of both methods to reach the sterility requirements, the effect on physical characteristics of elastomers as it relates to machinability of the components can be quite different. In an effort to understand the impact of the two sterilisation techniques on machinability, a study was performed by West Pharmaceutical Services (West) and Bausch + Ströbel Maschinenfabrik Ilshofen GmbH+Co. KG (Bausch and Ströbel). The objective of the study was to assess filling line speeds relative to performance of steam sterilised plungers versus plungers sterilised at two different levels of gamma irradiation. Machinability Study Design The machinability study was performed using plungers designed for a 1 mL Long syringe. The plunger design chosen for this study was laminated with a fluoropolymer film (FluroTec® barrier film) and coated with a cured silicone (B2-coating). The plungers were subjected to the same washing but different sterilisation processes. West collaborated with Bausch and Ströbel

to conduct a study using six plunger sample sets composed of two different elastomeric formulations (bromobutyl and chlorobutyl). Sterilisation variables included: i) steam autoclave processing for one hour, ii) gamma irradiation at 10-20 kGy and iii) gamma irradiation at 40-50 kGy. Both sample sets of gamma irradiated bromobutyl plungers were from the same manufactured, washed and B2coated lot; however, the difference was the degree of gamma irradiation. Also, both sample sets of gamma irradiated chlorobutyl plungers were from the same manufactured, washed and B2-coated lot; however, the difference was the degree of gamma irradiation. Machinability Assessment Each sample set was evaluated on a labscale filling line, which was equipped with a dosing trough, feeder bowl, sorting track and feed track. The filling line setup consisted of a 10-lane feed track with a maximum line speed of 600 plungers per minute. Four different line speeds were investigated to determine if the machining performance requirements were met. The performance was judged based on two criteria: a smooth consistent flow and lack of line blockages. The Autumn 2014 Volume 6 Issue 3

PAGO Stand No. 2H41, Hall 2 Paris, 7.-9. October 2014

Chapter Title feeder bowl and tracks were designed by Bausch and Ströbel for this study, and are shown in Figure 1. A high-speed camera was used to capture images of the plunger movement within the feeder bowl and tracks at each of the various speeds tested. The images were examined for areas of sluggish or undesirable performance during the test runs. The same study criteria and parameters were used for each sample set test run. Those parameters were: • • • •

Tested line speeds (as defined by plunger gripper settings): 200, 350, 500 and 600 plungers per minute Quantity of plungers tested per sample set: 25,000-30,000 plungers Run time per tested line speed: Approximately five minutes before incrementally increasing to the next higher speed Power setting for vibration solenoids of the dosing trough, feeder bowl, sorting track and feed track: Only one power setting (operation mode-full power) was used during the study. The power setting was not reduced during the initial filling of the sorting and feed tracks as typically performed during drug product fill/finish manufacturing. By initiating the power setting at operation mode-full power, performance differences between each sample set were recognised/identified more clearly. Cleaning and setup activities following each sample set test run: Removed all remaining plungers from the filling line and dismantled all change parts for preparation of cleaning. Removed all residual silicone and macroscopic contaminants from the complete system (dosing trough,

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Packaging per minute. Table 2 shows the overall results from the machinability study, as noted by Bausch and Ströbel. Table 2: Machinability Study Results Overview Test Sample Description Duration Maximum for Filling Speed Achieved the Tracks 1mL Long Bromobutyl 2.75 minutes 600 plungers/minute Plunger Steam Sterilised 1mL Long Chlorobutyl Plunger Steam Sterilised

3.00 minutes

600 plungers/minute

1mL Long Bromobutyl 3.00 minutes Plunger 10-20 kGy Gamma Sterilised

600 plungers/minute

1mL Long Chlorobutyl 4.25 minutes Plunger 10-20 kGy Gamma Sterilised

600 plungers/minute

1mL Long Bromobutyl >10.00 minutes Plunger 40-50 kGy Gamma Sterilised

Unable to run

1mL Long Chlorobutyl >10.00 minutes Plunger 40-50 kGy Gamma Sterilised

Unable to run

Results/Comments Ran very smoothly— Few or no fallen plungers with no blockage of flow Ran smoothly— Few fallen plungers with little or no blockage of flow Ran smoothly— Few fallen plungers with little or no blockage of flow Ran smoothly— Few fallen plungers with little or no blockage of flow Ran very poorly— Numerous fallen plungers with complete blockage of flow Ran very poorly— Numerous fallen plungers with complete blockage of flow

feeder bowl, sorting track and feed achieve maximum line speeds of 600 Additionally, the plungers gamma to 40-50 kGy wereper observed by Bausch Ströbel that track). Once cleaned, theirradiated system plungers minute. The and plungers to exhibit a “stickiness” between the plungers sliding past one another as well as moving along was returned to the same previous were gamma irradiated to 40-50 the contact surfaces of the filling line. The hypothesis is that elevated levels of gamma irradiation, kGy such as 40-50 setup. kGy, can alter the elastomer physical properties, thus leading to tacky/sticky operational showed poor performance and could characteristics. In such a case, the most common means to overcome this phenomenon would be not meet the machining requirements at to increase the level of lubricating agent (silicone oil) applied to the elastomer. Since the level of Machinability Performance of attributes the filling linefinal speeds, especially at silicone oil on the plunger takes into considerationany several of the package, it was beyondresults the scope of this machinability study. The study showed that the steam 600 plungers per minute. Table 2 shows sterilised plungers were consistently Page 4 of 54the overall results from the machinability quickest to fill the feed tracks, and could study, as noted by Bausch and Ströbel. achieve successfully maximum line speeds of 600 plungers per minute. The Additionally, the plungers gamma plungers gamma irradiated to 10-20 kGy irradiated to 40-50 kGy were observed were slightly slower to fill the feed tracks; by Bausch and Ströbel to exhibit a however, they also could successfully “stickiness” between the plungers sliding

past one another as well as moving along the contact surfaces of the filling line. The hypothesis is that elevated levels of gamma irradiation, such as 40-50 kGy, can alter the elastomer physical properties, thus leading to tacky/sticky characteristics. In such a case, the most common means to overcome this phenomenon would be to increase the level of lubricating agent (silicone oil) applied to the elastomer. Since the level of silicone oil on the plunger takes into consideration several attributes of the final package, it was beyond the scope of this machinability study. Summary Due to the overall importance of maximising operating speeds and minimising operating downtime, the pairing of parenteral packaging components, drug product, processing and fill/finish equipment must be assessed thoroughly. As indicated by the plunger machinability results, the elastomeric parental packaging components used in aseptic drug manufacturing can be impacted by the sterilisation method and conditions. It is the responsibility of the drug product sponsor to evaluate and understand suitability of packaging components during development, scale-up and commercialisation. Specific considerations should include understanding the impact of sterilisation on component machinability.

Simon Côté has more than 12 years of experience in the sterile drug product industry. Following the completion of his Bioprocessing Chemical Engineering degree at Pennsylvania State University, he worked for Centocor Inc. in bioreactor process development, then moved to Merck & Co., Inc. in sterile drug product process improvement and deviation management. Simon currently works for West Pharmaceutical Services Inc. in Exton, Pa., as the lead parenteral packaging component fill/finish machining expert. He is also a member of the International Society for Pharmaceutical Engineering. Email: 124 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2014 Volume 6 Issue 3

Scientia potentia est {Knowledge is power} Drug Delivery & Packaging

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Autumn 2014 Volume 6 Issue 3

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