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Volume 9 Issue 1

International Pharmaceutical Industry

Peer Reviewed

Supporting the industry through communication

MALDI Mass Spectrometry in Drug Discovery Gaining A Deeper Understanding

Three Ways to Mitigate the Risk of

Late-Stage Failure in CNS Drug Development

Data

The Foundation of Clinical Trials

Temperature Management Keep Your Cool

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Contents 06 Editor’s Letter REGULATORY & MARKETPLACE 08 Denmark; Small and Personalised International Pharmaceutical Industry

Supporting the industry through communication

DIRECTORS: Martin Wright Mark A. Barker EDITOR: Orsolya Balogh orsolya@pharmapubs.com BOOK MANAGER: Anthony Stewart anthony@ipimedia.com BUSINESS DEVELOPMENT: Clive Baigent clive@ipimedia.com DESIGN DIRECTOR: Jana Sukenikova www.fanahshapeless.com CIRCULATION MANAGER: Dorothy Brooks dorothy@pharmapubs.com FINANCE DEPARTMENT: Martin Wright martin@ipimedia.com RESEARCH & CIRCULATION: Maria Dominici maria@pharmapubs.com COVER IMAGE: iStockphoto © PUBLISHED BY: Pharma Publications Unit J413, The Biscuit Factory Tower Bridge Business Complex 100 Clements Road, London SE16 4DG Tel: +44 (0)20 7237 2036 Fax: +44 (0)01 480 247 5316 Email: info@ipimedia.com www.ipimedia.com All rights reserved. No part of this publication may be reproduced, duplicated, stored in any retrieval system or transmitted in any form by any means without prior written permission of the Publishers. The next issue of IPI will be published in June2017. ISSN No. International Pharmaceutical Industry ISSN 1755-4578. The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright. 2017 PHARMA PUBLICATIONS / Volume 9 issue 1 - Spring - 2017

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Personalised medicine means giving the right medicine in the right dosage to the right group of patients at the right time. Research involves developing methods to diagnose and stratify patient populations to allow for targeted treatment modified to the gene expression and disease profile. This means that networking is one of the crucial factors for creating the foundation for advances in the field of personalised medicine. Rasmus Beedholm-Ebsen is Special Advisor within Life Science at Invest, and explains how an advantage of a small country, like Denmark, is that networking is easier, with fewer degrees of separation between the scientist or scientific entrepreneur and the decision-makers, like government ministers, policy-makers, and industry leaders. 12 Comparison of Marketing Authorisation and its Requirements for Singapore and Thailand The availability of generic medication is an important issue in the ASEAN regions. The regulatory requirements of various countries of the world vary from each other. Therefore, it is challenging for the companies to develop a single drug which can be simultaneously submitted in all the countries for approval. The regulatory strategy for product development has to be established before commencement of developmental work in order to avoid major surprises after submission of the application. The JSS College team with Balamuralidhara V. at the Regulatory Affairs Group, Department of Pharmaceutics, JSS College of Pharmacy provides an overview on Singapore and Thailand’s marketing authorisation. 24 The Big Data Cure-all? Data management is an issue for any business these days, but particularly in life sciences where growing regulatory demands and commercial pressures are increasing the risk for companies that don’t have the latest information to hand. Drawing on examples from other markets, Elvis Paćelat, VP Compliance Solutions at Amplexor Life Sciences, distils some best-practice data discipline, which starts with a single version of the truth. 28 How Much Energy Do You Throw Away After Lights Out? When the last person out at night turns off the lights, how many of us are lulled into a false sense of security into thinking that the energy consumption of our offices or factory also switches off for the night? The following white paper, written by Mike Glanfield, Chartered Energy Manager at Epsilonium, questions whether we are doing enough. 30 Magnesium Alloys: Revolutionising the Pharmaceutical Industry The pharmaceutical industry has been growing by 7.8% year on year, and its worth is estimated to be $1.6 trillion by 2020. However, the pharmaceutical industry is facing a range of challenges, including rising customer expectations as well as declining R&D productivity. Therefore, it is increasingly important to get the best possible products to market by improving existing product lines and introducing new ones. This can often be difficult, with innovative solutions hard to come by Paul Lyon, Programmes Technology Manager at Magnesium Elektron, shares his views on revolutionising the pharmaceutical industry. INTERNATIONAL PHARMACEUTICAL INDUSTRY 1


Contents 32 The Expanding Role of Pharmacovigilance

54 Five Reasons to Rethink Paper ECGs

Pharmacovigilance is evolving into something much more than a regulatory compliance and safety-related discipline. Increasingly, it has a central role to play in product development and product management activities, as well as portfolio decisions. With that in mind, ProductLife Group recently brought together a number of leading figures in the life sciences industry to discuss several of the emerging trends around pharmacovigilance that together are changing the game. Cheryl Key, Head of Practice PV Platform Services/Principal Medic at ProductLife Group, focuses on the expanding role of pharmacovigilance. DRUG DISCOVERY, DEVELOPMENT & DELIVERY

Cardiac safety issues are among the most common reasons for promising drugs being halted in development and not brought to market. The ICH E14 Guidance for Industry requires every new drug to be tested for QT prolongation to predict the risk of Torsades de Pointes (TdP), a lethal arrhythmia. However, sponsors who rely on site-managed ECGs may be risking data quality. There are significant differences between site-managed and centralised ECG data collection and analysis. Ellen Street, Executive Vice President, Cardiac Safety at ERT, explains why it is critical that sponsors understand how their selected method could make the difference between success and failure as they develop new medical products.

36 MALDI Mass Spectrometry in Drug Discovery

56 Data – The Foundation of Clinical Trials

New MALDI technology looks set to boost discovery and early development of drug candidates, delivering new information and improved performance to scientists in both target selection and drug tissue distribution imaging. In this article, Dr Rohan Thakur, Dr Meike Hamester, Dr Dale Shannon Cornett and Dr Jens Fuchser at Bruker Daltonics guide us through the mentioned topic.

The life sciences industry has been fundamentally altered in recent years. Diseases that were once considered life-threatening and terminal are now being managed as chronic conditions. Previous chronic illnesses are treatable and curable, while other diseases have been reduced to irritations or consigned to the history books. Richard Young, Vice-President, EDC, Veeva Systems, discusses how a changing world brings data to the forefront, but how do we manage it all to make the biggest impact.

42 Innovation to Resolve Challenging Microsphere Drug Delivery Systems Formulation Process Due to their ground-breaking benefits and market share opportunity, the production of polymeric microsphere drug delivery systems is experiencing a fast-growing demand worldwide but remains a very challenging formulation process. New drug delivery devices such as PLA, PLGA, PLG or PEG polymeric microspheres have revolutionary applications. Camille Flores-Kilfoyle, Business Development Manager at Powder Systems Limited, submits a white paper on the drug delivery systems formulation process. CLINICAL RESEARCH 46 Three Ways to Mitigate the Risk of Late-stage Failure in CNS Drug Development Central nervous system (CNS) disorders have long been the Bermuda Triangle of drug development. For example, a 2014 study of Alzheimer’s disease (AD) drugs tested between 2002 and 2012 showed that 99.6% of them failed one of Phase I, II or III trials. Many of these AD drugs failed late, in large Phase III trials, making the failures costlier and more dispiriting for researchers, drug developers, and, certainly, patients. Rebecca M. Evans, MD, MS, Global Therapeutic Area Head for CNS and her team at Parexel, serve the readers with a detailed study of CNS drug development. 52 Improving Site Performance: It’s All About Relationships The relationships between sponsors, CROs and study sites can present many challenges in clinical trial planning and execution. Any relationship can be complicated, but the way in which these parties interact with each other can have a significant impact on the overall success of a clinical trial. In this article, Jeffrey Zucker, Vice President of Feasibility and Recruitment Optimization at Worldwide Clinical Trials, offers strategies for establishing and maintaining key relationships, and advice on how sponsors and CROs can build and enhance site partnerships to optimise study execution from trial start-up and recruitment through to implementation.

2 INTERNATIONAL PHARMACEUTICAL INDUSTRY

LOGISTICS & SUPPLY CHAIN MANAGEMENT 62

Temperature Controlled Logistics Conference – A Meeting of Minds

At the end of January 2017, Cecilia Stroe, staff editor of IPI, attended the Temperature Controlled Logistics Conference in London, and learned that a business is only as successful as its supply chain; exactly as the saying goes. In its 16th year and held in London for the first time ever, on January 31st and February 1st 2017, the Temperature Controlled Logistics Conference brought together at the ExCel Centre more than 500 life science professionals keen to tackle inefficiency out of the supply chain. 66 Temperature Management – Keep Your Cool The industry is experiencing an increase in sensitive and sophisticated pharmaceutics, and the compliance with new regulations governing temperature control during processing, storage and transport is on the increase. Any deviation outside the drug stability parameters can have a negative impact on the safety of a patient, which is of significant concern to pharmaceutical companies and regulators alike. In the following editorial, Heather Bogle, Supply Chain Solutions Manager, Almac Group, highlights temperature management in the pharmaceutical supply chain. MANUFACTURING 70 Off the Record: The Truth about Data Integrity in Pharma The Food and Drug Administration (FDA) has long emphasised the importance of reliable data in pharmaceutical manufacturing. Despite this clear recommendation, recent FDA reports have highlighted an increase in data integrity violations during several recent cGMP inspections. Lee Sullivan, Regional Manager at HMI/SCADA and software expert COPA-DATA UK, explores three data integrity pitfalls to which pharmaceutical manufacturers are most vulnerable.

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Contents 72 Antimicrobial Copper vs Antimicrobial Resistance The antimicrobial properties of copper have become widely known, harnessed by hospitals around the world in the form of touch surfaces that continuously reduce bioburden. Now, a potential role in combatting antimicrobial resistance is being proposed by researchers. In his article, David King, Senior Vice President at HOK, describes some of the latest developments in antimicrobial copper, looking at new science, its growing inclusion in guidelines and ratings systems, and a high-profile installation at a leading London research facility. 76 Simplified Bioprocess Setup through Automated Process Control Learning to use a bioprocess controller is a complex and often intimidating endeavor for the beginner. Indeed, even with previous bioprocess experience, moving to a new software platform can entail much learning and reduce efficiency. Although many textbooks and manuals exist on the subject, they are no substitute for hands-on experience. Ulrike Becken and her team at Eppendorf AG Bioprocess Center explain how automated process control can help users who are less familiar with bioreactors and fermenters. PACKAGING 80 Innovative Glass Production for Pharmaceutical Packaging Why is glass still the first choice of primary packaging for most pharmaceuticals today and how much high-tech do you need to manufacture a glass container that has good filling properties and keeps the content safe? IPI Media Director, Anthony Stewart, visits Gerresheimer`s pharmaceutical glass facilities in Lohr and Wertheim, and learns the process of the company’s high-quality glass manufacturing. 84 The Advent of Patient-centricity: What Does it Actually Mean? There is a lot of buzz in the pharmaceutical and healthcare industry right now around the concept of ‘patientcentricity’. The term can mean many different things to a lot of different factions within the healthcare space. With high-profile headlines about drug pricing in the market, the industry is coming around to the enlightening thought that it ought to be more overtly focused on the patient. Justin Schroeder, Executive Director, Marketing, Business Development & Design at PCI Pharma Services explains this is now borne out in many facets of the business. 88 Ensuring a Carefully Designed and Executed Product Packaging Interaction Study for Concise Cost-Effective Evidence in Support of New Drug Product Development The US Food and Drug Administration (FDA) Guidance for Industry document ‘Container Closure Systems for Packaging Human Drugs and Biologics’, addresses the review and evaluation of packaging requirements. According to this document, each new drug application (NDA) or abbreviated new drug application (ANDA) should contain sufficient information to demonstrate that a proposed container closure system and its components are suitable for its intended use. Last, but not least, Mike Ludlow, Technical Study Manager, CMC Analytical Services at LGC, focuses on product packaging and new drug development. 4 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Editor's Letter Spring is upon us in the northern hemisphere and the life science conference calendar has started again with full energy. I attended BioWales at the beginning of March in Cardiff, which was about health and wellbeing, and then last week saw BioEurope Spring being held in Barcelona, Spain. I will also be moderating the Future of Swedish and Danish Life Science event, which is an international event attended by 460 attendees and is in its sixth year at the ex-AstraZeneca site, which is now Medicon Village in the heart of the Medicon Valley, Sweden. This will be talking about what the future is, and whether we are all doing as much as we can for the sector. I think it is also hard not to get caught up in all the media buzz around Brexit, but life must go on, so that is why in this feature of the magazine we have some great articles. Is personalised medicine the invention of fiction, or are we ever going to be able to have our own individually designed drugs? Personalised medicine means giving the right medicine in the right dosage to the right group of patients at the right time. Research involves developing methods to diagnose and stratify patient populations to allow for targeted treatment modified to

the gene expression and disease profile. Rasmus Beedholm-Ebsen, Special Advisor within Life Science at Invest, explains how one advantage of a small country, like Denmark, is that networking is easier, with fewer degrees of separation between the scientist or scientific entrepreneur and the decision-makers, like government ministers, policy-makers, and industry leaders. Will Big Data cure all? Data management is an issue for any business these days, but particularly in life sciences, where growing regulatory demands and commercial pressures are increasing the risk for companies that don’t have the latest information to hand. Drawing on examples from other markets, Elvis Paćelat, VP Compliance Solutions at Amplexor Life Sciences, distils some best-practice data discipline, which starts with a single version of the truth. The life sciences industry has been fundamentally altered in recent years. Diseases that were once considered life-threatening and terminal are now being managed as chronic conditions. Previous chronic illnesses are treatable and curable, while other diseases have been reduced to irritations or consigned to the history books. Richard Young, Vice-President, EDC, Veeva Systems, discusses how a changing world brings data to the

forefront, but considers how we manage it all to make the biggest impact. The Food and Drug Administration (FDA) has long emphasised the importance of reliable data in pharmaceutical manufacturing. Despite this clear recommendation, recent FDA reports have highlighted an increase in data integrity violations during several recent cGMP inspections. Lee Sullivan, Regional Manager at HMI/SCADA software expert COPA-DATA UK, explores three data integrity pitfalls to which pharmaceutical manufacturers are most vulnerable. We have a special report on why glass is still the first choice of primary packaging for most pharmaceuticals today and how much high-tech is needed to manufacture a glass container that has good filling properties and keeps the contents safe. IPI Media Director, Anthony Stewart, visits Gerresheimer`s pharmaceutical glass facilities in Lohr and Wertheim, and learns the process of the company’s high-quality glass manufacturing. IPI will be attending the Anglo Nordic Conference on 31st May in London and we hope to see you at this event. I hope you enjoy this edition of the magazine as much as I do. Lucy Robertshaw Directer, Lucy J.Robertshow Consulting

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

Heinrich Klech, Professor of Medicine, CEO and Executive Vice President, Vienna School of Clinical Research

Catherine Lund, Vice Chairman, OnQ Consulting

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

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

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

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

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

Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group

Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

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

6 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation Maha Al-Farhan, Chair of the GCC Chapter of the ACRP Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

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

Spring 2017 Volume 9 Issue 1


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Regulatory & Marketplace

Denmark: Small and Personalised Personalised medicine means giving the right medicine in the right dosage to the right group of patients at the right time. The term emerged in the late 1990s with progress in the Human Genome Project. Essentially, research involves developing methods to diagnose and stratify patient populations to allow for targeted treatment modified to the gene expression and disease profile. This means that networking is one of the crucial factors for creating both the foundation and advances in the field of personalised medicine. One big advantage of a small country, like Denmark, is that networking is easier, with fewer degrees of separation between the scientist or scientific entrepreneur and the decisionmakers, like government ministers, policy-makers, and industry leaders. It is in this new field of personalised medicine that Denmark excels particularly, not just because of the ease of communication between scientists in labs, researchers in industry, and clinicians in hospitals, but also due to its history of such collaborations dating back to the early 1900s, well before the term “personalised medicine” moved into common parlance.

almost two centuries. It started with a longstanding agricultural tradition, initiated with beer, cheese and pork. Over time, the research competences developed from beer to microbiology, from dairy products to enzymes and from pigs to insulin, and today Denmark is home to world-leading companies in these fields. The Danish biotechnology cluster is a story about development through an instilled culture of collaboration, which has turned Denmark into a major world player in areas such as diabetes care, cancer, and CNS research, and industrial enzymes.2

In Danish society, there is a strong tradition for thinking of people as unique individuals, each with different needs. This way of seeing people is combined with a genuine respect for and interest in others and their ways of thinking and behaving. These two aspects of Danish society are also the cornerstones of personalised medicine, which focuses on each individual’s disease profile. At the same time, the research necessary to develop personalised medicine is highly interdisciplinary.

Why Personalised Medicine? Personalised medicine means giving the right medicine in the right dosage to the right patient at the right time, and research involves developing methods to diagnose and stratify patient populations to allow for targeted treatment modified to the genetic and disease profile. Personalised medicine ensures that all patients receive the exact optimal medical treatment, customised and based on their individual genetic traits. Where traditional medicine is based on the identification of symptoms and their treatment with a given medication, personalised medicine, conversely, is based on the fact that each patient’s symptoms can differ according to the individual patient’s hereditary endowment, cell division, metabolism profile, etc. Thus personalised medicine comprises individual diagnosis, allowing a stratification of the patients, resulting in an independently modified treatment.

Danes are always in the front line within development of new products and methods and that is why Danish researchers regularly announce new technologies and new medicines.1 This is not due to coincidence, but for historical reasons, since the history of the Danish biotechnological research industry can be traced back

The growing understanding of genes will reform the way we think about disease, whole diagnosis, treatment and prevention. Cheap and fast DNA sequencing will, in the coming decades, result in entirely new forms of individualised treatment and lifelong prevention.

8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The vision is prevention, targeted individuals, and personalised treatment when the disease hits. Interdisciplinary Collaboration Creates Personalised Medicine Collaboration between specialists from varying disciplines is crucial to the success of personalised medicine, as it requires specialist knowledge from various scientific areas to combine the genetic findings, clinical knowledge of specific diseases and expert skills in integrating large quantities of information. Furthermore, personalised medicine is based on integrating the knowledge of basic researchers and clinicians, and requires close collaboration between diagnostic and pharmaceutical companies. In Denmark there is a long tradition of close collaboration between research institutions, academic and commercial researchers, and a number of highly-skilled diagnostic companies. 3 The collaborations between academia and industry in Denmark are not only based on informal as well as formal relationships occurring between researchers in the same field, but are distinguished by being highly cross-sectional and interdisciplinary.4 Many Patients Do Not Benefit from their Medication A large proportion of the medicines used in the healthcare sector do not work, or are directly harmful to the patient (Figure 1). This is not only harmful for the patients, but it is also a major socio-economic challenge, especially since the trend is that the price for medication is increasing. As an example, 3000 Danish arthritis patients annually start treatment with biological medicine, but about 30 per cent of them either experience insufficient power of the given drugs, or they are not able to tolerate them. However, it is currently not possible to predict which drugs Spring 2017 Volume 9 Issue 1


Regulatory & Marketplace will be the most suitable for the individual patient and consequently the physician must try the drugs available almost haphazardly.

study disease development based on data input from a very large patient population over a very long time horizon.

It is not only the patients who benefit from the personalised medicine concept, but also the public healthcare system profits, since money can be saved. Patients can recover better and faster, and consequently it will be cheaper than before. Personalised medicine aims to increase the efficacy of therapeutics via genetic testing and companion diagnostics. Personalised therapeutics and associated companion diagnostics will be more specific and effective thereby giving pharma/biotech companies a significant advantage to recuperate R&D costs. Personalised medicine will reduce the frequency of adverse drug reactions and therefore have a dramatic impact on health economics. Developmental and diagnostic companies will benefit from lower discovery and commercialisation costs and more specific market subtypes. But since personalised medicine is still a relatively new field, there are few drugs on the market.

Another important factor regarding the public health service system in Denmark is the existence of numerous comprehensive registers and statistical databases of extremely high quality – not least Denmark’s national personal identification number system, by which means all residents are registered with the public health service system and other health organisations where they are receiving treatment.

Public Healthcare in Denmark and Bio- and Databanks The Danish government and Danish society feel strongly about public health, and substantial efforts are made to keep the Danish public fit and healthy. Health-promoting activities are being implemented, including campaigns for healthy food and healthy lifestyle, and a ban on smoking in public places. Crucial to personalised medicine is the fact that Denmark has a wellfunctioning public national health insurance system and hospital services of a very high standard. The high quality of the public health service in Denmark means that the entire population, regardless of social status, makes use of it. A major advantage of such well integrated public health services in Denmark is that the system operates with shared, integrated journals that follow the patient throughout his/her life – in fact, from the foster stage. This gives Danish physicians and researchers unique opportunities to www.ipimediaworld.com

The Danish national personal identification number system and the numerous statistical databases, disease registers and journal records offer unique opportunities for epidemiological research of extremely high quality. Given that the aforementioned registers have a long history in Denmark, Danish researchers also have a long tradition of performing register research, public health studies and epidemiological research, all of which are important prerequisites for the identification and segmenting of relevant target segments and patient populations within personalised medicine. An example is the Danish Cancer Register, a population-based registry containing data on the incidence of cancer throughout Denmark since 1942. Reporting of cancer was made mandatory by administrative order in 1987. Today, the register is considered to be one of the most reliable in the world and is used extensively in research into the causes and spread of cancer. The Danish Personalised Medicine Strategy Denmark has special opportunities because of the unique registers, databases and biobanks combined with the organisation of a homogeneous health service. The Danish national personal identification number system is the mainstay of this position and Denmark can therefore make a difference in the world. That is why the Danish government has just been engaging in initiatives to create better health

for future generations, with a new strategy for personalised medicine. In Denmark, the public healthcare sector is working on a project to realise the potential of personalised medicine, in which genetic information is applied to personalise treatment. During the project, 100,000 Danes are offered a personal genetic heritage analysis to completely customise their treatment. Both healthy and sick citizens will be part of the project, which is set to run for five years. The Personalised Medicine project will in the future ensure that patients gets not only better prevention, but also proper treatment with the greatest impact and the least side-effects, the first time they are given new medicaments. Over the last 20 years, various genome sequencing techniques have undergone industrial optimisation, resulting in an exponential decrease in the running costs, from the first human genome cost of €2.5 billion ($2.7 billion) to the average price today, which is only about a thousand euros ($1000). This is now presenting some new opportunities which Denmark wants to benefit from. Clinical Trials – Test of New Medicine Developing new personalised treatments and pharmaceuticals also means testing new drugs, perhaps in new ways. For this, the Danish databanks and registries are becoming very useful for the pharmaceutical industry. Denmark has a long history of accurate and comprehensive medical databasekeeping. These databases are among the most sophisticated in the world and provide researchers with a rich source of medical and genetic information. Because all residents in Denmark have access to healthcare, all segments of the population are included in the sampling. Furthermore, high reimbursement of healthcare costs ensures that people remain in the system. The majority of the databases are available to researchers at little or no cost once their research project has been approved. Once registered, subjects participating in clinical trials can be tracked via their personal INTERNATIONAL PHARMACEUTICAL INDUSTRY 9


Regulatory & Marketplace identification numbers. This ensures a stable number of subjects able to contribute to the successful completion of a large number of trials every year.6 Denmark is the third best country in the world, and the best in Europe, in which to conduct clinical research. Furthermore, the Danish publicationcitation record for clinical research studies is ranked as the best in the world.7 One of the reasons that Denmark achieves when it comes to clinical research is that the public recognises that research is needed in order to advance medicine and the Danish patients have, for some reason, no objections against participating in clinical trials for research. Thus, it is relatively easy to recruit and obtain consent from eligible study participants in Denmark. Hence, Denmark has the largest clinical pipeline of drugs undergoing clinical trials in Europe, in proportion to its size, with more than 100 candidates in clinical Phase I, II and III, and hence it has even surpassed Sweden.8 Denmark is strongly committed to retaining and developing that position. To that end, in 2011, the Danish regions and Danish industry established a joint project to create a simple and efficient portal for concluding agreements on clinical trials for the whole of Denmark. This is achieved via the Clinical Trials Office Denmark, which facilitates corporate access to preparing and planning clinical trials in Denmark and recruiting trial subjects. The Clinical Trials Office Denmark works to ensure that industry can make contact with a unified health service, processes and contracts are standardised and recruitment is streamlined. The model ensures joint allocation of roles and responsibilities between the Danish public healthcare and industry and consistent information. However, it is not a coincidence that the Danish drug development pipeline is so strong; rather it is due to the high number of innovative biotech companies. Denmark has more than 160 biotech firms, which is about equivalent to a country like France with a ten times larger 10 INTERNATIONAL PHARMACEUTICAL INDUSTRY

5. Spear, B.B., Heath-Chiozzi, M. and Huff, J., Clinical application of pharmacogenetics, TRENDS in Molecular Medicine, pp 201-204, Vol. 7, Issue 5, 2001 6. Northern lights, World Pharmaceutical Frontiers, pp 78, Vol. 2, Issue 018, 2010 7. The most-cited nations, Times Higher Education, September 2010 8. Denmark - The Heart of Life Sciences for Clinical Trials, International Pharmaceutical Industry, pp 32-34,Volume 5, Issue 1, 2013

population. Even though many of the Danish biotech companies are relatively small, it is important to have a critical mass of research companies in the sector in order to get drugs into clinical development, and it has been reported that Denmark is one of the best countries in the world for development of biotechnology.8 Furthermore, it is crucial that the strong position in drug development is backed by a proven ability to take drug candidates into preclinical and clinical development and further, to the market. Conclusion Being able to test and validate new medical and pharmaceutical products is essential for successfully developing new therapies, especially in the field of personalised medicine. In such a new area, a lot of clinical research is needed before a pipeline of products is ready to be sent to market. Combining interdisciplinary collaboration and access to robust databases is a critical part of this discovery process. REFERENCES 1. We’re number 1! Medicon Valley scores high in entrepreneurship, Medicon Valley Magazine, pp 24-26, October 2011 2. For Danish life science small is beautiful, Nordic Life Science Review, pp 46-47, Q1 2011 3. Beedholm-Ebsen, R., Doing things the Danish way, European Biotechnology News, pp 35-36, Volume 10, 2011 4. Denmark making global connections, Science, pp 357-364, Vol. 327, Issue 5963, 2010

Rasmus Beedholm-Ebsen Special Advisor within Life Science at Invest in Denmark, under the Ministry of Foreign Affairs of Denmark. Rasmus received his PhD in Medicine at Aarhus University, Denmark and worked as a post-doc at the Department of Medical Biochemistry at Aarhus University before joining Invest in Denmark. Most recently, Rasmus received a Bachelor of Commerce degree and a degree in Certificate in Business Administration. Besides, Rasmus is Scientific Expert Reviewer for the European Commission. Email: rasbee@um.dk

Spring 2017 Volume 9 Issue 1


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 11


Regulatory & Marketplace

Comparison of Marketing Authorisation and its Requirements for Singapore and Thailand The availability of generic medication is an important issue in the ASEAN regions. The regulatory requirements of various countries of the world vary from each other. Therefore, it is challenging for companies to develop a single drug which can be simultaneously submitted in all countries for approval. The regulatory strategy for product development is essentially to be established before commencement of developmental work in order to avoid major surprises after submission of the application. The role of the regulatory authorities is to ensure the quality, safety, and efficacy of all medicines in circulation in their country.1 It not only includes the process of regulating and monitoring the drugs, but also the process of manufacturing, distribution, and promotion. One of the primary challenges for regulatory authority is to ensure that the pharmaceutical products are developed as per the regulatory requirement of that country. This process involves the assessment of critical parameters during product development. Regulatory requirements and generic drug registration for ASEAN regions is made at the end of the section. In the ASEAN region, documentation can be filed in the ACTD format. Keywords: ASEAN, Documentation, ACTD, Regulatory Authority.

The ASEAN (Association of Southeast Asian Nations) group of nations, namely Indonesia, Malaysia, Philippines, Singapore, Thailand, Brunei Darussalam, Vietnam, Laos, Myanmar and Cambodia, has recently caught the eye of many pharmaceutical companies due to the growing population and attractive pharmaceutical market growth. A recent development includes the harmonisation of regulations favouring the market entry to these nations2 ASEAN was established on 8 August 1967 in Bangkok by the five original member countries, Indonesia, Malaysia, Philippines, Singapore and 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Thailand. On 8 January 1984, Brunei Darussalam joined ASEAN, Vietnam on 28 July 1995, Laos and Myanmar on 23 July 1997, and Cambodia on 30 April 1999. In 1999 a harmonisation initiative was started among the 10 ASEAN countries. One aim of this harmonisation should be to harmonise quality guidelines that are valid for all countries involved. Another focus lies in the technical co-operation. Therefore the ASEAN Consultative Committee on Standards and Quality Pharmaceutical Product Working Group (ACCSQ PPWG) was established. The objective of the ACCSQ PPWG is the development of "harmonization schemes of pharmaceuticals' regulations of the ASEAN member countries to complement and facilitate the objective of ASEAN Free Trade Area (AFTA), particularly, the elimination of technical barriers to trade posed by these regulations, without compromising on drug quality, safety and efficacy." ASEAN established the so-called ASEAN Common Technical Document (ACTD) and the ASEAN Common Technical Requirements (ACTR) to create harmonised requirements and a common format for all submissions of dossiers in the ASEAN countries. The ACTD is a common format and content acceptable for an application in the ASEAN member countries. The ACTR are a set of written requirements or guidelines intended to provide guidance to applicants in order to be able to prepare application dossiers in a way that is consistent with the expectations of all ASEAN DRAs. The strategy of the ACCSQ PPWG is the "exchange of information on the existing pharmaceutical requirements and regulation implemented by each ASEAN member countries, to study the harmonized procedures and regulatory systems implemented in the ICH region, development of

common technical dossiers with a view of arriving at MRAs (Mutual Recognition Arrangements)." From August 2003 to December 2004, each ASEAN country should implement a trial implementation period for the ASEAN requirements (like ATCD and ACTR). The full implementation of the ASEAN requirements was originally planned for January 1st, 2005. The transition period for the ASEAN requirements was extended to December 31st, 2008 as it was not possible for the ASEAN countries to implement the ACTD until January 1st, 2005. The full implementation of ACTD for new products was planned to be done in the ASEAN countries at different points in time between 2005 and 2008, which are summarised below: • Singapore and Malaysia by December 2005 • Thailand by December 2006 • Indonesia and Vietnam by December 2007 • Philippines, Cambodia, Laos and Brunei by December 2008

As the full implementation of the ASEAN requirements (like ACTD and ACTR) in the ASEAN countries is not yet finalised, a prolongation/ transition period was done. There is an interim period agreed wherein ACTD and national formats are allowed in most of the ASEAN countries, whereas in some countries like Singapore ICH CTD is accepted. The full implementation of ACTD for new products was expected by 31 December 2008, whereas the full implementation for currently registered products was expected to be done by 01 January 2012. According to information received from the ASEAN countries (January 2009) some of the ASEAN countries still accept the CTD format for MAAs of NCEs and NBEs whereas for RENs and VARs only the ACTD format is accepted by ASEAN countries. Spring 2017 Volume 9 Issue 1


Regulatory & Marketplace According to the information of the “forum institute seminar on October 21st and 22nd in Cologne” the full implementation of ACTD became mandatory by the end of 2008 for MAAs and already registered products had to be transferred to ACTD until 2012. All regulatory agencies in these 10 countries have a relatively weak infrastructure and limited resources. The agencies are structured differently and standards of scientific guidelines are not well established. A big problem of the agencies is the lack of consistency and transparency, especially regarding the evaluation of the dossier. To solve these problems, they are constantly improving with more dialogues in the industry. In all ASEAN countries a Certificate of a Pharmaceutical Product (CPP) from the reference country is required and builds the basis of the drug approval as the DRAs do not have the possibilities, capacities and scientific know-how to make a full evaluation of the submitted dossier (especially with regard to preclinical and clinical data).

containing the regional registration and administrative information is still presented as Part 1 of the ACTD. Based on this, the need for detailed documentation is less in most of the ASEAN countries compared to the ICH countries, e.g. most study reports are not required to be submitted. Module 1 of the CTD containing the regional registration and administrative information is still presented as Part 1 of the ACTD. Module 2 of the CTD does not exist itself for the ACTD. The Quality Overall Summary (QOS) and the overview and summaries of the non-clinical and clinical documentation (similar to the documents in ICH Module 2) are included at the beginning of these parts. Part II of the ACTD contains the pharmaceutical-chemicalbiological documentation (the quality information), which corresponds to the ICH Module 3. The non-clinical information is presented as Part III of the ACTD

(equivalent to ICH Module 4) and the clinical documentation is contained in Part IV of the ACTD (to be consistent with ICH Module 5). The differences between ICH-CTD and ACTD are presented in the attached comparison pyramid: As demonstrated above the ACTD is organised in four parts •  Part I: TOC, Administrative Data and Product Information •  Part II: Quality Document •  Part III: Non-clinical Document •  Part IV: Clinical Document Dossier Requirements The requirements for the dossier for the ASEAN countries are in principle very similar to the requirements for the ICH countries. The non-clinical overview and summary as well as the clinical overview and summary is put at the beginning of Part 3 and 4 followed then by the study reports

Dossier Format – ASEAN CTD As mentioned before, the ASEAN countries established the ACTD as their format for submissions. It is a standard derived from the ICH CTD. The ASEAN CTD is a guideline of the agreed-upon common format for the preparation of a well-structured ACTD application that will be submitted to ASEAN regulatory authorities for the registration of pharmaceuticals for human use. The ACTD is similar to the ICH CTD. The ICH CTD is divided into five modules, whereas the ACTD contains of four parts. The reason for doing this is the fact that the ASEAN countries normally receive a reference application, which is a dossier which was already approved in other countries in the world (mostly EU and USA) and make the evaluation of the parts mainly based on the overviews and summaries. Based on this, the need for detailed documentation is less in most of the ASEAN countries compared to the ICH countries, e.g. most study reports are not required to be submitted. Module 1 of the CTD www.ipimediaworld.com

Figure 1: ACTD & ICH Pyramid INTERNATIONAL PHARMACEUTICAL INDUSTRY 13


Regulatory & Marketplace and literature. For some ASEAN countries these non-clinical and clinical overviews and summaries are sufficient and no additional study reports need to be submitted. In most cases, it is sufficient to submit some publications from the mentioned studies in addition to the non-clinical and clinical overviews and summaries. Singapore: Legal Framework and Regulations Singapore's pharmaceutical market is worth about $500 million. It is also the wealthiest country in the Association of Southeast Asian Nations (ASEAN). All pharmaceuticals/drugs require a product licence to import or sell in Singapore. In applying for a product licence, dossiers must be in either the International Conference on Harmonization (ICH) CTD format or the ACTD format.3 For new product licences, Singapore has a new drug application (NDA) and a generic drug application (GDA). For products already approved by certain regulatory agencies (such as Australia's TGA, the US FDA, etc.), submitting an abridged dossier is possible. Applicants submit an online application through PRISM (Pharmaceutical Regulatory and Information System) and also submit a CTD dossier. A. Application Types In applying for a new product licence for a medicinal product in Singapore, there are two categories of applications: a new drug application (NDA) and a generic drug application (GDA): NDA – New Drug Application NDA-1; NDA-2; NDA-3; NDA-1 For the first strength of a product containing a new chemical or biological entity. NDA-2 1. For the first strength of a new drug product Containing a new combination of registered chemical or biological entities. •  Containing registered chemical or biological entity(ies) in a new 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

dosage form. •  Containing registered chemical or biological entity(ies) for use by a new route of administration •  Containing registered chemical or biological entity(ies) for new indication(s), dosage recommendation(s) and/or patient population(s) 2. For new drug products that do not fall under the requirements for NDA-1, NDA-3 or GDA.

NDA-3 For subsequent strength(s) of a new drug product that has been registered or has been submitted as an NDA-1 or NDA-2. The product name, pharmaceutical dosage form, indication, dosing regimen and patient population shall be the same as that of the NDA-1 or NDA-2. *Has not been registered before in Singapore. GDA – Generic Drug Application GDA-1: For the first strength of a generic chemical product. GDA-2: For subsequent strength(s) of the generic chemical product that has been registered or has been submitted as a GDA-1. The product name and pharmaceutical dosage form shall be the same as that for the GDA-1. A generic product is essentially similar to a currently registered product in Singapore (known as the Singapore reference product) but excludes biologics. Essentially similar is defined as having the same qualitative and quantitative composition in terms of active substances, having the same pharmaceutical form and being bioequivalent. By extension, the concept of essential similarity also applies to different conventional immediate release oral dosage forms (i.e. tablets and capsules) which contain the same active ingredient(s). Evaluation routes There are three types of evaluation routes for registration of a new product: 1. Abridged evaluation route Abridged evaluation will apply to a product that has been approved by at least one drug regulatory agency at the time of submission.

2. Verification evaluation route The verification evaluation route applies to a medicinal product that has been evaluated and approved by at least one of the following HSA’s reference drug regulatory agencies: •  Australia Therapeutic Goods Administration •  Health Canada •  US Food and Drug Administration •  The European Medicines Agency via the Centralized Procedure •  UK Medicines and Healthcare Products Regulatory Agency via •  The national procedure, or •  As the Reference Member State (RMS) via the Mutual Recognition Procedure or Decentralised Procedure.

However, approval by these reference regulatory agencies does not obligate HSA to approve the application. Additional Eligibility Criteria Include: 1.  The registration dossier must be submitted within two years from the approval date by a chosen reference agency; 2.  All aspects of the product’s quality, including but not limited to formulation, manufacturing site(s), specifications and primary packaging, must be identical to that currently approved by the chosen reference agency; 3.  The product is not a biologic product; 4.  The product and its intended use – i.e. indication(s), dosing regimen(s) and patient group(s) – has not been rejected, withdrawn, approved by appeal or pending deferral by a drug regulatory agency for efficacy and/or safety reasons; 5.  The product has not been approved by the chosen reference agency via an accelerated/fasttrack approval, approval under exceptional circumstances or an equivalent process. The chosen reference agency is defined as the reference agency for which the qualifying supporting documents (as outlined in this guidance) will be submitted. Administrative Documents •  Comprehensive table of contents •  Introduction •  Application Spring 2017 Volume 9 Issue 1


www.amplexor.com


Regulatory & Marketplace •  Labelling, package insert and patient information leaflet •  Approved SPC/PI/PIL •  Assessment report from reference agencies •  Description of batch numbering system •  Proof of approval •  Authorisation letters •  GMP certification/Proof of GMP compliance •  Patent declaration •  Declaration on rejection, withdrawal and deferral •  Declaration for GDA verification •  Registration status in other countries.

CTD Overview and Summaries Th e o v e r v i ew a n d s u m m a r y documents are to be inserted into Module 2 of the ICH CTD or into the relevant sections in Part II, III and IV of the ACTD. A completed Singapore Quality Overall Summary (SQOS) must also be inserted into Module 2, section 2.3 of the ICH CTD or Part II, section B of the ACTD, irrespective of whether an ICH or ACTD QOS has been included in the application dossier. Take note that the SQOS must be named and dated by the applicant prior to submission. The electronic copy of the Singapore QOS should be in Microsoft Word format.4

Quality Documents Body of Data Drug Substance •  Drug master file (DMF) •  Certificates of suitability (CEP) •  Control of drug substance (3.2.S.4) •  Stability data of drug substance (3.2.S.7) Body of Data Drug Product •  Pharmaceutical development (3.2.P.2) •  Process validation (3.2.P.3.5) •  Control of excipients (3.2.P.4) •  Control of drug product (3.2.P.5) •  Container closure system (3.2.P.7) •  Stability data of drug product (3.2.P.8) •  Product interchangeability (3.2.P.9) •  Blank production batch records Administrative documents specific to the verification evaluation route that are required at the time of submission include: 1. 1.4.3 – The proposed PI or PIL should be aligned to the currentlyregistered Singapore reference product PI or PIL; 2. 1.9 – Official approval letter, or an equivalent document, from the chosen reference regulatory agency that certifies the registration status of the drug product;

PRIMARY REFERENCE AGENCY

DOCUMENTARY REQUIREMENTS

HEALTH CANADA AND MHRA

• Complete clinical and quality assessment reports, including assessment on the question and answer documents between the sponsor and agency and all annexes. • Assessment reports and/or documents pertaining to post-approval variations, if applicable.

US FDA

• Complete clinical and quality assessment reports, including assessment on the question and answer documents between the sponsor and agency and all annexes. • Assessment reports and/or documents pertaining to post-approval variations, if applicable.

EMA

• Complete CHMP Assessment Report, including the following: — Rapporteur’s and co-rapporteur’s day 80 assessment reports (non-clinical, clinical, quality, overview and list of questions). — CHMP day 120 list of questions. Rapporteur’s day 150 assesment report (non-clinical, clinical, quality and overview). — Day 180 list of outstanding issues. — All other annexes and appendices. • Summary of CHMP opinion. • Assessment reports and/or documents pertaining to post-approval variations if applicable

.

TGA

• Complete clinical assessment reports, including assessment on the question and agency and all annexes. • Complete chemistry and quality control assessment report including assessment on the question and answer documents between the sponsor and agency and all annexes. • Assessment reports and/or documents pertaining to post-approval variations, if applicable.

Table 1: - Documents required according to DRA [5] 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

3. 1.13 – Official letter declaring that the application submitted to HSA or similar direction(s) of use, indication(s), dosing regimen(s) and/or patient group(s) have not been rejected, withdrawn, approved via appeal process, or pending deferral by any drug regulatory agency, with reasons in each case if applicable; 4. 1.14 – Official letter declaring that the drug master file provided is the same as that submitted to the chosen reference agency, if applicable; and, 5. 1.14 – Official letter declaring that all aspects of the product’s quality intended for sale in Singapore are identical to that currently approved by the chosen reference regulatory agency. This includes, but is not limited to, the formulation, site(s) of manufacture, release and shelf life specifications and primary packaging.

Technical Documents Required6 Complete quality documents for both drug substance and drug product, which include: 1.Module 3 dossier as initially submitted to the chosen reference agency; 2. From sponsor a. Question and answers between the chosen reference agency and sponsor – the answers should include supporting documents used in response to the questions; b. All post-approval variations a p p ro v e d by t h e c h o s e n reference agency up to the time of submission to HSA, including the application letter for the variation, supporting documents for the variation, questions and answers between the reference agency and sponsor, and the approval letter for the variation from the reference agency; c. Relevant documents required by HSA which have not been submitted to the chosen reference agency, e.g. stability studies in accordance with ASEAN Stability Guidelines, Singapore Quality Overall Summary, comparative dissolution studies, etc.; 3. From DMF holder, if applicable: •  The initial open and closed parts of the DMF submitted to the chosen reference agency from the DMF Spring 2017 Volume 9 Issue 1


Regulatory & Marketplace holder should be provided to HSA, together with the original letter of access; •  Question and answers between the chosen reference agency and DMF holder – the answers should include supporting documents used in response to the questions; and, •  All post-approval DMF updates approved by the chosen reference agency up to the time of submission to HSA, including the application letter for the DMF update, supporting documents for the DMF update, questions and answers between the reference agency and sponsor and the approval letter for the DMF update from the reference agency; •  Clinical documents, such as BE studies or justifications for bio waiver, as initially submitted to the chosen reference agency with all questions and answers, including supporting documents, between the reference agency and sponsor; and any additional documents to demonstrate product interchangeability with the Singapore reference product as described in section 17.3.2, where applicable.

The target processing timeline for screening dossiers (NDA, GDA, MAV-1, MIV-1) is 25 working days before the first query is issued. The screening timeline begins from the date of the dossier submission, which should be within two working days after PRISM submission to prevent delays in processing of the application. The date of submission will be defined as the date when HSA receives the complete dataset for the application.

DOSSIER TYPE

TARGET PROCESSING TIME (WORKING DAYS) NEW DRUG

GENERIC DRUG

MAJOR VARIATION

APPLICATION (NDA)

APPLICATION (GDA)

APPLICATION (MAV-1)

FULL

270

270

ABRIDGED

180

240

180

VERIFICATION

60

60

Table 2: Timeline for drug registration in Singapore

Thailand: Medicines are classified into two major groups: modern and traditional drugs.9 Modern drugs are further divided into four categories, namely: 1. Household remedies whose sales require no licence; 2. Ready-packed drugs that can be sold in drugstores by nurses or other medical professionals; 3. Dangerous drugs; and 4. Specially controlled drugs. Dangerous drugs can be bought without a prescription but must be dispensed by pharmacists. Drugs which may possess a potentially harmful effect on health, if misused, will be listed in the last category whose sales require a prescription. Traditional Drugs  Those are intended to be used in indigenous or traditional medical

Figure 2: Flowchart of the registration process and processing timelines:7 www.ipimediaworld.com

care as monographed in the official pharmacopoeia of traditional medicines or those declared by the Minister of Public Health as traditional medicines, or those permitted to be registered as traditional medicines. The control and registration of drugs in this group are less stringent than those for modern drugs.39

Registration Dossier: The complete dossier should be submitted within two working days after the PRISM application submission to prevent delays in processing of the application. The date of submission will be defined as the date when HSA receives the complete dataset for the application.

8

Format Followed: ACTD format with some countryspecific requirements Pharmaceutical Regulations in Thailand A. Regulatory Procedure Thailand's national drug control system stems from its Drug Act BE 2510 (1967) and its four amendments. The MOPH, along with the Drug Control Division of the FDA, is responsible for administering the system. Companies interested in manufacturing or exporting pharmaceutical products must obtain prior approval from the FDA. Both manufacturers and importers are required to get a licence to produce, sell or import any pharmaceutical products into Thailand.10 The pharmaceutical control system is divided into pre-marketing and post-marketing phases. In the pre-marketing phase, companies must obtain a licence to produce, sell or import any pharmaceuticals into Thailand, as well as register their products in the country. The Bangkok metropolitan area's Drug Control Division and surrounding provincial health offices are in charge of licensing. There are nine categories of licences, including a licence to produce, a licence to sell, a licence to act as a wholesaler of modern drugs, etc. a. Registration: Pre-marketing Phase The pre-marketing phase also INTERNATIONAL PHARMACEUTICAL INDUSTRY 17


Regulatory & Marketplace includes registration of products. FDA's Drug Control Division is in charge of Steps 1 and 3, while the Department of Medical Sciences handles Step 2. Thailand also has a regulatory procedure for new drug registration. Generally, there are three important steps for drug registration in Thailand: 1. Application for permission to manufacture or import drug samples (at Food and Drug Administration); 2. Application for an approval of drug quality control and analytical methods (at Department of Medical Science); 3. Application for granting of a drug registration certificate (at Food and Drug Administration). b. Registration: Post-marketing Phase In the post-marketing phase, following registration and sale of pharmaceuticals, the quality control system at the government level tends to focus on output, i.e. the last stage of the production process, rather than input/raw materials or in the actual production process itself. In this phase, pharmaceutical quality monitoring is done by regular inspection and pharmaceutical sampling through the National Adverse Drug Reactions Monitoring Center and its 19 regional offices. Academics from outside the FDA are often hired to consider technical papers involved in drug registration. However, follow-up drug re-evaluations are not routinely performed.11 Drug Registration The registration process is necessary to ensure quality, safety and efficacy of the drugs being marketed in the country. Only authorised licensees are qualified to apply for product registration. Manufacturing plants, in which drug products are manufactured, are subject to inspection for GMP compliance. According to the new Drug Act (expected to be enacted within 2003), a certificate of product registration is valid for five years as from the date of issuance. The process of drug registration will be carried out in two channels, which differ in degrees of control and dossier submission:12 18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

1. Registration of general medicines 2. Registration of Thai traditional medicines Because of differences in the requirements for dossiers to be submitted for product approvals, the general medicines will have to be further defined as:

New medicines include products of new chemicals, new indications, new combinations or new delivery systems and new dosage forms. New generics are medicines with the same active ingredients, doses and dosage forms as those of the new compounds registered after 1992.

•  Generics, whose registrations require only dossiers on product manufacturing and quality control along with product information; •  New medicines, whose registrations require a complete set of product dossiers; •  New generics, whose registrations require dossiers of bioequivalence studies in addition to the required dossiers for generics submission.

The process of drug registration of general medicines is divided into five procedures: •  Generic drug registration •  Traditional drug registration •  New drug registration – Original new drug – New generic drug •  Biological product registration •  Herbal medicine registration

Generics mean pharmaceutical products with the same active ingredients and the same dosage forms as those of the original products, but manufactured by different manufacturers.

Generic drug registration involves three steps: 1. Application for permission to manufacture or import drug samples (at Food and Drug Administration); 2. Application for an approval

Figure 3: Registration of Generic Drugs [12] Spring 2017 Volume 9 Issue 1


Driving quality and integrity in scientific research and development As a not-for-profit association we have around 2,500 members of which 40% are based outside of the United Kingdom and located in 59 countries worldwide, with many of our members working in an international environment and to international standards.

We continue to meet the needs of our members by: • Promoting quality standards in scientific research and development • Facilitating knowledge sharing through events, publications and networking • Liaising with regulatory agencies in the development and interpretation of regulations and guidance • Offering professional development opportunities • Working in partnership/cooperation with other organisations. Our membership caters for professionals including managers, scientists, auditors, inspectors and practitioners concerned with the quality and compliance of research and development. Our members focus on the safety and efficacy of pharmaceuticals, biologicals, medical devices, agrochemicals and chemicals in man, animals and the environment. More information on all of our first class services and products can be viewed on our website.

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www.therqa.com

T: +44 (0)1473 221411 E: rqa@therqa.com


Regulatory & Marketplace of drug quality control and analytical methods (at Department of Medical Science); 3. Application for granting of a drug registration certificate (at Food and Drug Administration). New generic drug registration procedure has following steps: •  A protocol on bioequivalence study must be submitted for approval at the Drug Control Division. •  Application to seek permission for import or manufacture of the drug samples. •  Performing the bioequivalence study according to the approved protocol in a specified government institute. •  Submitting an application for registration along with the bioequivalence report and other useful documents. Documents Required for Generic Drug Registration 13 The procedure of generic drugs registration is divided into two main steps: Step 1: Application for permission to import or manufacture drug sample intended to be registered. The following documents are required: a. Application form to be completely filled by authorised licensee b. Drug formula [active ingredients(s) only] c. Drug literature d. Drug labelling and packaging Step 2: Application for the approval of granted credential certificate. 14 The following documents are required: a. Application form to be completely filled by authorised licensee b. Permit to manufacture or import drug sample c. Drug sample d. Pharmacological and toxicological study (if any) e. Clinical trials, safety and efficacy study (if any) f. Complete drug formula g. Drug literature h. Labelling and packaging should consist of name of the drug, registration number, quantity of drug per packaging, formula which shows 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

active ingredient(s) and quantity of strength, lot number, batch control number, name of manufacturer and address, manufacturing date, the words "dangerous drug"/"specially controlled"/ "for external use"/ "for topical use" written in Thai and in red colour if the drug is considered to be one of them, the word "household remedy drug" written in Thai if the drug is considered to be, the word "for veterinary use" written in Thai if the drug is considered to be, and the expiry date i. Certificate of free sale (in case of imported drug) j. Manufacturing method k. In-process control with the relevant acceptable limits l. Raw material specifications of active(s) and inert ingredients with the corresponding control methods in detail m.Finished product specification with the corresponding control methods in detail n. Certificate of analysis of active ingredient(s) (raw material) [To be required in case the active substance does not conform to official pharmacopoeias (USP, NF, S. NO

BP…etc) o. Drug analytical control method p. Packaging q. Storage condition r. Stability studies of finished product s. Certificate of GMP (in case of imported drug) Fees for Approval15 Registration fees = 12,000 Thai bhat (approx 4000 US$) Thailand BE Studies16 Reference product/comparator product: A 'reference product' must be an 'innovator' product. If the innovator product is not available in the country, an alternative comparator product approved by the drug regulatory authority of the country can be used. Population: The studies are accepted only if done on the Thai population. International BE: Not accepted

ADMINISTRATIVE DOCUMENTS

1

APPLICATION FORM

2

COPY OF VALID CERTIFICATE OF BRAND NAME CLEARANCE

3

COPP

4

FSC

5

GMP

6

LICENSE FOR PHARMACEUTICAL MANUFACTURER

7

SMF

8

PERMISSION FOR MANUFACTURING AND MARKETING IN COUNTRY OF ORIGIN

9

LOA

10

LABELLING DOCUMENTS

11

PATENT INFORMATION

12

SPC

13

PIL

14

MOCK-UP AND SPECIMEN

15

ENVIRONMENTAL RISK ASSESSMENT

16

PRODUCT INFORMATION ALREADY APPROVED IN ANY STATE/COUNTRY

THAILAND

SINGAPORE

✓ ✓ ✓ × ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓

✓ ✓ ✓ × ✓ ✓ × × ✓ ✓ ✓ ✓ ✓ ✓ × ✓

DEPENDS

×

Table 3: Administrative Documents Comparison THAILAND

SINGAPORE

NON-CLINICAL DOCUMENTS

THAILAND

SINGAPORE

DRUG PRODUCT

×

NON-CLINICAL OVERVIEW

×

DESCRIPTION AND COMPOSITION

NON-CLINICAL WRITTEN AND TABULATED SUMMARY

×

×

×

×

×

PHARMACEUTICAL DEVELOPMENT

×

NON-CLINICAL STUDY REPORTS

MANUFACTURE

✓ ✓ ✓ ✓

✓ ✓ ✓ ✓

LITERATURE REFERENCES

CLINICAL OVERVIEW

QC OF EXCIPIENTS QC OF FINISHED PRODUCT REFERENCE STANDARD CONTAINER CLOSURE SYSTEM / PACKING

PRODUCT STABILITY

PRODUCT INTERCHANGEABILITY

Table 4: Technical Documents ComparisonDRA5

Table 5: Non-clinical Documents Comparison CLINICAL DOCUMENTS

THAILAND

SINGAPORE

✓ ×

× ×

TABULAR LISTING OF ALL CLINICAL STUDIES

×

×

CLINICAL STUDY REPORTS

ONLY BE

CLINICAL SUMMARY

Table 6: Clinical Documents Comparison Spring 2017 Volume 9 Issue 1


Regulatory & Marketplace Conclusion: It is noticeable that harmonisation of standards and regulations as well as MRAs are a major contribution to the integration of the ASEAN market. Even if tariffs are done away with and even with the most efficient transportation, true market integration will be out of ASEAN’s reach if the flow of products is hampered and slowed down by inconsistent regulations and varying standards. ASEAN standards bodies and regulatory authorities have been working closely with the private sector to address these technical barriers. None of the above achievements can happen without regional cooperation and strong collaboration of stakeholders. Moreover, regional cooperation on standards and conformance compels standards officers, regulators and industry to meet frequently and network effectively.

www.ipimediaworld.com

S. NO

COUNTRIES

1

THAILAND

BIOEQUIVALENCE STUDY ACCEPTABLE

OTHER COUNTRIES BIOEQUIVALENCE STUDY ACCEPTABLE

• Thai Guidelines for the Conduct of Bioavailability

and Bioequivalence Studies adopted from “ASEAN Guidelines for The Conduct of Bioavailability and Bioequivalence Studies”

NOT ACCEPTED

• ASEAN Guidelines for the Conduct of Bioavailability 2

SINGAPORE

and Bioequivalence Studies. Also in accordance with Appendix 12 Product Interchangeability and Biowaiver Request for Chemical generic drug applications of the Guidance on Medicinal Product Registration in Singapore 2011

ACCEPTED

Table 7: Bioequivalence Study Comparison Chart

Singapore and Malaysia are the only countries in ASEAN who have well-established pharmaceutical regulations and are more strict on quality and safety of drugs. These countries believe in innovation and give full protection to it. Hence there may not be many opportunities for small- and mediumscale generic companies in these countries unless their manufacturing procedures are well to do with regulatory requirements.

REFERENCES 1. The role of the regulatory authorities is to ensure the quality, safety, and efficacy of all medicines in circulation in their country. [Internet] http://www.ncbi.nlm.nih. gov/pubmed/23373001 [Accessed on February 15th 2013.] 2. Aseansec.org [homepage]. ASEAN (Association of Southeast Asian Nationals. [Internet] http://www. aseansec.org [Accessed on February 15th 2013.] 3. The ASEAN Common Technical Document (ACTD) for the

INTERNATIONAL PHARMACEUTICAL INDUSTRY 21


Regulatory & Marketplace

registration of pharmaceuticals for human use. Organization of the dossier. [Internet] http://www. hsa.gov.sg/publish/etc/medialib/ hsa_library/health_products_ regulation/western_medicines/ files_guidelines.Par.22449.File.dat/ ACTD_OrganizationofDossier.pdf [Accessed on February 15th 2013.] 4. Guidance on Medicinal Product Registration, Health Sciences Authority, Singapore. [Internet] http://www.hsa.gov.sg/publish/ etc/medialib/hsa_library/ health_products_regulation/ western_medicines/files_guidelines. Par.22361.File.dat/Guidance%20 on%20Medicinal%20Product%20 Registration%20in%20Singapore%20 2011%20(COMPLETE).pdf [Accessed on February 15th 2013.] 5. Singapore. Guidance on Medicinal Product Registration in Singapore – Target Processing Timelines. [Internet] http://www.hsa.gov.sg/ publish/etc/medialib/hsa_library/ health_products_regulation/ western_medicines/files_guidelines. Par.67117.File.dat/Appendix%201_ Target%20Processing%20 Timelines%202011 [Accessed on February 15th 2013.] 6. ASEAN guidelines for the conduct

of bioavailability and bioequivalence studies – questions and answers (Q & A) (Version 1). [Internet] http://portal.bpfk.gov.my/view_file. cfm?fileid=437 [Accessed on February 15th 2013.] 7. Health Sciences Authority, Singapore. [Internet]. http://www.hsa.gov.sg/publish/ hsaportal/en/health_products_ regulation/western_medicines/ guidelines.html [Accessed on February 15th 2013.] 8. Timeline for drug registration in Singapore. [Internet] http://www. hsa.gov.sg/publish/hsaportal/ en/health_products_regulation/ western_medicines/guidelines.html [Accessed on February 15th 2013.] 9. Food and Drug Administration, Thailand. [Internet]. http://www. fda.moph.go.th/eng/drug/intro.stm [Accessed on February 15th 2013.] 10. Food and Drug Administration, Thailand. [Internet]. http://www. fda.moph.go.th/eng/drug/pre.stm [Accessed on February 15th 2013.] 11. ASEAN Guidelines for the Conduct of Bioavailability and Bioequivalence Studies. [Internet]. http://portal.bpfk.gov.my/view_file. cfm?fileid=437 [Accessed on February 15th 2013.]

12. The process of drug registration will be carried out in 2 channels, which differ in degrees of control and dossier submission. [Internet] http://www.conceptfoundation.org/ files/meeting/14.%20Chawanon%20 -%20Drug%20Registration%20 Thailand.pdf [Accessed on February 15th 2013.] 13. Documents Required For Generic Drug Registration. [Internet] http:// www.pacificbridgemedical.com/ publications/new-regulatorytrends-in-thailand-spharmaceutical-market/ [Accessed on February 15th 2013.] 14. Application for the approval of granted credential certificate. [Internet] http://www.fda.moph. go.th/eng/drug/laws.stm [Accessed on February 15th 2013.] 15. Fees for approval of Generic Drugs. [Internet] http://www.thailawforum. com/fda-registration.html [Accessed on February 15th 2013.] 16. Thailand BE studies [Internet] http://www.pacificbridgemedical. com/news/ thailand-to-amendbioequivalence-requirement-fornew-generic-drugs [Accessed on February 15th 2013.]

G. Ravi

Balamuralidhara V.

Kaushik Devaraju

Vishal Kumar Gupta

Ph.D. Research Scholar, Department of Pharmaceutics, JSS College of Pharmacy, Jagadguru Sri Shivarathreeshwara University, Mysuru, SS Nagara, Mysore – 570 015, Karnataka, INDIA. Email: ravigundawar1@gmail.com

Ph.D. Research Scholar, Regulatory Affairs, Department of Pharmaceutics JSS College of Pharmacy, Jagadguru Sri Shivarathreeshwara University, Mysuru, SS Nagara, Mysore – 570 015, Karnataka, INDIA. Email: kaushik.devaraju@gmail.com

22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Assistant Professor, Department of Pharmaceutics, JSS College of Pharmacy, Jagadguru Sri Shivarathreeshwara University, Mysuru, SS Nagara, Mysore – 570 015, Karnataka, INDIA. Email: baligowda@jssuni.edu.in Professor, Department of Pharmaceutics, JSS College of Pharmacy, Jagadguru Sri Shivarathreeshwara University, Mysuru, SS Nagara, Mysore – 570 015, Karnataka, INDIA. Email: vkguptajss@gmail.com

Spring 2017 Volume 9 Issue 1


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Regulatory & Marketplace

The Big Data Cure-all? Data management is an issue for any business these days, but particularly in life sciences, where growing regulatory demands and commercial pressures are increasing the risk for companies that don’t have the latest information to hand. Drawing on examples from other markets, Elvis Paćelat, VP Compliance Solutions at AMPLEXOR Life Sciences, distils some best-practice data discipline which starts with a single version of the truth.

Life sciences organisations ought to be experts at managing information, given how much of it they have to collect and keep for regulatory purposes. Failure to keep detailed records carries heavy consequences, so companies must follow authorities’ specifications to the letter, and be able to track what was done when and where as they develop products and bring them to market. Responsibilities don’t end there, either. Companies also need measures in place to track their products in the market, and respond if issues arise (e.g. adverse effects) or as regulatory requirements change. This demands whole-lifecycle data management capabilities. The level of detail required is onerous too: every tweak to a product or the way it is supplied must be verified and validated – a huge and rigorous undertaking in terms of documentation and labour. Vigilance is paramount. One miscalculation – mislabelling or incomplete advice for a new market – could have such profound implications. It could mean direct risk to customers’ health, punitive fines and reputational damage. The result can be that companies become paralysed and afraid of change, a mindset that conflicts with 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the broader market need to be agile and innovative, in order to stay ahead of consumer demands, changing market dynamics and new competitive threats. Lifecycle Lessons: The Importance of Follow-through Although almost every market has its own data challenges in the modern age, few match the level of complexity and risk associated with life sciences. Take the industry’s huge number of product and compound variants – from initial formulation in the lab, to the manifold manifestations in each market. Long before a product exists in its marketable form, it has a development history that needs to be documented and is assigned an ‘identifier’ so it can be tracked in some form from day one. In other markets, such as healthcare, it is logical to follow the subject (e.g. a patient) right through their case lifecycle so that there is a continuous record of everything that has happened, where and when, and with what result – from the moment the case opened to the moment of discharge and beyond. Comprehensive digital patient records that can be accessed and updated across all aspects of treatment are seen as the answer, following the patient right across the lifecycle of their care. As a result of the requirement for Trusts in England to deliver discharge summaries to general medical practitioners within 24 hours of a patient leaving hospital, many Trusts have extended their electronic patient record systems to enable them to create and submit discharge summaries electronically (another benefit being the built-in audit trail). In advanced scenarios, hospitals capture everything from diagnoses, co-morbidities, investigation and results, to procedures and treatments, medications and any follow-up

arrangements, and issue a summary to the patient’s GP electronically. Extended systems can also be used to transmit an approved dispensing sheet to pharmacy, allowing medication to be dispensed efficiently. Episode coding is more reliable too in a joined-up digital system, because the recipient no longer has to decipher handwriting when interpreting a colleague’s notes. Avoiding Contra-indications Cross-discipline ontentmanagement, where this has been achieved, means not only that healthcare organisations can meet their regulatory obligations, but that they also benefit from slicker internal processes, reduced administration costs, and the ability to deliver improved patient care. Information sharing with other organisations – primary care-givers, other hospitals and specialist healthcare practitioners – is also made easier once content is stored electronically in a format that can be accessed by authorised partners. This fluidity of information collation, movement and sharing is not yet mirrored in life sciences, though the industry could probably benefit in many of the same ways if it managed to arrive at a similar digital information management scenario. More usually, however, life sciences data is recorded and stored locally in a format that suits the immediate task and supporting system. This may be manual, or a proprietary applicationspecific IT system. It does not serve the wider needs of the organisation; nor does it help the company deliver against increasingly strict information compliance demands. For a whole host of strategic and regulatory compliance reasons, the challenge now is for life sciences to think in terms of the same bigger picture – i.e. see beyond the immediate purpose of operational data. Spring 2017 Volume 9 Issue 1


Regulatory & Marketplace

Take that earliest product identifier – the code that defines the compound chosen as the basis for a new drug. Its existence should allow the business to track the development process as the selected combination of active ingredients is developed and brought on – from the lab and as it fulfils its market potential. Having a unique, consistent identifier throughout the research and development process allows an information trail to form, which will play an important role in the marketing authorisation process. The entire testing process and each round of results need to be easily traceable too, from pre-clinical to clinical trials, covering the overall safety of the new compound, to its efficacy and optimum administration route and dosage. From a patient and regulatory perspective, and indeed in the interests of risk management, all of this constitutes a duty of development. Marketing approvals are very specific too, based on agreed dosages and methods of application, reinforcing the need to get the detail right and keep it consistent. But the specifications, along with the eventual product name, can vary from country to country. This is where data capture and management become particularly complex in a life sciences context. Should companies define and track products by name and country, or by the chemical compound/active ingredient? www.ipimediaworld.com

For Maximum Effectiveness, Follow the Prescribed Advice Because of the implications of information governance for customer safety and market confidence, national and international authorities are continually tightening the controls and increasing their demands for data collection and reporting, so that the onus is on life sciences companies to have all of the answers at their fingertips and ready to submit at short notice. Without a single, joined-up view across operations and products, this is difficult to achieve. The emerging ISO Identification of Medicinal Products – IDMP – standard involves a highly involved set of information requirements. Even in the initial phase of the evolving standard, more than 30 different pieces of information are required – a figure that will rise to over 90 and then to hundreds of different elements, once the standard is more advanced. That’s a considerable administrative commitment. So there are multiple, compelling reasons for pharma organisations to take control of their information landscape. Although some momentum around IDMP preparation has been sacrificed in the decision to extend deadlines, these requirements will be enforced. Aligning information management systems and processes will take

time to get right in any case, so preparation should not be delayed – particularly if companies want to avoid a last-minute panic. If they do end up rushing to comply, this could compromise their ability to roll out a broader-reach solution that delivers greater business benefits. A positive side-effect of IDMP is that it fosters a consistency in data management that hasn’t existed before in life sciences – across research and development, manufacturing and quality assurance, and beyond. It marks a move away from a very fragmented approach to information governance, dictated by departmental silos. Holistic Treatment The practical way forward, companies are beginning to realise, is to move towards a holistic repository – a master resource, where all productrelated content is amalgamated (either physically or virtually), ensuring that all departments and parties along the supply chain are referring to the same data. A resource that meets the needs of IDMP and new marketing authorisation demands simultaneously. This requires a facilitating infrastructure, something that is typically lacking but which is increasingly prevalent in other industries.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 25


Regulatory & Marketplace Emerging data and document management models such as the DIA TMF reference model offer organisations a good starting point, and gradually organisations will find that there is a choice of good, configurable solutions to choose from that will help them to collate, store and process data and documentation cohesively, in the same standard format from one end of the product lifecycle to the other. Using rules-based workflow and data-sharing, such systems will help life sciences organisations accelerate deployment because they already provide the main building blocks that most companies need, allowing for minimal customisation to suit each company’s unique needs. The next consideration is who will champion and drive the harmonisation efforts. While regulatory affairs has traditionally acted as a collection point for compliance-related data, organisations should not assume this will continue. Holistic product data management is much bigger than a single department, and needs its own champion – a responsible party who will oversee the whole flow of data from R&D to eventual product withdrawal, and can help enforce consistency end to end. This is the approach commonly taken in other markets, and has become a model for best practice. As in other industries, responsiveness will be a key capability that organisations will need in future, for reasons of competitive advantage as well as compliance. In the case of pharma, the first draft of guidance on IDMP specifies that companies will have just 30 days to meet their IDMP data obligations once a marketing authorisation application has been submitted – a challenging requirement that cannot be met in a piecemeal way. It should be remembered that IDMP is just one of many new or improved regulations coming down the line. This is a further reason that firms can’t afford to be too fixed or niche in their information management plans. Bespoke, single-purpose systems lock companies in and undermine 26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

any aspiration towards greater agility. They are expensive to own and maintain, and cannot adapt easily to new requirements. The only real way that organisations can hope to prepare themselves for whatever the future brings, is to work towards a centralised master data resource and a configurable/adaptable system – in other words, an agile but uniform architecture. This is the conclusion that other industries are reaching in their data transformation efforts. If life sciences has declared itself a special case, it is only because its needs for data discipline are an order of magnitude greater than those of other markets, rather than because they are inherently different. • For the latest on the European Medicines Agency’s ISO IDMP data requirements, visit http://www. ema.europa.eu/ema/index.jsp?curl= pages/regulation/general/ general_content_000645 jsp&mid=WC0b01ac058078fbe2

Elvis Paćelat Business and technology executive with more than two decades of international experience in the Life Sciences market. With detailed technical understanding and expertise in compliance and regulatory content management solutions for Life Sciences, Elvis is a specialist in business impact analysis. As AMPLEXOR's VP Compliance Management, he is responsible for driving the corporate strategy and market success of the AMPLEXOR Life Sciences' suite business. Elvis is committed to delivering benefit for clients, partners and shareholders, whilst supporting client-centric strategies and spearheading groundbreaking innovations. Email: elvis.pacelat@amplexor.com www.amplexor.com

Spring 2017 Volume 9 Issue 1


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 27


Regulatory & Marketplace

How Much Energy Do You Throw Away After Lights Out? Is Air-Con Burning a Big Hole in Your Bank Balance? • Energy Monitoring Introduction • Three Case Studies • And the Good News… • The Value of Energy Monitoring • Conclusion

When the last person out at night turns off the lights, how many of us are lulled into a false sense of security into thinking that the energy consumption of our offices or factory also switches off for the night? Energy Monitoring Introduction We always fit energy loggers to record out-of-hours electricity consumption as part of the energy review carried out to implement the ISO 50001 Energy Management System. The results, as might be imagined, are very mixed, but on several occasions the logging equipment revealed some alarming instances where the non-working hours demands when the premises are unoccupied were not massively different from the working hours demands. The three examples that follow were obtained from real-world energy audits carried out as part of our lead assessor activities during the first phase of the UK Energy Saving Opportunity Scheme (ESOS). 1) Administration Offices The chart below illustrates an example of one of our energy loggers

monitoring the air-conditioning consumption on just one floor of a six-storey office building occupied by a pharmaceuticals company in Manchester. The blue rectangle highlights the electricity consumption between 7pm and 6am and reveals that nearly 300 kWh were consumed by the air-conditioning system for maintaining a set-point temperature of 19 degrees Celsius in the offices, despite the building being unoccupied. By extrapolating the kWh result by the number of non-working hours per year, the estimated wasted energy amounted to a staggering £16,640 per year and that was on just one floor of the building. It should go without saying that this is a cost to business that would otherwise get reported as gross profit in company accounts. If the shareholders of a business were informed of the amount of money being thrown away in unnecessary

Energy Consumption in Non-working Hours. 28 INTERNATIONAL PHARMACEUTICAL INDUSTRY

wastage, then there might be increased motivation to remedy the problem. Further investigation of the air-conditioning system revealed that the timer function on the local controllers appeared not to have been properly set up since the split units were installed several years previously. Occupancy sensors that may be purchased as an optional device

Occupancy Sensors can Easily be Retrofitted

Pharmaceutical Product Mixing Tanks

Energy Consumption in Non-working Hours. Spring 2017 Volume 9 Issue 1


Regulatory & Marketplace from the air-conditioning suppliers, or even retrofitted, switch off the AC when no people are present and can help to make a big dent in energy bills. 2) Pharmaceuticals Factory The Manchester-based pharmaceuticals company also occupied two factories that produced nasal sprays on behalf of a multinational. The space heating in the nasal spray factory comprised of direct gas-fired warm-air heaters controlled from a central location. The gas meter serving the factory had recently been upgraded to a ‘smart meter’ that permitted the client to view their gas consumption over any period selected on cloud-based software. The chart reprinted below shows the gas consumption for a typical period that spans productive and non-productive hours. The graph demonstrates that significant gas is being consumed during times when the factory is closed for production, i.e. at night time and over the weekend. By extending the kWh result by the number of non-productive hours per year and then multiplying the total by the current price of gas paid by the company, the estimated annual cost of wasted energy to heat the factory during non-productive time amounted to an eye-watering £20,845. It should go without saying that this is a cost to business that would otherwise get reported as gross profit in company accounts. If the shareholders of a business were informed of the amount of money being thrown away in unnecessary wastage, then there might be increased motivation to remedy the problem. Upon close examination of the heating controller, it became apparent that the heating function was erroneously set to ‘ON’ as opposed to ‘AUTO’. The heating system was being commanded to maintain a set-point temperature of 25.5 degrees Celsius in the factory, regardless of whether the factory was occupied or not. www.ipimediaworld.com

Energy Consumption in Non-working Hours.

Gas Heating Controls Erroneously Set to 'ON' instead of ‘AUTO’

3) Herbal Factory An anomalous result was obtained when the energy monitoring equipment recorded the 24-hour electrical energy consumption of the herbal factory. The energy logger registered a spike in consumption that commenced at approximately midnight when the factory was closed, and then mysteriously disappeared at about 2am.

Energy Consumption in Non-working Hours.

The unexpected result was reported to the client, which prompted a lengthy investigation. It was discovered that a split air-conditioning unit serving the factory offices was erroneously being commanded to switch on for about two hours after midnight. The local controller was duly adjusted to take account of the correct occupancy times and the spike in consumption has been eliminated.... It’s not all bad news… Ke e p i n g t r a c k o f e n e rg y consumption also reassuringly confirms when things are going as expected, i.e. for equipment to only consume energy during the operating cycle and at no other times.

In the following example, we monitored the consumption of an industrial dishwashing machine in the main factory for a 24-hour period. The results confirmed that no energy was being consumed by the dishwasher until it was required by the operators to perform a cleaning cycle and once completed, the energy consumption fell back to zero. The Value of Energy Monitoring The value of regular monitoring of both electricity and fossil fuel consumption is difficult to overstate, enabling irregularities such as the spurious switching on of HVAC systems and equipment to be readily identified and remedial action to be taken if determined necessary. Conclusion The findings of our energy investigations illustrate that significant improvement in energy performance can often be achieved with little capital outlay, or sometimes none at all, being required.

Michael Glanfield Chartered Energy Manager with the Energy Institute and founded Epsilon Energy Professionals. Michael has a practical background mainly working in Building Services Engineering Design. The company serve customers all over Europe from their offices in London, Dublin and the Isle of Man. Email: info@epsiloniom.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 29


Regulatory & Marketplace

Magnesium Alloys: Revolutionising the Pharmaceutical Industry The pharmaceutical industry has been growing by 7.8% year on year, and its worth is estimated to be $1.6 trillion by 2020 (PWC, 2012). In Europe alone, pharmaceutical production has grown exponentially since the turn of the century, increasing from €125,316 billion in the year 2000 to €225,000 billion in 2015 (EFPIA, 2016).

However, the pharmaceutical industry is facing a range of challenges, including rising customer expectations as well as declining R&D productivity. Therefore, it is increasingly important to get the best possible products to market by improving existing product lines and introducing new ones. This can often be difficult, with innovative solutions hard to come by. A recent development may offer potential new, ground-breaking solutions to the pharmaceutical industry. Magnesium alloys have been used in veterinary auto wormers to allow a drug to be delivered over specified, set intervals in the body, rather than at one single time. They have also been successfully developed for use in CE Marked cardiovascular scaffold implants. So, what are magnesium’s properties and how can it be used in pharmaceutical applications? A Bespoke Pharmaceutical Solution Bioresorbable materials are now being used increasingly in the medical device and healthcare industry to help address major challenges. Bioresorbable materials are advantageous for use in the body, as they achieve optimum healing by resorbing at a steady rate. Polymer materials are one example, but they do have their limitations because they have comparatively low strength, can cause foreign body reactions and can take a long time to resorb relative to other bioresorbable materials. 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Magnesium alloys offer an exciting alternative to polymers. Whilst it is a material which is already strongly associated with the aerospace and nuclear industries, it is also biocompatible and naturallyoccurring in the body. As a result, it is starting to be used with success in medical devices. As research continues into the therapeutic properties of magnesium alloys, it is becoming clear that they demonstrate not only biocompatibility, but also biosafety. Therefore, the uses and outcomes of magnesium as a biomaterial are more widely understood, as well as the potential for it to be used in a greater range of applications within the body. Magnesium’s biocompatibility means that the body has the ability to remove magnesium degradation products. Studies of blood, following the placement of magnesium within the body, revealed resorption caused little change to the composition, with no disorder to the liver or kidneys (Zhang et al., 2009). Furthermore, magnesium is needed for effective heart, muscle, nerve, bone and kidney function (Institute of Medicine, 1997) and the World Health Organization (WHO) recommends adults need 280-300mg of magnesium per day. The one main challenge magnesium faced was its potential to degrade too quickly under physiological conditions. However, magnesium alloys can now be designed to take advantage of the degradation process, creating tailored degradation rates. Magnesium can, therefore, be used in the body for a wide range of applications.

has begun to be used for healing within the body, however they have typically been produced from titanium and stainless steel, which are permanent materials that often require secondary operations should they need to be removed. In contrast, bioresorbable materials made from magnesium alloys allow optimal healing and tissue regeneration before resorbing into the body as the surrounding tissue replaces the implant. Bioresorbable implants also degrade within the human body, with matching resorption kinetics to the healing period. This avoids the need for secondary surgical procedures, which are costly and stressful for patients. The advantage of the degradation or resorption process of a magnesium implant is that it allows for new bone to grow inwards. This is in contrast to other bioresorbable materials such as polymers, which, as well as taking longer to degrade, have the potential to intake water during degradation, leading to a loss in structural integrity, as well as size (Hofmann et al., 2009). A good example of successful use of magnesium is in Magmaris, a bioresorbable cardiovascular scaffold from BIOTRONIK that received CE Mark in 2016.

How Magnesium Compares with Other Materials for use in Different Applications in the Body? Im plants are an example of an application where magnesium Spring 2017 Volume 9 Issue 1


Regulatory & Marketplace

Cardiovascular disease is the world’s most common and deadly condition and, as a result, is an area where a number of new procedures are being pioneered. Minimally invasive procedures, known as coronary angioplasties, are the most advanced solutions and involve the insertion of a stent into the coronary artery.

BIOTRONIK, one of the world’s leading manufacturers of cardio and endovascular medical devices, identified the need to introduce a new cardiovascular stent which would resorb over time. A partnership was forged with Magnesium Elektron, a global leader in magnesium technology, service and innovation to provide BIOTRONIK with a bespoke new technology. Following a ten-year research programme between Magnesium Elektron and BIOTRONIK, the magnesium SynerMag® 410 alloy system, an award-winning product offering a variety of advantages including flexibility, ductility and strength, was chosen as the platform material in BIOTRONIK’s Magmaris, the first clinically proven magnesiumbased resorbable scaffold to obtain CE Mark. Patients have now been treated successfully with Magmaris in Germany, Belgium, Denmark, the Netherlands, Switzerland, Spain, Brazil, New Zealand and Singapore since its launch in the summer of 2016.

Conclusion Magnesium is a material which can be used in a variety of therapeutic a p p l i c at i o n s , p a rt i c u l a r ly i n the medical device sector. The experience gained through these devices offers great promise for potential applications within the pharmaceutical market. As magnesium is resorbable and offers biocompatibility as well as biosafety, it has a number of advantages in comparison with other solutions, including bioresorbable materials such as those made from polymers. An example of a company with a successful history in producing magnesium alloys for commercial applications is Magnesium Elektron. Its magnesium alloy product, SynerMag, is being evaluated for use in multiple applications and can be designed to resorb at different rates for every individual requirement. To find out more about Magnesium Elektron and magnesium alloys and their applications, visit the website and download a new whitepaper about magnesium alloys in healthcare applications. Alternatively, for material and application discussions, you can contact Dr Robert Thornton, Quality & Programmes Development Manager – Biomedical at Magnesium Elektron, who can be reached on +44 (0) 161 911 1355 or robert.thornton@ magnesium-elektron.com.

REFERENCES 1. PwC - http://www.pwc.com/gx/ en/industries/pharmaceuticalslife-sciences/pharma-2020/ vision-to-decision.html 2. EFPIA - http://www.efpia.eu/ uploads/Modules/Documents/ the-pharmaceutical-industry-infigures-2016.pdf 3. Zhang E, Xu L, Pan F, Yu G, Yang L and Yang K. In vitro and in vivo evaluation of the surface bioactivity of a calcium phosphate coated magnesium alloy. 2009. Biomaterials, Volume 30, Issue 8, Pages 1512-1523 4. Institute of Medicine (IOM). Food and Nutrition Board. Dietary Reference Intakes: Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride. Washington, DC: National Academy Press, 1997. 5. Bostman OM. Osteoarthritis of the ankle after foreign-body reaction to absorbable pins and screws. The Journal of Bone and Joint Surgery. Vol 80-B No 2 March 1998. 6. Hofmann D, Entrialgo-Castano M, Kratz K and Lendlein A. Knowledge-based approach towards hydrolytic degradation of polymer-based biomaterials. 2009. Advanced Materials. 21, 3237-3245.

Paul Lyon Programmes Technology Manager for Magnesium Elektron, a Manchester, UK based developer, manufacturer and supplier of magnesium. In his role as Programmes Technology Manager, Paul is responsible for overseeing the development of bespoke magnesium alloys for use in a range of diverse markets including biomedical, pharma and aircraft interiors. He has more than 25 years experience leading teams in alloy development and promotion. Paul holds a First Class honours Degree in Metallurgy, and is a Chartered Engineer. Paul is also the author of numerous Magnesium alloy publications in the USA & Europe and Patent holder of several Magnesium alloys.

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 31


Regulatory & Marketplace

The Expanding Role of pharmacovigilance

Pharmacovigilance is evolving into something much more than a regulatory compliance and safetyrelated discipline. Increasingly, it has a central role to play in product development and product management activities as well as portfolio decisions. With that in mind, ProductLife Group recently brought together a number of leading figures in the life sciences industry to discuss several of the emerging trends around pharmacovigilance that together are changing the game. ProductLife Group’s Cheryl Key reports.

Diligence with regard to the safety of life sciences products must extend right through into the real world if patients and prescribers are to be clearly informed and kept up-to-date about the risks with such products. That is, patients and prescribers must continue their watch for unexpected things beyond the risks and adverse drug reactions named on product literature. Regulators demand it, and brand reputations depend on it. Pharmacovigilance (PV) will always be about protecting patients, but the discipline is growing in scope and evolving to a point of reach and influence within companies themselves. To explore what this means for those involved, ProductLife Group recently invited people on the front line to consider the new trends being seen today. Taking part in the discussion were: • Julia Appelskog, Qualified Person for Pharmacovigilance (QPPV) and Head of Pharmacovigilance, Bluefish Pharmaceuticals • Laura Dalsasso, Regulatory Affairs Office and PV Manager, E-Pharma • Paul Dolin, Head of Pharmacoepidemiology, Takeda Pharmaceuticals • David Ferguson, Head of International Pharmacovigilance, Shire Pharmaceuticals • Mariska Kooijmans, Head of Drug Safety and Pharmacovigilance 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

• • • •

International and EU QPPV, Amicus Therapeutics Lesia Tontisakis, Director of Pharmacovigilance, Allergan Lesley Wise, Managing Director, Wise Pharmacovigilance and Risk Management Erick Gaussens, Chief Scientific Officer, ProductLife Group Marco Anelli, Head of Pharmacovigilance and Medical Affairs Advisory Services, ProductLife Group Cheryl Key, Head of Practice PV Platform Services/Principal Medic, ProductLife Group

Here are six of the trends they identified. 1. Quality is Now a Top Priority for Pharmacovigilance Departments Although quality ought to be a given in pharmacovigilance, that hasn’t consistently been the case. In recent years, inspections by health authorities across Europe have taken issue with serious deficiencies in a number of companies’ pharmacovigilance quality systems. As a result, organisations have had to invest more resources in their safety departments and systems. As Julia Appelskog at Bluefish Phar-maceuticals put it, “Quality is the priority. You must have good-quality data, and inspections are increasing.” But there’s an upside: “While this creates challenges, it also helps us achieve a better system and better processes because business leaders understand now how important pharmacovigilance is and are allocating more resources,” she said. There is a balance to be struck, however. “With more audits than ever before, it can feel as though we’re feeding a hungry compliance animal rather than focusing on patient safety,” said David Ferguson of Shire Pharmaceuticals. The worry is that all of this regulatory rigour could detract

from “the nuts and bolts of patient safety data,” he suggested. Breaking down silos and establishing better cross-functional collaboration between pharmacovigilance and quality operations has also become of greater concern at many companies. “There are expectations by inspectors that there should be a good-quality system and a good pharmacovigilance system and that the processes should be aligned,” said Lesia Tontisakis of Allergan. When it comes to having to align and standardise activities globally, including those handled by affiliates, the challenge multiplies, she added. For managers at affiliates, processes must be in place to ensure that any safety information gets communicated into the central function. Overall accountability ultimately rests with pharmacovigilance at headquarters, however. A strong and connected relationship between pharmacovigilance and quality is also essential for maintaining a high-level perspective, according to Mariska Kooijmans at Amicus, who works closely with the head of pharmacovigilance quality. “Such a relationship enables us to map the systems and make sure there is integration,” she said. “The quality group has to be part of pharmacovigilance decision making and vice versa.” The question of responsibility for pharmacovigilance becomes more involved as the boundaries blur. Shire’s Ferguson said the pharmacovigilance system can touch almost any department in a pharmaceutical organisation. “One of the biggest challenges has been to create an understanding across the whole organisation that pharmacovigilance is a system for which others have responsibility as well,” he said. Spring 2017 Volume 9 Issue 1


Regulatory & Marketplace hear it’s not,” he said. “But you’ll never hear that until you go out and ask the question.”

For small companies, the quality requirements can be among the most-challenging aspects of pharmacovigilance, according to Laura Dalsasso of E-Pharma. Evaluation of a pharmacovigilance system tends to be outsourced, creating its own set of complications “because you have to audit your partners, and if several partners are involved, you have to spend time preparing agreements with each partner,” she said. E-pharma markets only a limited number of packages so it can avoid a sunset clause, but the company is still required to maintain a full pharmacovigilance system for evaluating the safety data of those products, a task that is time-consuming and resourceintensive. 2. Risk-benefit Balancing is a Continuous Process A growing emphasis on balancing the risk-benefit ratio requires that a company consider any benefit in terms of what it means to patients, as opposed to a scientific endpoint of efficacy. “It’s about what your drug brings to the party,” said Shire’s Ferguson. “For example, a cholesterol drug might demonstrate that it lowers cholesterol levels, but benefit is about answering such questions as, Do patients live longer? What’s the cost? and, Does your drug work better than others currently out there?” he said. The risk-benefit profile, too, isn’t static, which adds to the workload. Beyond the point of clinical trials, any new data is almost exclusively safety data, Lesley Wise of Wise www.ipimediaworld.com

Pharmacovigilance and Risk Management said. “That means pharmacovigilance or medical safety must be driving the risk-benefit discussion.” For some products, conditional approval is given with a requirement to conduct postauthorisation efficacy studies and post-authorisation safety studies. “Regulators want drugs on the market; they want innovation,” said Cheryl Key of ProductLife Group. They also have to make sure that what’s authorised is safe for patients.

3. Pharmacovigilance is Playing a Wider and More Strategic Role The more complete and reliable the picture being developed by pharmacovigilance activities, the greater the value to a business strategically. A clearer view of safety can have a bearing on whether a company should proceed with, for instance, acquisitions. Allergan’s Tontisakis said companies are now increasingly bringing in safety experts at the earliest stages of potential acquisitions to help assess target products or companies. “It doesn’t make sense to bring in a product that isn’t safe and would cost in the long run with lawsuits or from pulling the product from the market,” she said. For that reason, Shire’s Ferguson said he was surprised that pharmacovigilance usually doesn’t automatically have a full seat during the due diligence process. “It’s often assumed it will be all right until you

Reimbursement is another area where safety has to play a more prominent role. Kooijmans at Amicus said that ensuring reimbursement for a product requires a focus on health economics, including risk-benefit data, during the development plan of a drug. At Bluefish Pharmaceuticals, senior management seeks advice from pharmacovigilance before deciding to initiate a new product registration. “We’re asked what the implications will be for risk minimisation activities, whether a post-authorisation safety study might be required, and what the potential costs are,” Appelskog said. 4. Safety is Becoming a Product Differentiator One commercially interesting trend is the potential to use safety as a differentiator against other brands. Amicus’s Kooijmans used to work at Biogen, which recently had its first product approved for an orphan indication (nusinersen as a treatment for spinal muscular atrophy) because that product’s safety profile was better than that of the product that had been approved earlier, which led to a superior risk-benefit profile. Kooijmans’s current company, meanwhile, has been granted approval for an oral drug for treating Fabry disease—Galafold—which was found to be easier to tolerate and which had fewer side-effects compared with already approved and marketed IV treatments. “A product like that diminishes the risk side but also assists on the benefit side because the patient doesn’t have to go to the hospital to get an IV and can instead simply take a pill,” she said. “For companies focused on me-too products, having a safety focus would be a good approach because if you aren’t developing targeted, personalised medicine, you have to think about the two other areas to make your drugs stand out: better or safer—or both.” Wise said that when a company is looking to differentiate on safety, those activities will be part of the INTERNATIONAL PHARMACEUTICAL INDUSTRY 33


Regulatory & Marketplace clinical development plan, which is typically managed by clinical rather than safety – particularly at smaller or midsize companies. In larger companies, medical safety – as distinct from the operational aspects of pharmacovigilance – is firmly embedded in clinical development. “Using safety as a differentiator is an argument in the risk-benefit of a product,” she said. “If your risk-benefit is positive because your risks are lower but the benefits are the same, that’s an important thing to know when you’re going into a risk-benefit discussion.” 5. Good Pharmacovigilance Practice is Catching on Globally The European Medicine Agency’s (EMA’s) good pharmacovigilance practice is being watched closely by other regional markets, which are likely to adopt many of the same principles in time – but with their own emphases and tweaks, thereby creating more work for global players. Bluefish’s Appelskog points out the importance of good and ongoing dialogue, which is well established within EMA. “I’m concerned that with Eurasia and the Middle East, good pharmacovigilance practice will be brought in without discussion or willingness to adapt,” she said. “A lot still has to happen to agree on standards.” Other complexities include the requirement to have a responsible person for pharmacovigilance even in markets where a product might not be marketed. “Shire works in the area of rare diseases, and it might be we don’t even have a single patient in a small country such as Cyprus, but because we have Europe-wide marketing authorisation that is applicable to all European Union member states, we’re legally obliged to have a responsible person for pharmacovigilance in that market,” Ferguson said. One potentially troubling development is that the QPPV, which was traditionally a European role, is now becoming a requirement in more markets, Wise said. “That raises questions about who that QPPV is going to be, because on one hand, few QPPVs would be willing to take responsibility in markets outside 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Europe, given the legal liabilities, but because there’s only one pharmacovigilance system, it doesn’t make sense for a global company to have multiple QPPVs,” she said. 6. New Demands Call For New Roles So, what does all of this mean as 2017 continues to unfold? Wise said pharmacovigilance leaders must develop 1. the business skills needed to play full roles in clinical risk-benefit decision-making, and 2. the strategic skills for matching the responsibility of driving the evolution of a pharmacovigilance department that is a moulded part of the R&D organisation. The management of affiliates has become another priority for pharmacovigilance heads, said Shire’s Ferguson. In the past, in the hiring of a safety person in an emerging market, those roles would have focused on operational activities such as receiving adverse events, doing the translation, entering the data into the database, and ensuring the events were reported to the authorities on time. “Now I’ve brought those operational activities into the centre and hired third parties to manage them,” Ferguson said. “The skill set I now need from someone at the affiliate has changed: I look for people with pharmacovigilance and quality experience.

Cheryl Key MBBS, MFPM, head of practice PV platform services/principal medic at ProductLife Group, with final responsibility for all projects, programmes, and engagements in the platform, as well as for day-to-day management of the platform team. Cheryl has more than 15 years of drug safety experience in working with pharmaceutical and biotech companies, for contract research organisations, and for regulatory authorities. She guides her team to improve and optimise ways of working, achieve high performance, establish continuous improvement in consistent platform processes, and ensure compliance by all platform

I need people who can ensure compliance, who know about the regulations and how they affect everything we do.” The role of the QPPV has also evolved: today quality assurance is the primary concern, Amicus’s Kooijmans said. “When I started out in a QPPV role, the focus was more on discussing the minimal safety side with regulators. Now it’s much more on being ready for inspections, making sure your system works, and keeping the pharmacovigilance system master file up-to-date. This attracts different people to pharmacovigilance,” she said. “Equally, heads of safety require more of a business background because of the growing importance of health economics, so there’s a shift from the medical side towards a different breed of drug safety people.” Appelskog said that with so many changes taking place, the QPPV and heads of pharmacovigilance have to be able to apply innovative thinking in order to arrive at solutions.That in turn requires more collaboration, she concluded, pointing to the stakeholder platform introduced by EMA that facilitates intraorganisational discussion.

staff with legal, regulatory, and quality requirements. Before joining the pharmaceutical industry, Cheryl spent several years in medical practice in hospital and primary care. Cheryl has a medical degree from Charing Cross and Westminster Medical School, Membership of the Royal College of General Practitioners, a diploma in pharmaceutical medicine and Membership of the Faculty of Pharmaceutical Medicine, and is on the Specialist Register at the General Medical Council for Pharmaceutical Medicine. Cheryl is also a member of the board of the Faculty of Pharmaceutical Medicine. Cheryl is also a member of the board of the Faculty of Pharmaceutical Medicine. Email: ckey@productlife-group.com www.productlifegroup.com

Spring 2017 Volume 9 Issue 1


Keep Growing The BioFlo® 120 — easy to use, flexible, dependable The straightforward setup and process > Push button Auto Culture modes for control of the BioFlo 120 let you focus on microbial and cell culture applications what is important, your work. Designed to > Flexible operation with glass or BioBLU® Single-Use Vessels seamlessly integrate into your day-to-day > Scalable expanded working volume operation, the BioFlo 120 bioreactor/ range (250 mL – 40 L) fermentor emphasizes simplicity and ease > Universal connections for digital and of use, with no sacrifice on capability. analog sensors > Space-saving compact design for quick and easy installation

www.eppendorf.com/BioFlo120 Eppendorf ®, the Eppendorf Brand Design, and BioBLU® are registered trademarks of Eppendorf AG, Germany. BioFlo® is a registered trademark of Eppendorf Inc., USA. All rights reserved, including graphics and images. Copyright © 2017 by Eppendorf AG.


Drug Discovery, Development & Delivery

MALDI Mass Spectrometry in Drug Discovery Gaining A Deeper Understanding New MALDI technology looks set to boost discovery and early development of drug candidates – delivering new information and improved performance to scientists in both target selection and drug tissue distribution imaging.

In this article, recent innovations in MALDI (matrix-assisted laser d e s o r pt i o n i o n i s at i o n) m a s s spectrometry will be discussed, related to how two detection schemes that utilise these technology advances are being applied to accelerate pre-clinical drug discovery; one in ultra-high throughput screening (uHTS) programmes, the other in drug tissue distribution MALDI-imaging studies. A recurring mantra of R&D in pharma – fail early, fail cheap – has guided scientists for many years. This principle has been shown to drive innovation in a wide range of industries. The practice commonly adopted in pharma – using technology plus automation to rapidly screen compound libraries looking for ‘hits’; together with integrating ADME/TOX (absorption, distribution, metabolism, excretion/ toxicity) investigations as early as possible in the discovery process, to understand essential details of drug distribution and metabolism – has undoubtedly made a contribution to the rise in productivity in recent years. Year-on-year drug pipeline growth (2015 – 2016) has been estimated at 11.5%, with the biggest rise being seen in the pre-clinical phase. Here, the 6061 compounds reported to be in this phase in 2015 has grown to 6861 in 2016.1 Setting the Scene Much has been written about desirable characteristics of an ideal analytical tool for small molecule R&D – label-free, no probes, and with 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the ability to measure target analytes directly and quantitatively. Rapid, robust, easy-to-use, cost-effective and automation-ready are also features on most wish lists. Mass spectrometry (MS) inherently delivers on many of these criteria, and opened up a new arena for MALDI MS within the last years. MALDI is utilised with various MS analysers, the most common being axial TOF (time of flight) detectors, but others, such as orthogonal TOF or FT ICR (Fourier transform ion cyclotron resonance) are employed as well, depending on the analytical needs. Today, the technique is established across a range of applications in drug discovery and development. MALDI-MS is helping researchers identify the most promising small molecule leads, and is now expanding into the ultra-high

throughput compound screening programmes that ‘big’ pharma relies on. Likewise, MALDI mass spectrometry imaging (MSI) is helping developers understand the spatial distribution and tissue physiology of a candidate drug and related metabolites before quantitative whole body autoradiography (QWBA) experiments, thereby allowing for informed decisions whether to move the candidate to the next development stage. It is also important to note that many candidate compounds generate metabolites which possess biological activity. These active metabolites may have different pharmacology and PK properties than the parent drug. A thorough understanding of the properties of active metabolite is central to estimating toxicity – the number one reason for withdrawal of a drug. Early information about

MALDI imaging mass spectrometer experimental workflow. The MALDI imaging experiment is initiated by mounting a tissue section onto a target, applying a matrix and rastering a laser across the surface of the tissue. At each discrete location within a virtual grid the laser is fired, and a mass spectrum is acquired. By plotting the ion intensities as a function of the x and y coordinates on the tissue, ion images are generated. The principles of MALDI Imaging (MALDI IMS) Spring 2017 Volume 9 Issue 1


Drug Discovery, Development & Delivery the enzymes involved in the drug metabolism is very useful in the design of drug-drug interactions studies. In addition, but outside the scope of this article, MALDI is also being applied in quality control of biopharmaceuticals, as well as fundamental research and clinical diagnostics – for automated microbial identification, for example. New Technology, New Advanced Tools With MALDI becoming established as a powerful technique for drug discovery, instrument manufacturers have turned their attention to certain key components of the system. These have become the subject of intensive development as companies look to advance performance, reduce costs and streamline workflows for researchers. The goals for a user may be specific to each application: speed, throughput and cost per sample in HTS vs. resolution and sensitivity in imaging applications, for example. However, improving and optimising the critical components for an individual application can deliver improvements for all. At the heart of a system is a highspeed laser operating at 10 kHz. Stability is critical for both spatial and mass resolution, such that improving the precision of the optical bench which carries the ion optics and the necessary lenses, reflectors and detector modules, performance can be significantly upgraded. Figure 1 shows the configuration of a typical TOF/TOF optical bench. Importantly, expanding the performance envelope of a MALDI system requires a fast laser. Today’s cutting-edge systems imply a 10 kHz laser, but accommodating a 10 kHz laser raises many technical and mechanical issues that need to be solved. For example, traditional instruments reposition the sample relative to a fixed laser spot. The mechanics of moving a sample quickly and precisely enough to keep up with a fast laser are challenging. However, by reversing the traditional thinking and moving the laser relative www.ipimediaworld.com

Figure 1 - Ion path mounted on optical bench with TOF/TOF unit2

to a fixed sample position, Bruker has been able to fully realise the potential of the 10 kHz laser. In addition, developments in detector design, notably, incorporation of the academically acclaimed dynamically harmonised ParaCell™, developed by Professor Eugene Nikolaev and co-workers at the Russian Academy of Sciences in Moscow, into the solariXTM XR system. This remarkably innovative design stabilises the ion cyclotron resonance signal over a broad mass range. Mass spectra can be acquired with 10 million resolving power when high throughput is not required. In addition, the instrument also provides benchmark performance at faster acquisition rates, and resolving power is greater than 250,000 at m/z 400 in one second at 7T. This and other recent improvements create a nearly ideal and yet unmatched analyser for complex mixtures like those found in MALDI imaging. The challenge that fast analysis poses for control, capture and processing routines is also a significant consideration when an instrument is working at the speeds required for routine analysis. Unlike classical MALDI instruments, newgeneration systems now use strategies such as parallel computing threads, each fast enough to keep up with the speed of the analysis. Innovation in Practice: When configured for HTS, as with Bruker’s rapifleX MALDI Pharma-

PulseTM instrument, the result of the developments described above is a system that is up to 20 times faster than a traditional instrument, with improved robustness, sensitivity and extended mass range (MS/MS). Presented at the ASMS conference in 2016, a poster from Dr Peter Marshall et al. (GlaxoSmithKline, Stevenage, UK) described how their use of MALDI-TOF MS coupled with nanolitre liquid handling was enabling them to screen more than 1 million samples per week. The work was performed on a Bruker MALDI-TOF instrument with a 10 kHz laser. Mass spectra were acquired in the range of either m/z 80-400 or 700-3500, with 200 laser shots per sample. Under these experimental conditions, the system processed a 1536-well plate in 7.36 minutes. With a vast in-house collection of candidate compounds, simple scale-up calculations indicate that to analyse 2 million compounds would require 7.85 days. An assessment of the robustness of the system and the methodology were made – with good correlation of results before and after 108 measurements. They conclude that the technology and approach for uHTS was robust and can deliver very fast analysis times. The group has measured more than 1 million samples in a week and found that it has been possible to measure more than 2 million samples without having to clean the instrument lens stack. Finally, looking forward to even higher throughput, INTERNATIONAL PHARMACEUTICAL INDUSTRY 37


Drug Discovery, Development & Delivery the group achieved similar assay performance using 6144-well plates. If adopted into routine, this would cut the time required to screen 2 million compounds to 2.39 days. In contrast, where MALDI MSI is being used to understand the distribution of a drug and its metabolites in model tissue, features such as those seen on the Bruker solariX system are ideal. Traditionally, quantitative whole-body autoradiography (QWBA), and/or liquid chromatography coupled to mass spectrometry LC/MS, have been the methods used to obtain drug distribution and metabolism. Both have challenges. QWBA is a robust technique, and the data generated is accepted by regulatory bodies around the world, however, QWBA presents a composite of the total radioactivity present – it may include any combination of parent drug, metabolites, impurities and degradation products. Thus, it has severe limitations for researchers looking for insight into biochemical pathways and mechanisms. LC/MS analysis is performed on extracts from tissue homogenates. The technique cannot indicate any

38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

spatial information and, equally importantly, can be misleading. For example, if an analyte in the tissue is highly localised, the extraction and homogenisation process will act as a dilution, masking this distribution and giving a relatively low concentration, sometimes even below the limit of detection. Localisation of an analyte is often an indication of toxicity – and would be missed in this case. Alternatively, if an analyte is determined to have a high concentration from tissue homogenate, a researcher could draw incorrect conclusions about toxicity because the analyte is presumed to be evenly present throughout the tissue. By comparison, MSI takes a conventional tissue section and coats it with a matrix, which extracts molecules from the tissue – but retains the spatial relationships found in the underlying tissue. Following preparation, the sample is measured in the spectrometer. The result is spatially resolved mass spectra. Because the laser only probes the matrix crystals which are on the surface of the section, the underlying cellular features are not

Figure 2 – Optical scans of kidney tissue sections from PND 7–13 juvenile rats4

Spring 2017 Volume 9 Issue 1


Drug Discovery, Development & Delivery disrupted and can be taken through a standard histological staining routine so that a high-quality histology image can be captured. By merging this scan with the molecular information from the MALDI mass spectrometer, a histology-directed analysis of the tissue is possible. Recent work by M. Reid Groseclose et al. (ref) evaluated the additional information that MALDI IMS could provide over and above LC-MS in a nephrotoxicity study on the anti-cancer drug Dabrafenib (DAB)Â in rats. This work was in support of developing DAB for use in paediatric patients. Previous studies had identified some unexpected adverse kidney effects in juvenile rats. These effects had not been seen in adult studies.3 Initially, MALDI IMS could determine the distribution of DAB and its metabolites in the kidney (Figure 2). Subsequent analysis of tubular deposits seen in the first experiments provided the chemical composition

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 39


Drug Discovery, Development & Delivery at these locations and informed a more complete risk assessment for paediatric treatment with Dabrafenib than would have been possible using LC-MS analysis alone. Conclusion Pharmaceutical companies are seeking out innovative approaches and technology to facilitate a rapid route to market for new, safe and efficacious drugs. As we have seen here, MALDI technology is already making an impact in small molecule R&D, and many industry commentators believe that the coming years will see this grow significantly. Having emerged in basic research and subsequently proven its value in routine uHTS and MSI applications, forward-thinking researchers are investing in the latest instrumentation and expanding the application of the technique, anticipating additional insights and a deeper understanding of a candidate compound early in the development process.

REFERENCES 1. Pharmaprojects 2016. Pharma R&D Annual Review of 2016 2. Castellino S, Groseclose MR, Wagner D. 2011. MALDI imaging mass spectrometry: bridging biology and chemistry in drug development (Internet) https://www.ncbi.nlm.nih.gov/ pubmed/22074284/ [Accessed 15/12/2016] 3. Grosclose MR et al. 2015. Imaging MS in Toxicology: An Investigation of Juvenile Rat Nephrotoxicity Associated with Dabrafenib Administration. J. Am. Soc. Mass Spectrom. (2015) 26:887:898. DOI: 10.1007/s13361-015-1103-4 (Internet) https://www.ncbi. nlm.nih.gov/pubmed/25804893 [Accessed 15/12/2016] 4. Groseclose MR, Laffan SB, Frazier KS et al. 2015. J. Am. Soc. Mass Spectrom. 26: 887. doi:10.1007/ s13361-015-1103-4

Dr Dale Shannon Cornett Received his Ph.D. in analytical chemistry from the University of Georgia in 1993, working under the mentorship of Jon Amster. Following a post-doc with Terry Lee at City of Hope, Shannon joined Bruker and spent the next eight years working as Applications Scientist, TOF R&D Manager and a TOF Product Manager. In 2002, he moved to the Mass Spectrometry Research Facility at Vanderbilt University as Research Assistant Professor to work with Professor Richard Caprioli developing new tools and methodologies for the then-emerging field of imaging mass spectrometry. Shannon rejoined Bruker Daltonics in 2009 as a Product Specialist supporting the MALDI imaging and proteomics, and now serves as Applications Development Manager as well as Adjunct Research Professor in Biochemistry at Vanderbilt.

Dr Jens Fuchser Product Manager MALDI TOF Mass Spectrometry studied chemistry at the University of Gรถttingen, Germany. In 2000 Jens joined Bruker Germany to work in the field of mass spectrometry.

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Dr Rohan Thakur Executive Vice President at Bruker Daltonics, joined Bruker. Dr Thakur has over 20 years of experience in mass spectrometry, including 14 years in MS development, and has several patents in the field of ion optics. During his career he held positions as Director Global Marketing for mass spectrometry solutions at Thermo, and was Director of Drug Discovery at a pharma CRO for two years before joining Bruker. Dr Thakur received his Ph.D. in Chemistry from Kansas State University and did post-doctoral studies at Rutgers University, where his work involved using high-resolution MS analysis to prove the formation of ring-opened benzene metabolite-DNA and protein adducts.

Dr Meike Hamester Director Pharma Small Molecule Business, studied chemistry at the University of Hamburg, Germany. She worked 18 years in the field of mass spectrometry at Thermo Fisher Scientific and since 2012 Meike has worked for Bruker.

Spring 2017 Volume 9 Issue 1


Patient-focused drug delivery devices Drug Delivery Devices Innovative developments Customized solutions GMP contract manufacturing

www.nemera.net information@nemera.net Phone: +33 (0)4 74 94 06 54

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 41


Drug Discovery, Development & Delivery

Innovation to Resolve Challenging Microsphere Drug Delivery Systems Formulation Process Due to their ground-breaking benefits and market share opportunity, the production of polymeric microsphere drug delivery systems is experiencing a fast-growing demand worldwide but remains a very challenging formulation process. New drug delivery devices such as PLA, PLGA, PLG or PEG polymeric microspheres have revolutionary applications. These biodegradable particles work as miniature sustained release capsules for injectable drugs, to treat various conditions from cancer to diabetes, hormonal disorder, mental illness and addictions.

This revolutionary drug delivery platform is one of the most attractive vehicles for drug delivery systems. They provide valuable benefits such as less frequent injections thanks to the long-term sustained release they provide. They also improve greatly the patient comfort and lifestyle, as well as compliance. Reducing the logistic costs and providing drug protection are also significant advantages. Finally, microsphere products allow for a tailored drug release rate according to the application. Formulation of microspheres is a ground-breaking technology for patients, pharmaceutical companies, and governments and public organisations. The polymer-based drug delivery systems market was estimated at US$60Billion in 20101 Major blockbuster drugs such as Lupron Depot or Bydureon make up this growing market; patents are running out and there are significant unmet needs with only a dozen FDA approved drugs currently in the market. The formulation of such polymeric microspheres can be a very challenging process. The particles formulation must be controlled to achieve a specific particle size, distribution and morphology. The particles must be in the range 5-25µm up to 90-150µm. Too small or too large particles will not have the desired effect once injected 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

into the bloodstream. In addition to strict parameters to control, these drug delivery systems have difficult characteristics to work with during the formulation process. They are by nature sticky, soft and fragile, sensitive to temperature and humidity, and most of all sterility must be maintained at all time. For all of these reasons, the manufacturing of microsphere drug delivery devices on a commercial scale has been very challenging. Scaling up from small-scale batches of a few grams to large-scale production above 20kg batches has been almost unmanageable. Problem-free Downstream Formulation Process There are two main steps during the formulation of microspheres medicine: first the upstream process which consists of creating the polymeric microsphere particles containing the active ingredient; then the downstream process which consists of filtering, classifying, drying and recovering the micro size particles in a sterile manner ready to be filled, packed and stored (Image 1).

The devices used to inject these treatments can be vials or prefilled syringes. In any case, the microspheres must stay separate from a liquid phase due to their biodegradable characteristic, they are more stable in a solid form and last longer. During the production of polymeric microspheres, the particles need to be classified per size to only retain specific sizes for the final products. The microspheres need to then be washed from the solvent and dried under restricted conditions and recovered. All these processes require sterile handling. The downstream process became a problem for manufacturers to control because of the following challenges: • To accurately control the particle size, • To maintain the sterility envelope during the whole process, • To efficiently scale-up the R&D process to commercial manufacturing, • To maintain reproducibility with maximum yield. Th e ex i s t i n g t e c h n o l o g i e s developed so far such as sieving or

Image 1: Formulation process of polymeric microsphere drug delivery systems Spring 2017 Volume 9 Issue 1


Company ProямБle

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Drug Discovery, Development & Delivery screen filtering, centrifugal sifting and lyophilisation were causing many problems. Amongst the difficulties mentioned by manufacturers, the below were the most common: • Filtration mesh blocking causing difficult size classification, • Long drying time, • Breach of sterility resulting in batch loss, • Difficult process scale-up, • Insufficient yield performance, • High investment for several capital equipment.

Image 2: MicroSphere Refiner technology for drug delivery devices formulation

The MicroSphere Refiner (MSR™) technology has been developed to address these challenges as the demand for efficient microsphere formulation process became greater. Previous processes caused manufacturing issues impacting the finished drug delivery devices’ quality. They could not guarantee the correct size distribution, the sterility, and provide an acceptable yield. By working with drug producers, process specialist, PSL, innovated with a unique technology (Image 2) able to perform all the required process steps, and achieve: • an accurate size classification using a unique filtration technique that avoids the mesh to be blocked by keeping the particles in suspension; • a homogenous drying through vacuum drying, that gently dries the microspheres at low temperature; 44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

modular process systems contained with individual frame for each process equipment. Such process skids include all of the valves and pipework, sterile filters, sterilisation and clean-in-place lines, heat transfer and utilities systems.

Image 3: MSR vessel with PAT and instrumentation

• high yield thanks to a unique product offloading method resulting in almost 100% of the final product being harvested; • aseptic recovery with a discharge method that doesn’t require the intervention of an operator, being automatically controlled and confined; • process scale-up capability by providing the same technology from laboratory scale to pilot plant up to commercial scale; • process repeatability for constant batch quality; • one-step process to reduce total investment. For pharmaceutical manufacturers, it is essential to have a proven technology used during process development that can be scaled up to large-scale production, especially to respect the FDA (Food & Drug Administration) regulations and approval. The MicroSphere Refiner technology helps them to greatly reduce costs by using one piece of equipment instead of several process systems and sterile containment isolators. The operative and maintenance costs have been reduced considerably while the quality of each batch is uniform and reliable. The innovation also has a smaller footprint. The MSR technology has been developed and refined over 20 years and it has been adopted by blue chip pharma groups around the world. After successfully installing production lines in USA and Europe, five production lines have recently been installed in Asia. These installations consist of MSR formulation lines suitable for an aseptic production of 10 to 20L of final product. The installations were completed with process skids,

The microsphere formulation installations feature full automation of the MSR vessels and process skids through dedicated software and HMI/ PLC systems. A variety of process analytical technologies (PAT) in-line or off-line are necessary to ensure a problem-free formulation process. Automated process sampling is available along with a process camera, level sensor and cake volume indicator (Image 3). Temperature probe, mass spectrometer and particle analysers can be also added to the facility. Feasibility Study and Process Optimisation Before commercially producing microsphere drug delivery devices, manufacturers are required to work on process optimisation at small scale. Such feasibility studies ensure a successful scale-up approach to larger batch quantity. Process expertise is paramount and can be in-house, fully outsourced or supported by consultancy when required. R&D trials and feasibility studies of filtration and drying downstream formulation ensure an optimum product quality and repeatability. To address this increased demand for process support, the Center Of Process Excellence (C.O.P.E.) opened in 2016 in Philadelphia, USA. The centre hosts feasibility studies, trials and process development for laboratory and pilot plant. Drug developers are able to use the facility and work with process specialists to develop new microsphere drugs and optimise their manufacturing process. Polymeric drug delivery systems are revolutionary devices with a wide range of applications providing numerous benefits to patients, public health organisations and pharmaceutical manufacturers. Innovation in formulation process Spring 2017 Volume 9 Issue 1


Drug Discovery, Development & Delivery REFERENCES Trademarks and IP for MSR™ and GFD® are the property of Powder Systems Ltd. 1. Zhang L, Pornpattananangku D, Hu CM, Huang CM. Development of nanoparticles for antimicrobial drug delivery. Curr Med Chem. 2010;17:585–594. [PubMed]

Camille Flores-Kilfoyle Image 4: Award-winning MSR technology and process skid

was desperately needed to address a challenging manufacturing process and to market faster new treatments. With the MSR technology now available, cGMP standards are met and high yield with low operational costs are achievable. The MicroSphere Refiner™ range was awarded the best Mechanical Process Innovation at the ACHEMA 2015 Awards and best Innovation in 2016 by the Queens

Awards for Enterprise in Great Britain (Image 4). Proven track records by blockbuster manufacturers have brought generic manufacturers to adopt MSR technology, who will also contribute to the production and commercialisation of controlled drug release medication in a targeted manner that will improve the wellbeing of millions of suffering patients.

Business Development Manager Camille is the Business Development Manager of Powder Systems Limited (PSL) a process specialist company. She has been working on the development and market launch of the MSR technology, addressing existing challenges in the marketplace when it comes to the production of microsphere drug delivery systems. Email: info@powdersystems.com

Product News Sartorius Stedim Biotech launches two Single-use Sartocon® Loop Assemblies with Integrated Polyethersulfone (PESU) Membrane Assemblies save up to 60 percent on processing time and offer a safe approach to ultrafiltration of biologics and vaccines Sartorius Stedim Biotech (SSB), a leading international supplier for the biopharmaceutical industry, announced its polyethersulfone membrane (PESU) is now integrated into two new, sterile Sartocon® benchtop and production scale filtration assemblies. Using these assemblies guarantees rapid and safe ultrafiltration of biologics and vaccines. Due to the fully enclosed design, the Sartocon® assemblies are ideal for safely purifying vaccines and recombinant proteins, as well as monoclonal antibody manufacturing. This makes them suitable for use in cGMP environments for process development, clinical trials and small-scale production batches. The new single-use Sartocon® Selfcontained Filter Loop Assembly has been developed for use with SSB’s unique

The single-use Sartocon® Self-contained Filter Loop Assembly has been developed for use with SSB’s control unit, the FlexAct® UD.

www.ipimediaworld.com

control unit, the FlexAct® UD. While the Sartocon® Slice Self-contained Bag Loop Assembly has been designed for SSB’s benchtop crossflow system SARTOFLOW® Alpha plus SU. Both assemblies are supplied gamma sterilized and ready to use. The integrated PESU membrane is pre-wetted and flushed which saves hours in set-up and validation time, as well as eliminates the costs of using buffers and purified water to prepare the membrane. Since the Sartocon® assemblies are designed with the same hydrodynamic flow path as SSB’s larger production scale filter devices and all device materials and accessories are manufactured to the same industrial quality-assured specifications, linear scale-up and process transfer is a simple process. The PESU membrane inside the Sartocon® assemblies is available in several sizes and 10-300 KDa molecular weight cut-offs and is robust enough for use in broad pH and temperature ranges. These features combined with the Sartocon® assemblies’ single-use design, which prevents product cross-contamination, means they are perfect for use in R&D applications, Contract Manufacturing Organizations and multi-product facilities. “Following on from the successful introduction in 2015 of the Hydrosart® membrane in our single-use Sartocon® filter loop assemblies, we made our PESU membrane for these applications available as well. Now customers can select from a broader range

The Sartocon® Slice Self-contained Bag Loop Assembly has been designed for SSB’s benchtop crossflow system SARTOFLOW® Alpha plus SU.

of membrane polymers and cut offs for ensuring optimal parameter for their specific process. When compared with reusable filter cassettes, we estimate that using these new single-use, PESU membrane-based assemblies will reduce processing time by around 60 percent and could save up to 2,000€ per batch on buffer and water costs”, Frank Meyeroltmanns, expert for crossflowfiltration at SSB explains. Contact: Sartorius Stedim Biotech GmbH August-Spindler-Str.11 7079 Göttingen www.sartorius-stedim.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 45


Clinical Research

Three Ways to Mitigate the Risk of Late-stage Failure in CNS Drug Development Central nervous system (CNS) disorders have long been the Bermuda Triangle of drug development. For example, a 2014 study of Alzheimer’s disease (AD) drugs tested between 2002 and 2012 showed that 99.6% of them failed one of Phase I, II or III trials (Cummings, Morstorf and Zhong, 2014). Many of these AD drugs failed late, in large Phase III trials, making the failures costlier and more dispiriting for researchers, drug developers, and, certainly, patients. The most recent casualty was a novel tau aggregation inhibitor (tau is a bodily protein that many neuroscientists believe contributes to the brain-destroying effects of AD) that failed to improve cognitive or physical function in the Phase III trial of 891 AD patients (Garde, 2016).

The prevalence of CNS disorders worldwide is staggering. An estimated 350 million people suffer from depression (World Health Organization, 2016a) and over 46 million people live with dementia (Prince, 2015) – a number expected to grow to 131.5 million by 2050 due to aging populations. Approximately 50 million people have epilepsy (World Health Organization, 2016b), and more than 21 million patients have schizophrenia (World Health Organization, 2016c), a disease that places them at high risk for medical comorbidities, higher rates of suicide, and self-harm. Severe mental disorders cost the world an estimated $2.5 trillion annually, a number expected to increase to $6 billion by 2030, while the global societal cost of dementia has been pegged at $604 billion per year (Bloom et al., 2011). Despite the urgent need for new CNS therapies, many drug developers have reduced their investment or abandoned the field altogether (RAND Corporation, 2013) due to development times that are 18% longer than those for non-CNS compounds (Tufts Center for the Study of Drug Development, 2014), 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and the aforementioned low success rates. High-risk CNS Decisions are Challenged by Incomplete Scientific Knowledge Late-stage failures in drug development are sadly not uncommon and they involve tens of thousands of participating patients in multiple therapeutic areas, including CNS (Grignolo and Pretorius, 2016). But CNS drug development is particularly treacherous. First of all, the pathophysiology of most CNS disorders is poorly understood. CNS diseases are diverse and range from AD to Parkinson’s disease, multiple sclerosis, stroke, epilepsy, depression, addiction, anxiety, pain management, and schizophrenia, to name a few. These conditions may have various etiologies including autosomal dominant conditions, genes associated with increased risk for disease, neurodegenerative conditions, environmentally acquired conditions and many whose etiology is unknown. Despite recognition of heterogeneity within specific diseases, most CNS diseases are diagnosed clinically, particularly for psychiatric conditions. As Jill Heemskerk, Director of the Office of Research Administration and Acting Deputy Director at the National Institute of Biomedical Imaging and Bioengineering, observed recently, “On average, a marketed psychiatric drug is efficacious in approximately half of the patients who take it. One reason for this low response rate is the artificial grouping of heterogeneous syndromes with different pathophysiological mechanisms into one disorder” (Cedarbaum et al., 2014). At present, however, most CNS diseases lack specific diagnostic biomarkers, as well as other biomarkers (i.e., disease progression, predictors of drug response) that can facilitate separating diseases into more specific syndromes.

Most CNS drug studies test one drug (monotherapy) versus placebo, although some trials use add-on regimens in which an investigational drug is combined with an existing therapy. In CNS, it is quite unusual to combine complementary investigational drugs, even if there is thought to be significant potential for greater efficacy when combined (e.g., a beta secretase inhibitor plus an antibody therapy). The regulatory complexities and hurdles for combination therapies are, understandably, much higher than those for a monotherapy. Regulatory agencies are receptive to two-drug combinations only when: 1) the treatment is for a serious illness; 2) there is a strong biological rationale for the combination; 3)comprehensive preclinical characterisations have been completed for each drug individually and for the combination product; 4) preclinical and/or clinical data demonstrate a more durable response or a better toxicity profile for the combination product versus each agent; and 5) there is a strong rationale for why the drugs cannot be developed independently. As the FDA notes in its guidance documents, “Codevelopment generally will provide less information about the clinical safety and effectiveness and dose-response of the individual new investigational drugs intended to be used in combination than would be obtained if the individual drugs were developed alone” (U.S. Food and Drug Administration, 2013) The placebo effect is another significant issue in CNS drug development. Although not unique to CNS, the placebo effect particularly plagues the field due to the lack of objective methods to assess outcomes and the need to rely on patient reports or other subjective clinical assessments that can be susceptible to bias. The placebo effect has been discussed extensively Spring 2017 Volume 9 Issue 1


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eHEALTH SOLUTIONS eClinical Solutions Safety & Regulatory Solutions Financial Lifecycle Solutions

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Clinical Research in the CNS literature and is a notorious issue in studies of depression and schizophrenia. The effect size of the placebo response, which can range from 30% to 60% in depression, has resulted in placebos appearing more effective than investigational agents in some studies of these diseases. Animal models have not been very successful in predicting efficacy of CNS drugs in man. Metabolic, anatomic, and cellular differences between mice and humans have been blamed for many a failure (Gawrylewski, 2007). Moreover, the traditional heavy reliance on healthy volunteer dose escalation data in early development has not worked well in CNS disorders, generating countless results that could not be reproduced in target patient populations. An example of misleading results from animal testing and healthy volunteer (HV) studies is Exelon (rivastigmine), an acetylcholinesterase inhibitor which was approved in 2000 for treating mild-tomoderate Alzheimer’s dementia, and subsequently also approved for Parkinson’s dementia. The drug originally failed in Phase II/III trials because the dose identified as effective in animal models and HV trials was inadequate. Exploratory biomarker readouts from CSF testing that evaluated ex vivo acetylcholinesterase/butyrylcholinesterase inhibition in AD patients who received higher Exelon doses resulted in a plausible ‘go ahead’ signal for additional testing. Repeat confirmatory studies demonstrated efficacy in AD and the drug was ultimately approved. Testing a drug’s penetration across the blood-brain barrier has not until very recently been routinely performed, even though an understanding of CSF pharmacokinetics/pharmacodynamics is essential in evaluating a drug for potential effective doses. In the past, this step was often skipped due to the planning and expense involved, with additional testing often needed in animal models, new imaging ligands, and development of new biomarkers to evaluate target 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

binding and engagement. Resolving chemistry, manufacturing, and control (CMC) issues unique to CNS penetration, and to binding/engaging biologic targets, can increase budgets and elongate development timelines. However, proceeding without this knowledge is more likely to result in inadequate dosing and a diminished understanding of pharmacodynamic effects — which in turn can lead in the long run to more money and time invested or another CNS drug failure. Most drug developers acknowledge the importance of this early-phase work. They place an increasing emphasis on demonstrating CNS penetration and pharmacological effects of relevance in the target population, typically using a biomarker. Once a drug passes this stage, strategies to de-risk the later-phase clinical development plan become paramount. A number of clinical trial practices have been adopted to help de-risk late-stage development and to ensure that decision-making around assets is data-driven. These practices include: 1.  Rigorous proof of concept (POC) standards 2.  More efficient, adaptive study designs 3.  Close oversight of patient identification and enrolment. Plus continuous monitoring

Rigorous Proof of Concept (POC) Standards A high-quality preclinical data package that establishes a solid foundation for a drug’s mechanism of action provides the starting point for POC testing in man. In Phase I studies, sensitive measures to evaluate an early signal of efficacy are often included. However, given the limited sample size of Phase I studies, there is typically inadequate power for statistical assessment of these results. Relying too heavily on these data can be misleading for POC studies. Biomarkers may be incorporated into studies for disease diagnosis, progression, and drug response. Preplanning for how the data collected will be used in go/ no-go decision-making is essential

for ensuring objective decisionmaking. Researchers at Pfizer have argued (Morgan et al., 2012) that true POC is not achieved — and drug candidate “survival” is not likely — until solid Phase II data demonstrates: 1. Exposure at the target site of action over a desired period (pharmacokinetic/ pharmacodynamic principles) 2. Binding to the pharmacological target as expected for the drug’s mode of action 3. Expression of pharmacological activity proportional to target exposure and binding This “three pillars” approach to POC focuses on dose-response evaluation and uses imaging and other biomarkers to measure pharmacodynamic activity. For example, the Pfizer study looked at data from Phase II decisions for 44 internal programmes across the company (covering multiple therapeutic areas) between 2005– 2009 and found that of the 14 drugs that met all three pillars, 12 achieved positive POC, and eight advanced to Phase III trials. When none of the three pillars was met, no compounds achieved POC (Morgan et al., 2012). Properly applied, this POC approach can facilitate better compound advancement decisions, allowing companies to terminate failing compounds earlier in development, prior to expensive later-phase studies. Although Pfizer’s POC model has concentrated on Phase II data collection and advancement decisions, the process begins in Phase I. The basis for a go/no-go decision in Phase I is validation (or lack thereof) of a drug’s mechanism of action. Does it locate and engage the intended target? Does engagement of that target induce potentially important pharmacological activity? •  Positron emission tomography (PET) and cerebrospinal fluid (CSF) analysis can provide evidence that a drug has crossed the bloodbrain barrier and engaged targeted receptor(s). New pharmacodynamic methodologies to quantify a drug’s Spring 2017 Volume 9 Issue 1


Clinical Research pharmacological effects include: Functional magnetic resonance imaging (fMRI) – Dynamically evaluates brain regions/networks and their activation. For example, neural activity can be indirectly measured by regional changes in the blood-oxygen level dependent [BOLD] signal in response to a specific task performed by a subject. •  Resting state fMRI (R-fMRI) – A relatively new method for evaluating regional interactions that occur when a subject is not performing an explicit task. R-fMRI potentially reveals the effect of the drug on the connectome, the as-yet unfinished map of neural pathways that underlie human brain function (Neuroscienceblueprint.nih. gov,2016) •  Quantitative electroencephalography (qEEG) and event-related potentials (ERP) – These noninvasive techniques that analyse brain electrical activity can be used to identify biomarkers, document CNS penetration (pre- and postdrug administration), measure adverse events (particularly seizure activity, but also sedation), and evaluate patterns of connectivity.

If a Phase I compound effectively reaches and engages its target, and that engagement correlates with a pharmacological signal, it should advance to Phase II development, assuming safety and tolerability criteria are also met. If Phase I data suggest the target is not engaged, the compound may need to be shelved or further studies may be needed. Too often, compounds advance despite unconvincing evidence from Phase I. Raising the bar for POC in both Phase I and Phase II by utilising the right scientific tools to assess the viability of a drug candidate helps reduces that risk. More Efficient, Adaptive Study Designs Many Phase II POC clinical trials provide an efficacy signal when in fact a drug has no effect, i.e., a Type I error. Reducing Type I errors in Phase II would result in fewer compounds failing in Phase III. Thus improved study designs in Phase II help provide a faster, and potentially more www.ipimediaworld.com

accurate, read on a drug candidate. Examples of smarter study designs include: Seamless Phase I study designs Traditionally, studies in HVs are used to determine the maximum tolerated dose (MTD) for an experimental drug before it can be administered to patients with active disease. However, in CNS, the effects of a drug on a normally functioning brain can be quite different than on a brain affected by the disease of interest. New study designs combine dose escalation cohorts of healthy volunteers with cohorts of appropriate patients to de-risk drug candidates and support more confident ‘go/no go’ decisions. Adaptive designs In early-phase trials, measuring biomarkers and the magnitude of relevant drug effects can inform dose escalation and allow re-estimation of sample sizes. For example, in AD, the levels of two key proteins (Tau and amyloid beta) in the blood can reveal whether a beta-secretase (BACE) inhibitor is producing sufficient inhibition. Adaptive Phase I and II trials allow dose ranging to be tested more fully and efficiently. Pharmacokinetic and pharmacodynamic test results may show that a planned dose overlaps a prior dose cohort and does not need to be tested, or it may be found that prior modelling was not predictive, and an intermediate dose needs to be evaluated. Planning for flexibility in dose cohorts in both single ascending dose (SAD) and multiple ascending dose (MAD) studies maximises a company’s early-phase investment by enabling faster, more informed go/ no-go decisions. A recent analysis demonstrated how an adaptive trial led to early termination of an experimental schizophrenia drug (Shen et al., 2011). The early-stage dose-finding study was meant to identify the optimal dose from among seven doses for use in later trials. Instead, using dose-response modelling, the study found that further testing of the drug would be futile. What was the payoff of the adaptive design? The trial enrolled only 202 patients before reaching a pre-determined

threshold for lack of activity, versus the estimated 450 patients that would have been required under a conventional design. Close Oversight of Patient Identification and Enrolment, Plus Continuous Monitoring In CNS, reducing the heterogeneity of the patient population is critical as heterogeneity can skew behavioural, biological, and neurochemical response to controls, especially in psychiatric disorders. Enrolling precise subpopulations through the use of stringent inclusion/exclusion criteria and the use of biomarkers should help reduce variability in response to a drug. Conducting placebo run-in phases in which patients who respond to placebo are withdrawn from a study before randomisation begins may help combat the placebo effect. These key strategies come at a cost, however. For example, slower patient enrolment and randomisation can extend development timelines and increase expenses, potentially endangering a product’s success due to later market entry or ROI-driven factors resulting in less competitive pricing. Various techniques can remotely assess whether or not subjects meet the entry criteria for enrolment into a clinical trial. These remote rater assessments are employed most often in psychiatric studies, especially those in depression and schizophrenia. Recently, a PAREXEL client used digital audio recordings at screening to increase the appropriateness and homogeneity of a study population. The result was high confidence in the results of this POC study, which evaluated a novel mechanism drug to treat acute schizophrenia. Patients enrolled in the trial consented to the use of digital audio recordings as part of the screening procedure. Screening assessments included recordings of the Brief Psychiatric Rating Scale (BPRS) and the Mini International Neuropsychiatric Interview (MINI), as well as several other tests. Electronic images of assessment documentation, annotations, and INTERNATIONAL PHARMACEUTICAL INDUSTRY 49


Clinical Research audio of patient interviews were also collected for remote review. Interviewers/screeners dictated additional clinical information after the interview. This data was reviewed remotely by a qualified rater to ensure that only appropriate subjects were enrolled. The process helped deliver a more homogeneous sample of subjects and resulted in higher study retention rates than were projected from historical data. The digital audio recordings did not impede study enrolment, which was more rapid than projected. The study demonstrated efficacy and assay sensitivity, supporting a confident test of the drug’s mechanism. Similar data capture of audio recordings or video recordings is important for the assessment of primary and some secondary endpoints in psychiatric studies. These centralised ratings help ensure blinding of the rater, reduce bias and placebo effect and minimise variability in rating scales. The FDA has stated they have a clear preference for the incorporation of centralised ratings for outcome measures in clinical trials for psychiatry. Recently there has been a fundamental shift in the conceptualisation of neuropsychiatric disorders. Today, psychiatric disorders are seen as the result of dysfunction in several domains of brain function, such as cognition, motivation/reward, and fear/anxiety. Each domain and sub-domain presents symptoms or measurable findings that are linked to brain circuitry networks. A dysfunction in any given domain is reflected in circuitry changes that can be demonstrated in preclinical and clinical studies. This sets the stage for science-based symptomatic (phenotypic) development versus the use of a diagnostic system that rests on traditional, more subjective, and less reliable measures. The National Institute of Mental Health’s Research Domain Criteria (RDoC) initiative, dedicated to creating “a new kind of taxonomy for mental disorders,” is at the vanguard of potentially transformative neurocircuitry-based approaches in CNS 50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

drug development (National Institute of Mental Health, 2016). RDoC assumes that dysfunction in neural circuits can be measured by electrophysiology (qEEG, ERP), functional neuroimaging (MRI, FDG-PET), neurocognitive/ behavioural assessments, and other methods for quantifying connectivity. It connects symptoms and measurable findings in patients with their brain circuitry networks, which could guide the classification of patients for specific research studies. It has the potential to improve go/ no-go decisions by adding data about a drug’s effects on a patient’s neurocircuitry which goes beyond just measuring its impact on a behavioural clinical endpoint, such as a rating scale. What could RDoC mean for CNS clinical trials now? •  Early trials could be sized to generate data on objective, more targeted neurocircuitry and behavioural/cognitive measures •  As new mechanisms to assess circuitry/connectivity emerge, accuracy may improve •  Patients can be screened/enrolled on the basis of deficits in a mechanism, rather than on a classic psychiatric Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnosis •  Later-phase trials may be more cost-effective as sites using neurocircuitry techniques may serve as hubs, with other sites referring patients to these sites •  Strong evidence of biomarker/ neurocircuitry changes can be gathered throughout development to support label claims to regulators and post-approval gatekeepers (i.e. health technology assessment agencies)

The RDoC approach, however, is in its infancy regarding data collection and validation of this circuitry. It will take time and much work to establish what neurocircuitry changes correlate with desired clinical benefits for this approach to become a standard part of drug development. In addition to remote rating and RDoC approaches, there is a wide range of tools and strategies that can aid developers in identifying specific

enriched patient subpopulations, and enrolling them earlier in the development process in order to enhance signal detection. These include: •  Conducting feasibility studies to obtain clear data on variations in patient availability, medical coverage and the current standard of care across different regions, countries, sites, investigators, and concurrent, competing trials. •  Assessing comorbid illness patterns as well as typical drug prescription profiles in the target population can help to inform impractical inclusion/ exclusion criteria. Utilising rating scale training programmes and site surveillance procedures (such as remote monitoring, independent external raters, and the like) •  Promoting study drug compliance by both patients and investigators through targeted training, written or interactive communications and even social media (using new technologies to monitor pill-taking and provide reminders) •  Reducing the incidence of dropouts through specific retention strategies

Reducing Risk to Fight a Worthy Battle CNS disorders inflict devastatingly high human and societal costs, but also pose huge risks to drug developers. High profile late-stage trial failures crush the hopes of tens of thousands, even millions, of patients battling disabling diseases, and inflict material financial losses on pharmaceutical companies. The result is a negative feedback loop that diminishes enthusiasm for new drug development in CNS. While the techniques and methods described in this article add time and expense to the conduct of trials, they are likely to save developers money in the long run by reducing the risk of late-stage drug failures. If a company has insufficient expertise in-house to pursue all of these measures, it is well worth tapping external resources. CNS developers can ensure that their POC studies in CNS are rigorous Spring 2017 Volume 9 Issue 1


Clinical Research and adequately powered by employing creative, flexible designs. Doing so allows them to wring better predictive and more definitive data from clinical trials while using state-of-the-art methods for precisely targeting patient populations. This may reduce their risk in a worthy battle that has already seen far too many drug development casualties. REFERENCES 1. Bloom, D.E., Cafiero, E.T., JanéLlopis, E., Abrahams-Gessel, S., Bloom, L.R., Fathima, S., Feigl, A.B., Gaziano, T., Mowafi, M., Pandya, A., Prettner, K., Rosenberg, L., Seligman, B., Stein, A.Z. and Weinstein, C. (2011). The Global Economic Burden of Noncommunicable Diseases. Geneva: World Economic Forum. Available at: http://apps.who. int/medicinedocs/documents/ s18806en/s18806en.pdf [Accessed 2 Sep. 2016]. 2. Cedarbaum, J., Stephenson, D., Rudick, R., Carrillo, M., Stebbins, G., Kerr, D., Heemskerk, J., Galpern, W., Kaufmann, P., Cella, D., Isaac, M. and Walton, M. (2014). Commonalities and Challenges in the Development of Clinical Trial Measures in Neurology. Neurotherapeutics, 12(1), pp.151-169. 3. Cummings, J., Morstorf, T. and Zhong, K. (2014). Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther, 6(4), p.37. 4. Garde, D. (2016). Promising Alzheimer's treatment flops in new trial. [online] STAT. Available at: https://www.statnews. com/2016/07/27/alzheimers-drugtaurx/ [Accessed 2 Sep. 2016]. 5. Gawrylewski, A. (2007). The Trouble With Animal Models: Why did human trials fail? The Scientist. [online] Available at: http://www.thescientist.com/?articles.view/ articleNo/25184/title/The-Troublewith-Animal-Models/ [Accessed 3 Oct. 2016]. 6. Grignolo, A. and Pretorius, S. (2016). Phase III Trial Failures: Costly, But Preventable. Applied Clinical Trials, [online] 25(8). Available at: http://www. appliedclinicaltrialsonline.com/ phase-iii-trial-failures-costlywww.ipimediaworld.com

preventable [Accessed 3 Oct. 2016]. 7. Morgan, P., Van Der Graaf, P., Arrowsmith, J., Feltner, D., Drummond, K., Wegner, C. and Street, S. (2012). Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival. Drug Discovery Today, 17(9-10), pp.419-424. 8. National Institute of Mental Health. (2016). NIMH » Research Domain Criteria (RDoC). [online] Available at: https://www.nimh. nih.gov/research-priorities/rdoc/ index.shtml [Accessed 3 Oct. 2016]. 9. Neuroscienceblueprint.nih.gov. (2016). The Human Connectome Project. [online] Available at: https://neuroscienceblueprint.nih. gov/connectome/ [Accessed 3 Oct. 2016]. 10.Prince, M. (2015). World Alzheimer Report 2015: The Global Impact of Dementia. [online] Alzheimer's Disease International. Available at: https://www.alz.co.uk/research/ WorldAlzheimerReport2015.pdf [Accessed 2 Sep. 2016]. 11. AND Corporation. (2013). The New Neglected Diseases? Policy Interventions Are Needed to Encourage CNS Drug Development. Perspective. [online] RAND Corporation. Available at: http://www.rand.org/ pubs/perspectives/PE117.html [Accessed 3 Oct. 2016]. 12.Shen, J., Preskorn, S., Dragalin, V., Slomkowski, M., Padmanabhan, S., Fardipour, P., Sharma, A. and Krams, M. (2011). How Adaptive Trial Designs can Increase Efficiency in Psychiatric Drug Development: A Case Study. Innovations in Clinical Neuroscience, [online] 8(7),

pp.26-34. Available at: https:// www.ncbi.nlm.nih.gov/pmc/ articles/PMC3159542/ [Accessed 3 Oct. 2016]. 13.Tufts Center for the Study of Drug Development. (2014). CNS Drugs Take Longer to Develop and Have Lower Success Rates than Other Drugs. [online] Available at: http:// csdd.tufts.edu/news/complete_ story/pr_ir_nov_dec_ir [Accessed 3 Oct. 2016]. 14.U.S. Food and Drug Administration. (2013). Guidance for Industry: Codevelopment of Two or More New Investigational Drugs for Use in Combination. Silver Spring, MD: U.S. Food and Drug Administration. Available at: http://www.fda.gov/downloads/ drugs/ 15.World Health Organization. (2016a). Depression. [online] Available at: http://www.who.int/ mediacentre/factsheets/fs369/ en/ [Accessed 2 Sep. 2016]. 16.World Health Organization. (2016b). Epilepsy. [online] Available at: http://www.who.int/ mediacentre/factsheets/fs999/ en/ [Accessed 2 Sep. 2016]. 17.World Health Organization. (2016c). Schizophrenia. [online] Available at: http://www.who.int/ mediacentre/factsheets/fs397/ en/ [Accessed 2 Sep. 2016].

Rebecca M. Evans

MD, MS, Global Therapeutic Area Head for CNS.

Larry Ereshefsky

Pharm.D., BCPP, VP and Global CNS Leader, Early Phase (at the time work was performed).

Alberto Grignolo

Ph.D., Corporate Vice President, Global Strategy.

Sy Pretorius

MD, MMedSc, MBA, MS, FFPM, Senior Vice President & Chief Scientific Officer at PAREXEL International.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 51


Clinical Research

Improving Site Performance: It’s All About Relationships The relationships between sponsors, CROs and study sites can present many challenges in clinical trial planning and execution. Any relationship can be complicated, but the way in which these parties interact with each other can have a significant impact on the overall success of a clinical trial.

Here, Jeffrey Zucker, Vice President of Feasibility and Recruitment Optimization at Worldwide Clinical Tr i a l s , offe rs s t rat e g i e s fo r establishing and maintaining key relationships, and advice on how sponsors and CROs can build and enhance site partnerships to optimise study execution, from trial start-up and recruitment through to implementation. Site Relations and Alliances With the evolving trend towards patient-centric trials, combined with the introduction of many technological solutions over recent years which all improve clinical trials outcomes, such as risk-based-monitoring and eCOA, it is my opinion that sites and investigators are being somewhat forgotten in the process. They need to be re-engaged. Relationships are increasingly being created via email, Skype, text etc., and while technology has clear benefits in terms of both time and cost efficiencies, today’s researchers can still learn a lot from the time when communication and processes weren’t electronic. It is important that the industry continues with its patient-focused activity, however, it is also crucial for sponsors and CROs to balance this with increased site engagement, in order to forge and maintain strong relationships with site study teams ‘on-the-ground’. An engaged site can serve as a key advocate at every level. While traditionally, communication between a site and the sponsor or CRO has been driven via the CRA, and this will continue, if sponsors and 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

CROs want to improve interaction and build stronger relationships, they need to create additional communication links and put in place structured processes for this. As a CRO, Worldwide is always interested in knowing site expectations and what we can do to make communication as effective and efficient as possible. Ultimately, CROs and sponsors should want to make it easier for sites to work with them as they are the ones carrying out the work, and therefore can (and should want to) provide valuable input in order to support effective protocol development. The majority of sites we work with relish the opportunity to be more involved. They can offer insights on operational issues, before, during and after a trial, which if used effectively can improve the protocol assessment, study start-up, patient recruitment, and data quality. Ultimately, a collaborative design process will benefit all involved and result in more positive study outcomes. Site Relationship Process Building and maintaining site relationships should be a structured process, starting with early engagement with site/network leaders. A solicitation meeting should take place as soon as possible, at which a mutual confidential disclosure agreement (CDA) should be put in place so information can be shared back and forth freely. A face-to-face meeting should also be set up with the main study coordinators, including the principal investigator, at which lines of communication should be agreed. This meeting should also discuss potential pain points for the sites, sponsor and CRO, and how these could be addressed. Next, high-level processes should be agreed for the following; pre-award

input: how is the sponsor/CRO going to reach out to get a site’s input on protocols, rather than just perhaps issuing a survey? Site identification: how is the site going to become one of the sponsor/CRO’s preferred sites and vice versa? Issue escalation: how will this be handled (by all parties) without undercutting the CRA? Communication: frequency is key but it should also be with purpose, so how will this be managed? In order to create effective processes, collaboration at all levels is vital. In order to execute the process effectively, all involved must follow the escalation and communication strategies established during planning. In my opinion, one or two site visits per year, in addition to ad-hoc meetings as needed, is practical. That said, this will vary from site to site and should always be tailored for each relationship. In addition, group meetings with key investigators can be a successful way of gaining feedback. Industry conferences are an effective time to gather a group of the investigators together and create a forum where people can raise issues and come up with solutions together. Finally, collegial relationships, based on openness and trust, are important, in order to build lasting relationships and successful partnerships. Sponsor and CRO Benefits CROs and sponsors should work very closely together when interacting with study sites and utilise strengths of any existing relationships. When possible, they should attend meetings together to set up relationships, even when there is an existing relationship, and maintain this throughout the trial. Ultimately, better site engagement and strong relationships come from great communication. Being proactive in communication can Spring 2017 Volume 9 Issue 1


Clinical Research impact of a suggested design before the trial begins. Site Benefits For sites, fostering strong relationships with sponsors and CROs also has its benefits. Early, as well as frequent, engagement with protocol design and programme development will result in a clinical study which is easier for them to execute, and consequently, most sites will thrive off the opportunity to contribute not only at the start, but throughout the study.

not only improve site commitment, but will avoid delays in responses which can result in strained and difficult relationships, accelerate the consultation process, speed up the start-up process, and result in higher-quality outcomes. By creating a strong synergy between sites and themselves, sponsors and CROs can utilise the site’s relevant experience and knowledge to improve protocol design. By being given the opportunity to contribute, sites can provide information which sponsors and CROs may not necessarily be aware of. For example, a site may be particularly experienced with running trials for a specific indication, more so than any other party involved, and are therefore ideally placed to offer valuable insights on how the study should be executed from a practical operations point of view. This information sharing does not always have to mean changing protocols, but could quickly and quite simply be used to support recruitment and retention, and will also assist in highlighting any challenges that are likely to occur. In my opinion, transparency is key – even if alterations to the protocols cannot be made, gaining input from the sites will at the very least mean sponsors are aware of the potential www.ipimediaworld.com

Being involved in planning will mean sites know what to expect, and are aware of exactly what they should be looking for when it comes to patient recruitment, allowing them to be proactive and optimise start-up in a tailored fashion, giving the study the best chance of retention. In addition, by agreeing upon processes and operating procedures in advance, all parties are aware of the expectations on them, and work towards these from the offset. Sites can also share best advice from previous similar studies, and recommend other suitable sites to engage with if appropriate/necessary. Engaging Physicians As well as engaging sites from an operational point of view, it is also important for sponsors and CROs to seek advice on clinical excellence. By reading articles, attending conferences, working with associations including the Center for Information and Study on Clinical Research (CISCRP), the Association of Clinical Research Professionals (ACRP) and Mission Model Agreements & Guidelines International (MAGI), and linking with relevant support and advocacy groups, sponsors and CROs can aid understanding, learn about the latest developments and create opportunities to information share. Communicate with Purpose While much of this article has highlighted the importance of communication, it is important that sponsors and CROs manage the frequency and nature of this, to avoid becoming a burden, which could result in the opposite desired effect.

Visiting sites shows dedication, and face-to-face interaction is essential, however, this should be balanced with phone calls, Skype meetings and emails etc., to ensure communication is timeand cost-effective. With clinical trials budgets becoming tighter and tighter, cost can often be a barrier to travel, but it is important the sponsors and CROs find the funds and make the time for this. The reality is that most sites appreciate hearing from sponsors and CROs, as it demonstrates that they are being supported. Final Thought Despite the increased complexity of today’s clinical trials, by improving communication and setting clear expectations and goals for each other, sponsors and CROs can make it easier for sites to conduct trials and improve commitment. However, in order to achieve this, they must consider sites as true partners throughout and beyond the study. Furthermore, by maintaining post-study communication, sponsors and CROs can not only sustain the important relationships they have created, but also take learnings from the work carried out and use this to influence future trial design and execution.

Jeffrey Zucker Vice President of Feasibility and Recruitment Optimization at Worldwide Clinical Trials. His current responsibilities include growing and continually improving the global and site feasibility capabilities at Worldwide. Moreover, Mr Zucker oversees the evolving Patient Recruitment and Site Relations departments. He has been in the clinical research industry for nearly 20 years, most of which has been focused on feasibility, patient recruitment, and site identification & relations.

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Five Reasons to Rethink Paper ECGs Why Gamble with SiteManaged ECG Collection? Cardiac safety issues are among the most common reasons for promising drugs being halted in development and not brought to market.

The ICH E14 Guidance for Industry requires every new drug to be tested for QT prolongation to predict the risk of Torsades de Pointes (TdP), a lethal arrhythmia. Digital data and ECG waveforms are required for submission, and centralised ECG analysis is recommended (whether assessing QTc in a Thorough QT study or in Phase I with concentration effect modelling as now allowed under recent ICH E14 revisions). Regardless of the phase of clinical development, sponsors who rely on site-managed ECGs may be risking data quality, which could extend study timelines, increase costs and, most importantly, place patients, trials and compounds at risk. There are significant differences between site-managed and centralised ECG data collection and analysis, so it’s critical that sponsors understand how their selected method could make the difference between success and failure as they develop new medical products. Protect the Compound

1. Nearly 80% of the time, cardiologists and other physicians cannot recognise a long QT when they see one. Sites may claim to be proficient at reading ECGs, but how skilled are they? A 2005 study of more than 900 physicians tells a different story: While QT experts correctly recognised a long QT 96% of the time, cardiologists and other physicians only got it right 22% and 21% of the time, respectively (Figure 1). Morphology issues are 54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 1: Inaccurate electrocardiographic interpretation of long QT: The majority of physicians cannot recognise a long QT when they see one1

also challenging to identify.1 By taking this gamble with data quality, sponsors who rely on site-managed ECG analysis are putting their compounds at risk of termination due to inaccurate QT readings.

2. Site-managed ECG screening errors can later result in false positive QT signals. If a site under-measures QTc at baseline, but the patient’s QTc is correctly measured later on in the trial, the compound under study will appear to be responsible for an increase in QTc. At a minimum, this may require further investigation and explanation to regulators. Worse, a false positive signal for drug-induced QT prolongation could lead to delays or termination of the trial and possibly the compound. Improve Patient Enrollment and Study Efficiencies

3. Patient recruitment takes longer with site-managed ECG measurements. A 2015 analysis of 270,000 ECGs from multiple oncology studies where patient eligibility was determined by site-managed ECG measurements

concluded that as many as 45% of the patients excluded due to prolonged QTc were actually eligible for enrolment when correctly evaluated through centralised ECG measurement.2 Similar data trends have been documented in therapeutic areas beyond oncology. In an environment where every day of clinical development averages $37,000 or more in operational costs, sponsors can ill afford to exclude suitable patients and the resulting delays in meeting recruitment goals and trial completion.3 Protect Your Patients

4. Site ECG measurements lead to unnecessary interruptions in treatment. The same analysis of ECGs from multiple oncology studies found that up to 77% of dosing interruptions based on site-managed QTc measurements were unnecessary, as the centralised QTc measurements were considerably lower.2 By making decisions about dose interruptions based on site-managed ECGs, sponsors may be denying cancer patients potentially life-saving medications and might even eliminate them from the trial.

5. Site-managed ECGs delay recognition of patient safety issues. When sites manage ECGs, they produce a paper ECG without a digital file. The measurements must be manually entered into the CRF or EDC system, risking transcription errors and query delays. Since the ECGs are not saved as digital files, they are not accessible for risk-based monitoring and cannot be submitted to the FDA as required. With paper ECGs, perhaps the greatest risk is that study teams do not receive Spring 2017 Volume 9 Issue 1


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real-time alerts or notifications when a site finds a safety issue, potentially jeopardising patient safety across the trial. Furthermore, if site investigators are not experienced cardiologists, they may miss important safety findings entirely. ECG Centralisation Mitigates Risks, Protects Compounds and Patients In today’s environment where drug development costs and timelines continue to escalate, sponsors cannot afford to gamble with data collection methods that put their compounds and study patients at risk. Centralising analysis through trained and experienced experts enables trial sponsors to gain confidence in ECG accuracy, overcome the challenge of inter-reader variability caused by site-managed readings, and yield the highest-quality data so their compounds have the greatest chance for success. www.ipimediaworld.com

REFERENCES 1 Viskin S, Rosovski U, Sands AJ, et al. Inaccurate electrocardiographic interpretation of long QT: the majority of physicians cannot recognize a long QT when they see one. Heart Rhythm. 2005; 2:569–574. 2. Kleiman, R, et al. Benefits of Centralized ECG Reading in Clinical Oncology Studies. Therapeutic Innovation & Regulatory Science. 2016, 50:123-129. 3. Roswell, Carol. "Case Study: Boosting the Predictability of Clinical Trial Performance." Technology Research. Gartner, Inc., 28 Mar. 2007. Web

Ellen Street As head of ERT’s Cardiac Safety solutions, Ellen is responsible for driving innovation and leveraging the company’s complementary offerings into the product suite, including data analytics. She has more than 20 years of product management, commercial leadership, and strategic marketing experience across multiple segments of the life science marketplace, including Healthcare IT, Medical Devices, and Imaging. Most recently, Ellen was VP and General Manager, Global Monitoring Solutions Ecosystem and Analytics at GE Healthcare, where she led the company’s patient monitoring data and analytics strategy within its Life Care solutions business. Email: ellen.street@ert.com

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Data – The Foundation of Clinical Trials A changing world brings data to the forefront, but how do we manage it all to make the biggest impact?

The life sciences industry has been fundamentally altered in recent years. Diseases that were once considered life-threatening and terminal are now being managed as chronic conditions. Previous chronic illnesses are treatable and curable, while other diseases have been reduced to irritations or consigned to the history books.

The life sciences industry has been fundamentally altered in recent years. Diseases that were once considered life-threatening and terminal are now being managed as chronic conditions. Previous chronic illnesses are treatable and curable, while other diseases have been reduced to irritations or consigned to the history books. Clearly, there is much to celebrate, but also still much to do. Advanced solutions are needed to treat multiple cancers, heart disease, obesity, Alzheimer’s, and Parkinson’s, to name a few. The speed of innovation and the acceleration of new solutions to market will be increasingly important. Within pharmaceutical companies, the quest for understanding has accelerated, leading to the establishment of a knowledge-based economy with data as the currency. The more we know, the more we can develop these advanced solutions to not only meet, but also get ahead of, expectations. Scientific breakthroughs will continue the more we understand the human body – not just the biochemical pathways, systems, and organs, but also the inter- and intrapersonal behaviours that form our very makeup. This process will accumulate vast quantities of data, especially in clinical trials. As the volume of clinical data rises, the ability to turn that data into quick decisions is limited by today’s technology approaches, including electronic data capture (EDC) systems. Consequently, sponsors and 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

sites are not equipped to support new and innovative trial designs, such as adaptive clinical trials. Making complete and accurate data available will enable life sciences to finally run the trials they want, not just the trials today’s EDC systems allow. If clinical researchers can have their data in real time, the life sciences industry can better address the problems that are leading to distress, illness, and even death. It is the accumulation and conversion of this data into actionable insight that will drive the era of personalised or precision medicine. Major Shifts Impacting the Industry The Rise of Personalised Medicine The industry has long discussed the end of the blockbuster era and life sciences companies’ pursuit of alternative solutions they can bring to market. This is now closer than ever. In January 2017, ClinicalTrials. gov showed that since 2014, the number of registered studies had increased by almost 50%. Likewise, new records for FDA approvals were consecutively set in 2014 and 2015. It is easy to conclude that more trials reaching more patients and generating more data is resulting in more products to market, but in 2016 that trend was reversed. This speaks to the rapidly changing environment, and highlights the need for yet more innovation.

products were slated to lose their patent protection. Patent expirations for highly prescribed medicines will continue to influence healthcare spending as lower-cost generics are allowed to compete in the larger marketplace and drive down costs. Although it depends on the type of treatment, the average price of a generic can be as much as 80–85% per cent lower than its patented brand-name counterpart.1 In fact, between 2009 and 2014, more than $120 billion in pharmaceutical sales was lost to patent expirations.2 An Increased Focus on Patient Outcomes Another major change is linked to consumption models and patients. With every new scientific development, there is renewed expectation of long-term benefit. Armed with heightened anticipation, patients don’t buy drugs anymore; they buy outcomes. This means manufacturers will see their reimbursement strategies set on a value-based principle, which depends not only on direct therapeutic effect, but also on patient compliance and adherence. Understanding patient behaviour will be vitally important and not only serve to validate, but also play a key role in the treatment regimen itself. Exercise, mobility, social interactions, and behavioural patterns will play a greater role in determining whether a

Further exacerbating the challenge is the escalating patent cliff. In 2016, several high-profile, brand-name Spring 2017 Volume 9 Issue 1


Clinical Research patient perceives a sense of wellbeing, as opposed to just being told they are getting better. Understanding the mode of action at a chemical level is crucial, but understanding human nature and human behaviour is often the key to determining where a new treatment will actually work. Patient outcomes combine collective and individual experiences, enabling clinicians to fast-track conclusions in the lab into everyday clinical life. Companies will take this even further with accelerations in personalised medicine, recognising that all human beings are different, and our characteristics, behaviours, and experiences shape wellbeing. Data Currency in Clinical Trials While clinical research continues to advance, the demand for better, faster, more effective treatments shows no sign of slowing. Scientific advancements that took 10 years to reach mainstream could soon take less than two years. To sustain this quest for better knowledge and more effective treatments, however, researchers need to better understand the biochemical processes in vivo and in vitro. That means connecting individuals across the globe, from patient to caregiver, from life sciences to healthcare organisations, and beyond, into the regulatory landscape. Data is the unit of intelligence, currency, and commodity all wrapped into one neat package. To establish a free-flowing data stream is difficult enough, but data in itself does not deliver the end result. Data is ubiquitous and comes in a wide range of volume, variety, and velocity. To successfully operate in a knowledge-based economy, data must be consumable and available in real time to derive actionable insight. Today, industry is investigating the use of wearable devices, such as Fitbit, Garmin, and many others – each capable of generating tens of millions of data points daily. Imagine combining that data with real-time observations, clinical assessments, long-term medical histories, financial data, behavioural data, and even social data. Exploring and characterising www.ipimediaworld.com

patients from so many dimensions would enable clinicians to create a picture of each individual on a macro and micro level, from cradle to grave, from their very genetic beginnings to their current day. But the data is not enough, and neither is reviewing the data sources in isolation or combining the data into a periodic data set. Companies will need to create a complete picture of the individual, refreshed every time a new data point is generated or recorded, in order to turn raw data into actionable insight and decisions. A direct line must be drawn between decision-making and continuous improvement in patient wellbeing. Pulling together this vision of an individual has another acute benefit. By sharing the outcomes and the characteristics of that individual, the industry can connect caregivers and patients across the globe, adding to the knowledge pool and advancing research in unimaginable ways. By mining data confidently, companies can find patterns and draw conclusions that have always evaded researchers until the very end of a clinical study, enabling real-time course corrections that reduce exposure to unnecessary treatments and redirect efforts to the best options available. This is the overriding principle behind the 100,000 Genomes Project, run by Genomics England: “The project will sequence 100,000 genomes from around 70,000 people. Participants are NHS patients with rare diseases, plus their families, and patients with cancer. The aim is to create a new genomic medicine service for the NHS – transforming the way people are cared for. Patients may be offered a diagnosis where there wasn’t one before. In time, there is the potential of new and more effective treatments. The project will also enable new medical research. Combining genomic sequence data with medical records is groundbreaking. Researchers will study how best to use genomics in healthcare and how best to interpret the data to help patients. The causes, diagnosis and treatment of disease will also be investigated. We also aim to kick-start a UK genomics industry.

This is currently the largest national sequencing project of its kind in the world.” https://www.genomicsengland. co.uk/the-100000-genomes-project/

In parallel to clinical results, companies will also be able to seek operational patterns and identify problems, challenges, and obstacles faster. Many clinical trials still rely on manual, paper-based, or obsolete systems to collect, manage, and report clinical trial data. Time from event to analysis is still measured in weeks and months, when the need is for minutes and seconds. The application of first-generation e-clinical platforms has been heralded as a big achievement, but that cannot be reconciled with the fact that these efforts have yet to accelerate clinical research or reduce the costs of research in any significant way. In order to achieve a state of complete and concurrent data, in which data equals knowledge and knowledge leads to better decisions, data should be managed with a single software platform that empowers participants to optimise their contributions to the data value chain. The platform needs to create a coherent and contiguous environment for management of patient data, enabling research in all of its formats, through all of the contributors and consumers of that data. A Better Way is Needed Electronic data capture (EDC) systems were first introduced 40 years ago for clinical data management, but really took off at the turn of the century. However, today’s EDC is arguably still not a central, critical part of the clinical trial process. More often than not, clinical investigators still turn to paper and pen before EDC. While clinical trials are getting more complicated, technology is not being leveraged to simplify this complexity. If anything, it is common to find investigators bypassing technology completely in favour of manual data capture and then inputting that data into EDC systems as an afterthought. Does this actually render today’s EDC unfit for purpose? INTERNATIONAL PHARMACEUTICAL INDUSTRY 57


Clinical Research Let’s explore that for a few moments and consider the stumbling blocks to widespread EDC adoption and making it core to clinical trials. • E for Electronic: Many EDC solutions are still reliant on traditional paperbased processes, and most patient visits are recorded using paper and pen. These manual steps expose the entire clinical trial process to unnecessary risk and inefficiency. • D for Data: EDC solutions are really e-CRF (e-case report form) tools that fail to address total data needs. In fact, e-CRF data can easily represent less than 20% of study data, according to various estimates. • C for Capture: If all your EDC solution does is enable data capture, what about data management, monitoring, and reporting?

For clinical trial solutions to be classed as “fit for purpose,” all of the incoming data must first be accessible in real time and in one place. This provides a complete and concurrent view of data that is specific to every patient, effectively creating a patient passport. A real-time window into the patient’s own world can deliver a better understanding of their symptoms, behaviours, and actions. Consolidating data not only advances the patient cause, but also improves the likelihood of success. Trials become faster, better informed, more knowledgeable, and better placed to react to whatever events arise.

To be fit for purpose, a data management tool, (perhaps EDC) needs to address each and every data type plus the four Vs of data. • Volume: Manage vast quantities of data (structured and unstructured) without system performance degradation or financial loss. Today’s EDC and e-CRF solutions 58 INTERNATIONAL PHARMACEUTICAL INDUSTRY

are designed to just manage data entered at site, which is typically just a fraction of the total data in a study, according to various estimates. • Variety: Manage data from a variety of sources, in differing formats and data types. Many EDC and e-CRF solutions are designed to manage structured data in limited format types. • Velocity: Manage data in real time, consuming and supplying data with simplicity and elegance. EDC and e-CRF solutions often are not designed to handle large volumes of data. Adding significant volumes causes severe performance delays. • Veracity: Recognise that not all data is equal, and much of it requires different strategies to each data point (in essence, a risk-based data strategy). EDC and e-CRF solutions are designed to manage data by type, and therefore need external assistance to drive more varied strategies.

Advanced, fit-for-purpose EDC solutions will address the need for volume, variety, velocity, and veracity and lead companies to full-value assessments, aiding better study design, execution, and conclusion. Realising the Clinical Trials of the Future, Today The life sciences industry will, very soon, have the ability to eliminate the need for paper in a clinical trial setting. However, companies need to not just eliminate paper, but also completely redefine user experiences to be paperless – electronic systems will no longer be designed to look and behave as pieces of paper. This will result in user interfaces that are far more intuitive, much like the experience of buying a book on Amazon, in which advanced functionality such as search and automatic grouping is designed inherently into the system. The second step towards real progress is to tackle data at the source, literally. More often than not, source data is still recorded on paper with a pen, or in a paper-like format (using Microsoft Excel or Word). The resultant source-data verification has significant negative impact on the ability to reduce time or cost, and has been subject to many recent

reviews that highlight only minimal quality advances. As patients record more of their own data, paper is still the preferred solution. This only exacerbates and extends traditional challenges. The proof of this idea is already well established. The “car-park syndrome” is well documented: patients forget to fill out their diaries or questionnaires, so they try to recreate their experiences and symptoms as they sit in their cars just before they walk in to see their doctors. If companies tackle the source-data challenge correctly, they not only advance clinical research, but also create a path to better, faster long-term medical records, facilitating data-sharing across multiple solutions (i.e., EDC and EHR). While cloud-based technology and big data management have proven results across the board in all industries, the life sciences industry has been slow to adopt a true cloud-based solution that can deliver on global usage, minimise costs, and handle data. This has been mainly because there has not been a true cloud solution that addresses these issues to date. When software doesn’t work, it makes routine tasks and processes more difficult. The Next Wave of Innovation in Clinical Data Management Clinical trials are a very patientcentric, patient-driven process. Someday soon, patients will have complete control of their data. Personalised medicine is designed to ensure that our research delivers medical solutions that are better defined and increase an individual’s likelihood of responding. To understand individuals, each patient must be closely examined, including data that hasn’t yet been considered for clinical trials. The true “fit-forpurpose” EDC solution will handle all the data a patient can generate, and use that data to derive real-time decisions for patients and caregivers. Clinical research can become truly global, connecting patients and caregivers across the globe. This opens up new vistas for clinical data capture and management to bring the trial to the patient. The internet Spring 2017 Volume 9 Issue 1


Clinical Research of things (the interconnection via the internet of computing devices embedded in everyday objects, enabling them to send and receive data), for example, has increased the ability of data to be shared in real time and opened up the possibility of integrated data from varied sources into clinical trials. With it, the industry can take clinical research to unimaginable places – such as a site-less clinical trial. For instance, rather than a site finding a patient, patients can remotely find trials through smart devices, and drugs can be administered and monitored from thousands of miles away. The true, fit-for-purpose EDC solution will handle all the data a patient can generate, and enable life sciences companies to use the accumulating data to make confident and robust decisions in real time. Succeeding quickly is a critical goal, but failing early is vitally important too. Not every new clinical solution will drive benefit; therefore, there is opportunity to redirect money, resources, and patients. Cloud, mobile, big data, and the internet of things hold immense potential when it comes to transforming clinical trials, especially ones that span geographic boundaries. A global, cloud-based solution for clinical data management makes installation, ongoing maintenance, and performance inherently easy, while managing costs, time, and resources. The true, fit-for-purpose EDC solution will work anywhere, any time, and enable life sciences companies to design and execute the trials they want, not the trials that are limited by technology today. As important, this type of internet-enabled cloud solution will increasingly support a global economy, including emerging and developing countries, where 54% of adults identified themselves as internet users in 2015.3 Of course, the digital divide remains a challenge, but as more tech giants, such as Google with its “Project Loon” initiative and Facebook’s “Internet.org” initiative, drive innovations forward to bring the internet to more people… this challenge will slowly, but certainly, diminish.4 www.ipimediaworld.com

Conclusion Life sciences is at an inflection point when the drive for patients, treatments, and research (clinical trials) is increasingly global, medicine is becoming personalised, and there is an increased demand for bringing drugs to market faster. With these demands, a true, cloud-based clinical data management solution that delivers global clinical trials and incorporates a high variety, volume, and velocity of data to deliver personalised clinical trials is needed. This system will go far beyond the EDC solutions of today, which have not delivered on innovation in well over a decade, as well as beyond the e-CRF limitations that have historically governed clinical trial processes. Clinical trials are still largely paper-based and EDC systems often serve as data-entry systems. The next generation of EDC solutions will combine data from every source, in real time, and present that data to all consumers and facilitate clinical trials. This will mean embedding technology across the clinical trials process, from patient to regulator, ensuring that every observation, result, and event is captured as it occurs. Currently, data is recorded on paper first and entered five days later. Instead, it would be digitised at the source, precisely when a patient event is happening, anywhere in the world, at any time, and this would become part of the global data set immediately, not days or weeks later. Learning, patient management, and ability to address challenges will all happen in real time. Technology will not only support the clinical trial, but the wider healthcare systems, feeding data into the patient’s long-term medical records. The benefits of harmonising across life sciences and healthcare will reap huge rewards, and ultimately save the need for some research altogether. While the world has been overtaken by the digital transformation, with cloud, mobile, big data, and the internet of things altering every aspect of business, the life sciences industry still has a long way to

go when it comes to leveraging technology to transform clinical data management. The industry is moving fast toward digitalising clinical trials on a global scale, and the life sciences companies that are not quick to ride this change will soon be left behind with insurmountable costs, unable to keep up with the changing economy. The data management world of the 1990s looks remarkably similar today. To change clinical research is to change patients’ lives, which comes from fresh innovations and identifying the barriers that stop advancement. Data and knowledge help us to learn, and it is through learning that we can make real change. REFERENCES 1. FDA.gov, “Facts about Generic Drugs.” For more: http://www.fda.gov/Drugs/ ResourcesForYou/Consumers/ BuyingUsingMedicineSafely/ UnderstandingGenericDrugs/ ucm167991.htm 2. Drugs.com, “Looking Ahead – Pharma Projections for 2016 – & Beyond.” For more: https://www. drugs.com/slideshow/lookingahead-pharma-projections-for2016-and-beyond-1230 3. Pew Research Center, “Smartphone Usage and Internet Access Continues to Climb in Emerging Economies,” by Jacob Poushter, February 22, 2016. For more: http://www. pewglobal.org/2016/02/22/ smartphone-ownership-andinternet-usage-continues-toclimb-in-emerging-economies/ 4. Global Citizen, “Google wants to deliver internet to the developing world – via balloon,” by Hans Glick, June 3, 2015. For more: https://www.globalcitizen.org/en/ content/google-wants-to-deliverinternet-to-the-developing/

Richard Young Vice president of Veeva Vault EDC. With almost 25 years of experience in life sciences, Richard is known for his executive vision and proven operational experience in data management, e-clinical solutions, and advanced clinical strategies.

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Company Profile

Controlled Nucleation Utilising ControLyo™ & SMART Technology Enables Streamlining of your Product and Cycle Development Processes By Richard Lewis, Biopharma Group, Winchester Increasingly, industry has become driven by stringent regulations where companies are being asked to understand specific material properties of intrinsic value during the design and implementation of an efficient lyophilisation recipe, to ensure successful drying which doesn’t impact potential product efficacy….and all in the shortest time period possible. As a result, the need for state-ofthe-art equipment, such as the SP Scientific Lyostar3, to carry out contemporary freeze-drying (lyophilisation) techniques and reduced product cycle time, appears to be becoming far more pronounced. The Lyostar3 moves users away from the ‘trial-and-error’ elements traditionally associated with the cycle development process, which can be time-consuming and costly, toward more efficient means, such as the unique SMART technology that enables fast and easy optimisation, whilst ensuring the smooth transfer from laboratory to production-scale. SMART Technology The principle behind SMART technology is the combination of m a n o m et r i c t e m p e rat u re measurement (MTM), and automation of shelf temperature/ vacuum set-point control. Following automated measurements, product temperature at the sublimation interface is calculated and the application then determines the ideal parameters for preventing product collapse or melt-back during drying, without the necessity of placing thermocouples or other temperature sensors in the product vials. Instead, MTM relies on an isolation valve being placed between the product drying chamber and the freeze-dryer condenser. During 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

execution of the lyophilisation cycle, this valve is rapidly and automatically opened/closed. The rise in pressure is then measured for 25 seconds at regular intervals during primary drying. Accumulated raw data is used in the MTM equation to calculate the product temperature at the ice surface interface, the dried layer resistance, ice thickness, and heat flow/mass transfer – all critical R&D parameters to understand. This information is then applied to automatically adjust the shelf and vacuum set-points of the lyophiliser, during the cycle, as previously discussed, thus achieving and maintaining the product temperature precisely at the target temperature throughout the process. In practice, in order to get good MTM data, the following aspects should be adhered to:

• Minimum product surface area of greater than 300 square centimetres or three-quarters of a sample tray • Aqueous sample only • Solid content between 3 and 15 % • Optimal vial fill being one-third the volume of the selected product container

In d e p e n d e nt s t u d i e s h av e confirmed the use of the SMART software, above, has offered an average cycle development time reduction in the order of 78%, and has been known to reduce average cycle optimisation to one or two runs, rather than the conventional series of six to eight runs – thereby not only reducing development time, but also lowering materials costs by one-third or more. ControLyo™ Nucleation Technology Further to SMART technology, the Lyostar3 has also been designed for use with the ControLyo™, also now owned by SP Scientific, to remedy another well-known area of difficulty associated with freeze-drying. Namely, the freezing step itself. This is because freezing or ice nucleation is generally considered to be a stochastic process, so the degree of super-cooling will likely vary both inter and intra-batch. Spring 2017 Volume 9 Issue 1


Company Profile

However, to combat this phenomenon, ControLyo™ utilises a sudden decrease in pressure to induce the nucleation of every vial in the product chamber at the same time, while maintaining the temperature to within 1°C of a product’s freezing point, minimising the super-cooling effect. Ultimately, the samples produced should have lowered product resistance, higher quality and yield, complete with propensity to reduce cycle times by as much as 40%, in some cases. Also, due to the nature of ControLyo™, many competitive technologies encounter more issues in order to maintain the sterile boundary within the freeze-dryer, as well as successfully scaling the process up from development to manufacturing level. For these reasons more and more R&D/ production operatives recommend the technology. Tunable Diode Laser Absorption Spectroscopy (TDLAS) One of the most advanced and exciting contemporary technologies in the area of freeze-drying is that of TDLAS, where research scientists have already begun to adopt the method as their ‘desired’ end point determination tool. Developed by Physical Sciences Inc. (PSI), and integrated within the Lyostar3 a (TDLAS) sensor can now be applied for monitoring the mass flow rate of water vapour between the product chamber and condenser of commercial freeze-dryers used for process development and the production of pharmaceutical products. The sensor itself measures water vapour concentration (molecules/ cm3) and gas flow velocity (meters/ second) using a pair of non-intrusive, line of sight spectroscopic absorption measurements across the gas flow in the duct. The sensor combines sensitive near-IR (NIR) absorption-based water www.ipimedia.com

vapour concentration measurements and quantified measurements of Doppler-shifted absorption to determine gas flow velocity – a combination which provides a direct measurement of water vapour mass flux (grams/sec/cm2).

product-driven/cost-efficiency needs and therefore it is imperative that lyo based labs are able to act upon the demands of their own client demands by passing on the streamlining efficiencies offered by the likes of SMART & ControLyo™.

The mass flux measurements are combined with the knowledge of the flow duct cross-sectional area to enable the determination of the water vapour mass flow rate (grams/second). The instantaneous mass flow rate measurements are integrated during freeze-drying cycles to provide a measurement of the total amount of water removed during the process.

If you would like more information on any of the details provided within, please contact Richard Lewis at Biopharma Group: rlewis@biopharma.co.uk +44 (0)1962 841092 www.biopharma.co.uk

While other methods of residual end point determination have previously dominated the freezedrying environment, now, TDLAS is being adopted by large pharma because it is one of the only PATs that can be implemented in both R&D and production scale. Present Day Bio-pharmaceutical Market: Just as the expectations of biopharma industries continue to increase in tandem with the demand for more efficient and cost-effective manufacture, companies seek to maximise profits through the development and safe production of material in a robust and efficient manner. Therefore, instruments capable of capturing critical data-sets, like those associated with Biopharma Group’s SP Scientific Lyostar3, are set to continue their rise into the future to meet these INTERNATIONAL PHARMACEUTICAL INDUSTRY 61


Logistics & Supply Chain Management

Temperature Controlled Logistics Conference – A Meeting of Minds End of January, Cecilia Stroe, staff editor of IPI, attended the Temperature Controlled Logistics Conference in London, and learned that a business is only as successful as its supply chain; exactly as the saying goes. In its 16th year and held in London for the first time ever, on January 31st and February 1st 2017, the Temperature Controlled Logistics Conference brought together at the ExCel Centre more than 500 life science professionals keen to tackle inefficiency in the supply chain. Featuring 60 expert speakers, 40 workshops, 60 exhibitors and 24 hours of networking, the conference focused on identifying opportunities and uncovering the latest innovations in temperature controlled technology, and left no stone unturned. Insights into trends, challenges and opportunities having an impact on healthcare logistics – as well as hot topics in the industry such as supply chain security and temperature control, regulatory compliance, supply chain visibility, optimisation and cost management – were all addressed extensively in the presentations and debates. Graham Martin, Senior Manager, Pfizer, gave An Industry Practitioner View on how to Future-proof your Cold Chain: by investing in the latest technologies and sustainability, that is. Martin shared his insight on where the industry is heading and which emerging trends and challenges will most affect the pharma supply chain in the future. Where is the industry`s focus and strategies? Cold chain to temperature control, wider temperature ranges for biologics, targeted therapies for rare diseases, increased demand for personalised drugs/medicines. Martin mentioned the increase in global clinical trials to complex country/ market requirements, which is adding 62 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to their cost and complexity and the fact that as cold chain processes are becoming more global, there is an increasing focus on quality and product sensitivity. “Regulations and [the] regulatory landscape [are] changing, drugs are developed with mandatory requirements, product integrity testing is being requested after distribution, post form fill but before final packaging,” Martin explained. According to the expert, market pressures are driving demand for improved supply chain efficiencies, manufacturers are outsourcing more of the processes to 3PLs, forwarders are developing `end to end` strategies and value-added services; there is a mode shifting and intermodal service; packaging is evolving to meet new requirements and standards; investments are being driven by sustainability initiatives. But above all, Martin said, investment in new technology is crucial. Terry Madigan, GDP inspector, MHRA offered to the audience his expertise on How to remain Regulation Compliant and Inspection Ready. In his presentation, Madigan highlighted as common issues gaps in GDP requirements, the understanding and application of quality risk management (QRM) (“large companies understand it, small ones struggle”), and the control of outsourced transportation activities. He stressed the importance of QRM consistency across systems and organisations, as precisely the challenges of applying QRM are accounting for the so-called “unknown unknowns”. Martin mentioned situations in which consultants are brought in to fix a problem that never existed and emphasised the importance of identifying and supporting acceptable levels of risk in regard to temperature excursions and proactive oversight.

For Jeff Carrico, Director of Pharmacy – Investigational Drug Service, Florida Hospital System and Distribution Committee Expert Member, US Pharmacopeia – “the conference has been very enlightening” on the issues that come way before the product gets to the end user. “There are different ways to get where you need to be. The `last mile` in the supply chain depends on where you stand in the process,” said Carrico. He presented the US Pharmacopeia Update: The Past, The Present and Future of General Chapters, Packaging and Distribution – the New General Chapter on Storage and Distribution of Investigational Drug Products. According to Carrico, guidance will soon exist for IPs that will supplement regulations and the attention paid to good distribution practice for IPs will lead to further confidence in the results of a clinical trial. In future, he assured the conference, USP will continue to look at developing guidance on the proper storage and distribution of drug products and materials. “A continued goal is to develop guidance that [will] fill gaps or give clarification on topics related to the proper storage and distribution of products and materials. Currently, the Expert Committee is focusing on the areas which pose the greatest risk to the quality of products as they move through the supply chain.” There is no doubt about it, the industry is changing. Everyone is aware of the challenges raised by the ageing population or the growth in lifestyle diseases such as type 2 diabetes, said Cathy O`Brien, Managing Director, UPS. “But are we ready [for] the changing healthcare landscape? We have to keep asking ourselves.” O`Brien talked about the rise of the “flex shopper” using retail channels and devices to best suit personal convenience as a trend that has moved into healthcare, Spring 2017 Volume 9 Issue 1


Logistics & Supply Chain Management and the shift from “Doctor Knows Best” to ePatient and participatory healthcare. Therefore, logistics is changing, O`Brien said. In her presentation, she focused on How to Use your 3PL Partnership to Thrive in a Changing Healthcare Landscape. “There is a greater need for temperature control and management; it is no longer about active and passive, there is now choice and complexity. Making changes in the supply chain is essential for a company to not be left behind.” According to Cathy O`Brien, competition is fierce; that`s why supply chain flexibility is paramount. Mentioning a case in which a global pharma company made the choice of “using a sledgehammer to crack a nut”, she stressed the importance of real partnerships. “The answer is to collaborate with your logistics provider,” O`Brien thinks.

chain professionals to ensure GDP alignment. The recent additional investment in environmental chambers will enable more in-depth and wider-ranging chamber trials including further stress and profile range testing. A triplicate testing schedule is already in progress to support GDP requirements. TP3’s simulation software will now allow TP3 to provide supporting data to enable logistics managers to take a risk-based approach on lane management. “We’re seeing a huge step forward within TP3 Global at the moment, which is all geared towards supporting our technical partner approach to customer support,” said Clive Wheeldon, CEO & Chairman of TP3. Finding the right solution can be a game-changer in today`s market. Addressing the topic of IoT in the

Commercial Supply Chain, Simona Vatzova of Teva and Gisli Herjolfsson, CEO of Controlant presented two case studies showcasing the importance of choosing the right supply chain monitoring solutions. What to look for in an IoT solution? As Gisli Herjolfsson put it, if the task is finding the most optimal solution to proactively track and monitor the highest risk products in real time, then “the value lies in the data, not the device.” It is a case of the right data at the right time, automation, less human involvement, collaboration and data sharing. And in regard to the device management, “don`t add complexity” is the take-home message; “stay focused on what you are best at,” Herjolfsonn said. Results? Better visibility and stability of the supply chain.

There is the need to be agile, to be able to react quickly, to reduce overall costs to address budget overrun issues but maintain quality standards. Packaging needs to go back into the cycle, quality to be delivered cost-effectively. “Increase quality, reduce risk and secure overall cost. We have to keep reinventing ourselves, looking for partners with experience, collaborating with our suppliers, avoiding over-engineering and over-paying.” Demonstrating a considerable step change at Temperature Controlled Logistics was TP3 Global, manufacturer of the successful SilverSkin range of thermal pallet covers used by many of the major pharmaceutical companies globally. For the first time, Q Products & Services, recently agreed American joint venture partners, joined the TP3 team at the event by presenting a united range of single use and multi use thermal protection products. In only its fifth year, TP3 Global announced considerable investment in its technical department, aimed at providing the necessary qualification and validation data used by quality assurance and supply 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Logistics & Supply Chain Management

Temperature Management – Keep Your Cool The industry is experiencing an increase in sensitive and sophisticated pharmaceutical, and the compliance with new regulations governing temperature control during processing, storage and transport is on the increase. Any deviation outside the drug stability parameters can have a negative impact on the safety of a patient, which is of significant concern to pharmaceutical companies and regulators alike.

Shipments may experience a range of temperature effects that can impact the stability of a product, leading to temperature excursions that cause the product to become unfit for patient administration, and, ultimately, cause rejection. Discovering that a product has been compromised costs money and wastes time; not knowing is a much worse outcome, potentially threatening the study and patient safety. Steps must therefore be taken to reduce the risk of temperature excursion and importantly have the data to support adjudication on the product. It is therefore pertinent to develop strategies in order to reduce the impact of temperature excursions experienced during the product ’journey’. Doing so decreases any potential risk which will help to bring studies in on time, within budget, and more importantly, with no safety concerns for patients. Clinical sites are involved in much more than dosing patients with investigational drug. They can manage tens to hundreds of protocols with various sponsors who all require completion of a host of documentation, reports and other tasks. Now, due to tightening of re g u l at i o n s o n t e m p e rat u re monitoring, some sponsors are requiring sites to place separate temperature monitors within controlled storage (2-8oC, 15-25oC, -20oC, etc.) and download the readings monthly. 66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Sponsors are attempting to comply with these regulations to ensure that investigational drug is stored within the allowed limits, but doing extra monitoring can be challenging for sites. Transportation Options Air, land and sea freight each experience different variables that can affect temperature and each mode of shipping has its own risks in regard to cost, climate, time and storage locations. Therefore riskbased strategies must be applied when identifying and selecting transportation routes. For example, air freight is commonly accepted as the quickest transportation option available; however, it also presents

greater risk due to temperature fluctuations. In addition, due to the significant cost differential versus surface shipping, there is a tendency to transport smaller batches to reduce cost. Temperature is managed and controlled whilst stored both in an airport and the cargo hold of an aircraft; however, once the product is exposed to the elements transit points, e.g. on the runway or clearing customs, there is an increased risk for a temperature excursion. In addition to carefully considering the mode of transportation, it is essential to determine the number of storage locations and depots which will be required for the duration of the transit from origin to destination. Spring 2017 Volume 9 Issue 1


Logistics & Supply Chain Management Each change in location and stoppage throughout a product’s journey will impact temperature conditions caused by exposure to varying climate changes and conditions. For example a shipment distributed from Canada may be transported via sea freight to Australia, then stored for a period of time, before being moved by air to its final destination in New Zealand. Each and every movement of the product must be assessed to ensure risk is minimised throughout the entire shipment process. Temperature Monitoring Comprehensive, Good Distribution Practice (GDP) compliant monitoring of all temperature-controlled material is essential throughout all shipments. The most appropriate method to ensure all relevant information is captured is to include a temperature monitor which collects essential primary data, offering accurate readings correlating to specific dates and times during transit and storage. Any temperature excursion experienced can support decisions on the product and can be easily associated with the transit route. This can enable retrospective comparison and analysis of the methods of transport chosen. This visibility offers a level of control providing information to make decisions on how future material should be shipped and stored. The existing method of collecting and manually assessing this essential data often means managing multiple vendors and software applications. The analysis of temperature data is hugely valuable, however it is labourintensive and time-consuming, which has the potential to impact study timelines. Single-source temperature systems offer a simple solution to house all collated data on one single report in the most efficient way possible. The speed at which the information is available offers accessible data for interrogation and instant analysis, enabling companies to quickly put logistics strategies in place to reduce risk. This singlesource also better aligns companies with new regulations concerning patient safety, saving money, time and lives. 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Data Stability Mitigating against risks is vital and, whilst they cannot be eliminated, fully assessing transportation and temperature management is the first step – fine-tuning product stability data is the next. Most quality assurance departments manually assess and evaluate each out of spec temperature excursion as and when it occurs. Clearly, due to the nature of this process, mistakes happen and efficiencies are low, causing potential delays. If a system could track all excursions cumulatively for a particular product lot, shipment, or kit to document the product history, as well as hold predetermined excursion allowances based on the product stability, quality assurance could make product quality evaluations more accurately and quickly because the decision-making and justification is performed up front. For products with appropriate temperature stability profiles, the data can be used to create predetermined allowable excursion criteria and support a more flexible approach to product evaluation. This could minimise the need to discard material that may be viable due to temperature excursions. For example, a product labelled with storage conditions of 2-8°C may actually be stable at 9-15°C for 180 minutes and at temperatures of 15-25°C for 30 minutes before the product is deemed not viable. Giving QA groups predetermined and visible criteria for excursion adjudication allows for a robust and justifiable process for product disposition that is based on data and risk to the patient. Compliant Personnel Finally, it is essential to ensure those personnel responsible for handling temperature-controlled shipments are adequately trained to pack, receive, unpack and store the material in the most appropriate, compliant and efficient way possible. Without this knowledge, the risk of incorrect handling will inevitably cause risk to product integrity, and ultimately the patient. Personnel stationed at depots must be fully competent in unpacking and repacking shipments

in addition to handling temperature monitors correctly. All site staff must be compliant in the immediacy of unpacking and storing temperature-sensitive material in the most appropriate conditions, in addition to handling the actual temperature monitor. It is imperative that personnel appreciate the monitor should be treated with the same diligence as the product. Conclusion In order to ensure companies are minimising risk associated with shipping temperature-sensitive material from origin to destination, it is vital to combine valuable data analysis and assessment with appropriate distribution methods. However, as technology advances, companies must also take a proactive approach to avail of new solutions offering more efficient and effective methods of temperature management. This not only provides sponsors with the opportunity to maintain their competitive advantage by saving time and money associated with distribution, but also enables them to ensure patient safety through a compliant approach applied throughout the entire shipping process.

Heather Bogle Supply Chain Solutions Manager, Almac Group. Heather Bogle graduated from Queens University, Belfast with a BSc in Chemistry. She joined Almac in 2001 and has worked with a wide range of Pharma and Biotech companies, from small specialist providers to multinationals, to manage supply chains across the full range of sponsors and trial designs. Heather has first-hand experience in managing the supply chain for studies across the globe with temperature sensitive products. She has expert knowledge on the challenges with temperature management through the supply chain and extensive experience in developing creative, efficient and robust solutions.

Spring 2017 Volume 9 Issue 1


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 69


Manufacturing

Off the record: The Truth about Data Integrity in Pharma The Food and Drug Administration (FDA) has long emphasised the importance of reliable data in pharmaceutical manufacturing. Despite this clear recommendation, recent FDA reports have highlighted an increase in data integrity violations during several recent current Good Manufacturing Practice (cGMP) inspections. Here, Lee Sullivan, Regional Manager at HMI/SCADA software expert COPA-DATA UK, explores three data integrity pitfalls to which pharmaceutical manufacturers are most vulnerable.

In simple terms, cGMP states that pharmaceutical manufacturers should follow instructions and document actions correctly, so that if any deviation occurs in the product, the company can investigate it and put measures in place so that the same error does not happen again. This guarantees the repeatability and safety of the product being manufactured and protects the brand. Data integrity refers to the completeness, consistency and accuracy of data, which needs to be attributable and legible. Data integrity violations can lead to warning letters and even fines. More importantly, drugs approved on the back of inaccurate data could pose a threat to patients’ lives. For all these reasons and more, data integrity is at the heart of the pharmaceutical records discussion. Common violations of data integrity include not recording activities contemporaneously, copying existing data as new data, discarding data, backdating or even fabricating data. To avoid such violations, manufacturers need to design their systems and procedures in a way that encourages compliance with the principles of data integrity. This includes, for example, authorised access to raw data for staff performance checking activities; it also requires 70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

user access rights that prevent data amendments, as well as automated data capture systems. Below are some of the pitfalls pharmaceutical manufacturers should keep in mind. Audit Trails The pharmaceutical industry has been slowly transitioning from manual paper records to often automated, electronic records. Batch records predominantly take an electronic form today, but other systems, including production processes, such as start-ups, changeovers, running documentation and sampling, are not always digitalised. Although paper records can work well for some companies, they leave more room for human error and data manipulation than their electronic counterparts. The true benefits of digital records become obvious when companies use reliable HMI/SCADA software that automatically records the actions each user carries out. The software also makes data manipulation impossible; once a user inputs data, the action is saved automatically. If the input is wrong, the system records the error and the user is required to leave a comment in order to continue with production. Another advantage of using HMI software for electronic records is that the system can be set up so that the user can’t start or finish a batch without filling in a minimal amount of information. This means there are no more gaps in the records, which in turn improves data accuracy. Finally, HMI/SCADA software can automatically log any critical event and allows users to set alarms or notifications should any of the pre-defined values exceed set parameters. This ensures that any deviation in the process is identified in real time, automatically shared with relevant members of staff and recorded for the audit trails.

For critical data entered manually, there should be an additional check on the accuracy of the data. This check may be done by a second operator or by validated electronic means. The criticality and the potential consequences of erroneous or incorrectly entered data should be covered by risk management. There are several possibilities to achieve this. For example, users can set variable limit values, which can then be used to determine the severity of the limit, such as “for information only”, “warning”, or “violation”. These limit values can be predefined or dynamic, giving the possibility to have them either set by recipes or calculated. When a limit is violated in addition to the usual audit-trail and alarm possibilities, additional real-time functions can be called. This function can be a pop-up screen informing the user that a violation has taken place, giving the possibility to correct a mistake and ensuring the user inserts a comment on the event. A second authorisation can be configured to always request an additional person to authorise the change of a value or execute a function, such as a “batch accept”. This process further ensures data accuracy. The Login Dilemma One of the best ways to guarantee data integrity is to assign individual logins on a per user basis. There are several ways of achieving this; a common method is to assign each operator an individual username and password. Other secure reliable methods could be using active directory logins, or personal cards with a scannable bar code. With individual user login enabled, the system can record any action or change made by an operator, thus offering a clear picture of the overall process. Spring 2017 Volume 9 Issue 1


Manufacturing Individual logins also increase a system's security at no additional costs, as they allow a company to attribute different authorisation levels to users. Data Safety Another common concern of pharma companies is data safety – how does a manufacturer know its production data is safe and cannot be manipulated? By using reliable HMI/SCADA software, companies can help eliminate this issue. Computerised systems exchanging data electronically with other systems should include appropriate built-in checks for the correct and secure entry and processing of data in order to minimise the risks. When exporting archives to an external database, there are internal mechanisms that check during the transfer that the data has been correctly and completely transferred. If the transfer fails for some reason, the software will automatically resend the transfer next time it starts a cycle, so data is never lost or corrupted. When using the communication drivers to connect with PLCs, each variable has a status showing if the value has timed out, for example. The software will also log the incident chronologically in the events list.

restricted access to computer equipment and data storage areas. Some industrial automation software has integral user authorisation to enable a secure, closed system that requires users to uniquely identify themselves, using either an ID and password or using an external system to verify the person. Any logical control function or element which has user interaction can be limited with authorisation levels, which will restrict user access. For example, you could restrict access to certain screens, when modifying set-point values or accepting a batch. As a rule, pharmaceutical manufacturers should evaluate computerised systems periodically to confirm that they remain in a valid state and are compliant with cGMP. Such evaluations should include, where appropriate, the current range of functionality, deviation records, incidents, problems, upgrade history, performance, reliability, security and validation status reports. Conclusion The benefits of using electronic records in pharmaceutical manufacturing go beyond regulatory compliance. Looking to the future, companies who strive for continuous improvement can use electronic records to achieve this business goal. By integrating the HMI/SCADA software into a top-level ERP system, pharmaceutical manufacturers can identify potential areas for savings, such as a decrease in energy consumption and raw material wastage. Companies can go one step further and reduce, or even eliminate, unplanned downtime by applying predictive maintenance.

To ensure data safety, the software stores critical data such as audit trails and alarm lists in binary files – which are illegible to the human eye – in a proprietary format. Authorised users can modify data within the software, but the modification will always be logged in the audit trail. This practice ensures the archive is accessible, easy to read and accurate for authorised users, while also adding an additional layer of protection against unauthorised access.

It also allows manufacturers to free up the staff that traditionally record data manually and better employ their skills elsewhere in the business.

Physical and logical controls should be in place to restrict access to computerised systems. Suitable methods of preventing unauthorised entry to the system may include the use of keys, pass cards, personal codes with passwords, biometrics,

Digital records that guarantee data integrity and safety allow companies to breeze through regulatory compliance and focus on improving and growing their business, comfortably complying with the FDA and cGMP.

www.ipimediaworld.com

Lee Sullivan COPA-DATA develop zenon, a leader in its field of HMI/SCADA solutions. Compliant software that spans many industries, standards and pushes boundaries. Lee Sullivan is responsible for proactive management of the southern region of the UK, to generate business in-line with COPA-DATA Key Industries and maximize use of COPA-DATA products to define solutions that provide business benefit. Email: support@copadata.co.uk

INTERNATIONAL PHARMACEUTICAL INDUSTRY 71


Manufacturing

Antimicrobial Copper vs Antimicrobial Resistance The antimicrobial properties of copper have become widely known, harnessed by hospitals around the world in the form of touch surfaces that continuously reduce bioburden. Now, a potential role in combatting antimicrobial resistance is being proposed by researchers. This article describes some of the latest developments in antimicrobial copper, looking at new science, its growing inclusion in guidelines and ratings systems, and a high-profile installation at a leading London research facility.

First, a quick recap: copper is a powerful antimicrobial with broadspectrum efficacy against bacteria and viruses, and has been shown to rapidly destroy pathogens, including influenza A, E. coli and norovirus, and resistant bacteria such as MRSA. It shares this benefit with a range of copper alloys – including brasses and bronzes – forming a family of materials called ‘antimicrobial copper’. These familiar engineering materials perform their primary function – delivering hard-wearing surfaces that meet the demands of a busy clinical environment – with the additional benefit of continuously reducing bioburden and thus reducing the risk of infections spreading. An Additional Weapon in the Fight Against Antimicrobial Resistance Antimicrobial resistance (AMR) threatens the effective prevention and treatment of an ever-increasing range of infections caused by bacteria, parasites, viruses and fungi. Of these, antibiotic-resistant bacteria have the most serious implications for health. At the World Health Organization’s 68th World Health Assembly in May 2015, a global action plan 1 was endorsed for tackling antimicrobial resistance, including antibiotic resistance. It includes the prevention of infection as one of five strategies 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Infographic presenting the threat of AMR and antimicrobial copper’s potential to combat it

to tackle the global rise of AMR. If not stemmed, the WHO advises AMR could result in one death every three seconds by 2050. In September 2016, all 193 UN member states agreed to combat the proliferation of drug-resistant infections and reaffirmed their commitment to develop national action plans on AMR, based on the WHO's Global Action Plan on Antimicrobial Resistance. According to Dr Beth Bell, CDC Deputy Director for Infectious Diseases and Director of the Office of Infectious Diseases, infection prevention is the foundation of preventing antimicrobial resistance. Pathogenic bacteria can survive on standard environmental surfaces in healthcare facilities, leading to the risk of patients acquiring an infection. Reducing healthcareassociated infections reduces the need for antibiotics, which is another of the WHO’s five strategies. It is accepted that hand hygiene, and surface cleaning and disinfection, are standard measures to prevent and control healthcare-associated infections, but more needs to be done to prevent the spread of pathogens by staff, visitors and patients touching contaminated surfaces. What is not always appreciated is that bacteria

deposited and surviving on a surface can exchange genes – including those for antibiotic resistance – which can result in new, resistant strains. This process is called horizontal gene transfer. Professor Bill Keevil, Chair of Environmental Healthcare at the University of Southampton and member of the Network for AntiMicrobial Resistance and Infection Prevention (NAMRIP), is a leading expert on the hygienic properties of copper, and believes replacing frequently-touched surfaces with antimicrobial copper equivalents – teamed with good hygiene practices – could help address both the environmental spread of pathogens and the rise of antibiotic resistance. He explains: 'Our work2 has shown that antibiotic resistance genes are rapidly transferred from one superbug to another species on touch surfaces such as stainless steel, meaning that an infected traveller with poor hand hygiene can fly into an airport, touch various surfaces leaving his superbug behind and then another person from another part of the world can add their bacteria to the same surface to create an even greater superbug threat.

Spring 2017 Volume 9 Issue 1


Manufacturing are acquired outside ICUs. Here, 20 frequently-touched surfaces – in medical and surgical suite patient rooms, en-suite bathrooms and areas external to patient rooms 0150 – were replaced with antimicrobial copper equivalents. Both occupied and unoccupied rooms were studied to determine background bacterial concentrations.

Professor Bill Keevil stands by the efficacy of antimicrobial copper to reduce the spread of infection

'Cleaning these touch surfaces every hour is impracticable. This is where measures affording 24/7 protection become an important adjunct to regular cleaning. Indeed, our work has shown that copper alloys used for touch surfaces quickly kill bacteria, viruses and fungi, and just as importantly prevent antibiotic resistance gene transfer on touch surfaces. ‘The bacteria include the superbugs MRSA, C. difficile, Acinetobacter baumanii, extended spectrum betalactamase (ESBL) producing E. coli and carbapenamase producing Klebsiella pneumonia (KPC), which are now causing many outbreaks worldwide. The viruses include influenza, adenovirus, human coronavirus (a close relative of SARS and MERS) and the highly robust norovirus, which suggests that antimicrobial copper surfaces should be efficacious against Ebola and more.' Although cleaning and disinfection are more frequent and robust in healthcare settings than other areas, such as airports, the fact remains that they cannot happen often enough to completely eliminate the spread of bacteria, and the potential for horizontal gene transfer to occur. A different approach is needed to boost regular cleaning and hand hygiene, round the clock, and in hospital trials, antimicrobial copper surfaces have been found to harbour >80% less contamination than non-copper surfaces.3 A multi-centre ICU trial in the US further found the www.ipimediaworld.com

bioburden reduction was associated with a 58% reduction in infections.4 Researchers have concluded that the strategic deployment of antimicrobial copper touch surfaces can significantly and continuously reduce the number of microbes on surfaces, reduce the risk of transmission of infection and prevent the transfer of antibiotic resistance between bacterial species, providing an additional tool in infection control and the war on antimicrobial resistance. Maintaining ‘Terminal Clean’ Hygiene Levels New research that builds on the existing US trial data – published at the end of 2016 in the American Journal of Infection Control – reports antimicrobial copper touch surfaces installed in hospital patient rooms not only significantly reduced c o n c e n t rat i o n s o f b a c t e r i a , but sustained them at levels prescribed on completion of terminal cleaning. Grinnell College’s Associate Professor of Biology, Shannon Hinsa-Leasure, PhD, and her team conducted research over 18 months at Grinnell College and Grinnell Regional Medical Center (GRMC) in Iowa, with more than 1500 samples. The study found significantly fewer bacteria on copper alloy products – such as grab bars, toilet flushes, IV poles, switches, keyboards, sinks and dispensers – than on traditional, non-copper hospital room surfaces.5 The study notes more than half of all healthcare-associated infections

‘Even the most conscientious cleaning will not remove all bacteria cells from a surface, allowing for recolonisation,’ says Hinsa-Leasure. ‘To reduce the risk of patients acquiring an infection while in the hospital, we need to reduce the number of bacteria surrounding them. This is what makes copper so important: it is always working to destroy micro-organisms and will maintain a clean environment for patients.’ With weekly sampling over the course of 12 months, 88% of the samples collected from copper components in occupied areas were below the recommended terminal clean level (250 CFU/100 cm2). During the same period, 55% of control surfaces had burdens above this threshold. More surprisingly, in unoccupied rooms (given a terminal clean after the patient vacated), 51% of control samples were above the threshold. The observation that microbial populations are re-established on hospital surfaces subsequent to cleaning supported observations made in previous research.6 93% of the copper samples from unoccupied rooms were below the threshold. The researchers further noted most of the copper surfaces went unnoticed by patients, and concluded antimicrobial copper should become an important part of hospital infection control, working in concert with hand hygiene and daily and terminal cleaning. Copper in Guidelines and Ratings Systems As the evidence base for antimicrobial copper has grown and awareness becomes more widespread, it is being included in infection prevention INTERNATIONAL PHARMACEUTICAL INDUSTRY 73


Manufacturing and control guidance, healthcare accreditation schemes and green, hygienic and well building schemes. Some of these reach beyond the healthcare environment, highlighting where and how antimicrobial copper can be of benefit in many different building types. A few recent developments follow. Centrum Monitorowania Jakości w Ochronie Zdrowia (CMJ) is a government agency of Poland, re s p o n s i b l e fo r e n c o u ra g i n g healthcare facilities to improve the quality and efficacy of services and patient safety standards. It runs a national hospital accreditation programme.

Preventing Cross-contamination in Laboratory Settings The prestigious Francis Crick Institute research facility, in the heart of London’s Knowledge Quarter, has antimicrobial copper door furniture throughout its laboratory and high-traffic areas, including auditorium doors in the visitor area. In addition, antimicrobial copper handles and bathroom turns have been used for WC doors and storage cupboards throughout the building.

Most recently, in February 2017, Finland’s Building Information Foundation (RTS) issued its first guidelines on indoor environmental hygiene for new build and renovation projects across all building types. These establish four levels of hygiene, and various measures to deliver the required standard. Antimicrobial materials for high-touch surfaces are included in the three most stringent categories, and copper is singled out as the most recognised and effective antimicrobial material in the accompanying guidance. 74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

With research suggesting copper could play a role in curbing the rise of antimicrobial resistance, a n d i n c re a s i n g n u m b e rs o f recommendations in building guidelines and rating systems, its myriad colours and forms look set to become a familiar sight, boosting other hygiene measures and providing continuous protection against pathogens. REFERENCES

In late 2015, it was the first European health agency to recognise the use of antimicrobial copper touch surfaces as an infection prevention and control measure, awarding a higher accreditation score for hospitals that installed antimicrobial copper surfaces. On a global level, the WELL Building Standard™ is a new evidence-based system for measuring, certifying and monitoring the performance of building features that impact health and wellbeing – the first of its kind. High-touch surfaces made from ‘an abrasion-resistant, non-leaching material that meets EPA testing requirements for antimicrobial activity’ are an optimisation option for the two highest levels of the standard. Copper and more than 500 ‘antimicrobial copper’ alloys fulfil this requirement.

through the gold of brasses and the brown of bronzes, right up to a silver colour resembling stainless steel – these products are seeing more extensive use than ever, and offer some exciting benefits over other engineering materials.

Antimicrobial copper door furniture installed at Francis Crick Institute. Courtesy of Allgood.

David King, Senior Vice President at HOK – the architects that jointly designed the facility with PLP Architecture – observes, ‘The Francis Crick Institute is the largest and most advanced research facility of its kind in Europe, but science is constantly evolving and therefore requires a highly collaborative environment to facilitate scientific research. We are delighted that our holistic design solutions will aid the Crick’s aspiration of “discovery without boundaries”, helping to keep London and the UK at the forefront of innovative medical research.’ Conclusion With copper’s antimicrobial efficacy confirmed and now widely known, companies around the world offer a wide range of antimicrobial copper touch surface products, for use in hospitals and in the communities beyond, anywhere hygiene is of concern. Available in a range of colours – from the red of copper,

1.  Global Action Plan on Antimicrobial Resistance. World Health Organization. 2015. 2.  Horizontal Transfer of Antibiotic Resistance Genes on Abiotic Touch Surfaces: Implications for Public Health. SL Warnes, CJ Highmore and CW Keevil. mBio 2012, Vol. 3 No. 6 e00489-12. 3.  epic3: National EvidenceBased Guidelines for Preventing Healthcare-Associated Infections in NHS Hospitals in England. 4.  Copper Surfaces Reduce the Rate of Healthcare-Acquired Infections in the Intensive Care Unit. CD Salgado, KA Sepkowitz, JF John, JR Cantey, HH Attaway, KD Freeman, MG Schmidt. Infection Control and Hospital Epidemiology 2013, 34(5), 479–486. 5.  Copper alloy surfaces sustain terminal cleaning levels in a rural hospital. Shannon M. HinsaLeasure, Queenster Nartey, Justin Vaverka, Michael G. Schmidt. American Journal of Infection Control, 28 September 2016 6.  Intrinsic bacterial burden associated with intensive care unit hospital beds: Effects of disinfection on population recovery and mitigation of potential infection risk. Hubert H. Attaway III, Sarah Fairey, Lisa L. Steed, Cassandra D. Salgado, Harold T. Michels, Michael G. Schmidt. American Journal of Infection Control, December 2012, Volume 40, Issue 10, Pages 907–912. Spring 2017 Volume 9 Issue 1


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Manufacturing

Simplified Bioprocess Setup through Automated Process Control Learning to use a bioprocess controller is a complex and often intimidating endeavour for the beginner. Indeed, even with previous bioprocess experience, moving to a new software platform can entail much learning and reduce efficiency. Although many textbooks and manuals exist on the subject, they are no substitute for hands-on experience. Automated process control can help users, who are less familiar with bioreactors and fermentors, to achieve quick and easy initial culture success.

Successful bioprocessing requires the monitoring and control of environmental parameters, like temperature, pH, and dissolved oxygen (DO). The ideal setpoints for these parameters depend in large part on the cultivated cell line or microbial strain. Setting up control loops to maintain the actual process values close to their setpoints can be complex, because various factors have to be taken into account. As an example, let’s look at the control of DO in the culture. Oxygen transfer to the medium is influenced by different variables, like the agitation speed, the gas flow rate, and the oxygen concentration in the gas mixture. All these parameters can be varied to keep the actual DO concentration in the culture broth at the setpoint. How this is done best depends on the respective bioprocess. For microbial cultures, researchers often apply a cascade that first increases the agitation speed before raising gas flow rate and oxygen concentration. In contrast, this strategy might not be the best choice for the cultivation of shear-sensitive eukaryotic cells. Here a DO control strategy, that keeps the agitation speed low and as a result minimises shear stress, will lead to better culture results. And it becomes more complex, because to optimise agitation speed and gassing conditions, further factors like the vessel type and size and the impeller type and number have to be taken into consideration. 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

This is where automated process control comes in. The idea is to build a control software that is equipped with tried and tested setpoints and control loops for different applications and vessel types. Using these, the researcher can get started quickly and achieve initial culture success easily. To further optimise the bioprocess, setpoints and modes of operation can then be adjusted and optimised. The Auto Culture modes of the BioFlo® 120 bioprocess control station offer automatic process control for some of the most common microbial (E. coli) and mammalian (Chinese Hamster Ovary, CHO) cultures. When activated, process control loop modes and setpoints are automatically turned on and populated with values recommended by our experienced applications development team. In this article we give an overview on the settings and parameters of the Auto Culture mode for the cultivation of E. coli and show the results of a test batch fermentation. Material and Methods Inoculum Preparations We used an E. coli strain (ATCC® 259–22GFP TM ) which produces green fluorescent protein (GFP). The inoculum and fermentation medium was Terrific Broth (TB), prepared as described previously.1 We prepared the inoculum by inoculating two 1 L baffled shake flasks (VWR ®, USA), each containing 200 mL of TB medium, using a frozen vial from a mini cell bank.2 The flasks were then incubated overnight at 37 °C and 200 rpm in an Eppendorf Innova® 44 shaker. Fermentation Starting the automatically controlled process involved three steps: 1. Preparation of the control station We selected the correct vessel size

and type from the list of available choices in the bioprocess control software. For the experiment, a 2L autoclavable, heat-blanketed, directdrive vessel was selected. We calibrated the gel-filled pH sensor according to standard protocol using pH 7 and pH 4 buffers. We calibrated the pumps per the protocol outlined in the BioFlo 120 operating manual. The BioFlo 120 used in this experiment had the hardware configuration shown in Table 1. 2. Vessel preparation We added 2 L of TB medium to the fermentor before sterilising the vessel. We calibrated the DO sensor according to the protocol outlined in the BioFlo 120 operating manual. A sterile bottle containing 25 % (v/v) ammonium hydroxide was connected to a liquid addition port for pH control. The tubing was connected to pump 1, which served as the base pump. Acid was not connected for this experiment. If the user desires, an acid bottle can be connected through pump 2. Auto Culture pH control would call for base from pump 1 and acid from pump 2, as needed. Finally, the vessel was inoculated with 100 mL of the inoculum (5 % of the initial working volume). 3. Culture start To begin the culture, the Auto Culture mode for E. coli was started in the software. After confirming that the sensors were calibrated, the process began when all the relevant control loop modes were automatically changed to the appropriate state. The setpoints for each control loop were autopopulated as outlined in Table 2. Sampling and Monitoring the Fermentation The fermentor was monitored offline by taking a 5 mL sample hourly using Spring 2017 Volume 9 Issue 1


Manufacturing each control loop on the summary screen, CSC (Cascade) indicates that the control loop is involved in a user-defined automatic control algorithm. The maximum gas flow rate is set to 1 Vessel Volume per Minute (VVM) as had been determined sufficient in previous experiments3

Table 1: BioFlo 120 hardware configuration

the swabable Luer Lock port. Cell growth was monitored by offline measurement of the OD 600 value with an Eppendorf BioSpectrometer® kinetic photometer. To measure GFP production, a Bacterial Cell Lysis Kit (GoldBio®, USA) was employed to release the GFP from the cells into the supernatant. The GFP yield was then quantified using an Eppendorf BioSpectrometer fluorescence photometer. DO Control During Fermentation Since oxygen supply is often the critical limiting factor during fermentation, care was taken to ensure that the Auto Culture mode responds to culture demand appropriately. Usually, user-defined cascades for DO control that adjust the agitation speed, gas flow, and oxygen concentration are established over time, after optimisation of a process by the scientist. In the Auto Culture mode, a tested

cascade is provided for every vessel configuration and automatically populated and activated when Auto Culture is initiated. This DO control cascade is shown in Figure 1 for the 2L autoclavable vessel used at maximum working volume. For

The control loops that are enabled in the DO cascade operate in series, resulting in the first loop (in this case, agitation) reaching maximum setpoint before the next control loop (in this case, gas flow) responds. Therefore, in this experiment, agitation will increase to a maximum of 1200 rpm to attempt to maintain DO at setpoint before gas flow will begin to increase from a minimum of 0 SLPM to a maximum of 2.2 SLPM.

Figure 1: BioFlo 120 Auto Culture mode DO cascade for the current configuration. For each vessel type, the maximum flow rate is adjusted to 1 VVM, while the other setpoints remain unchanged.

By the time the cascade is completely executed, agitation reaches 1200 rpm, gas flow reaches 2.2 SLPM, and O2 as a percentage of total flow reaches 100 %. All of this occurs automatically, without user intervention.

Table 2: E. coli Auto Culture mode setpoints and loop modes which are populated upon start. Loop setpoints listed as “Auto” are determined by the DO control cascade. *Maximum flow rate is determined upon pump calibration. www.ipimediaworld.com

Results and Discussion The batch E. coli fermentation using a GFP-expressing strain in Auto Culture mode was completed successfully. As shown in Figure 2, within 6 h, the OD600 value reached 14 and the GFP production was 650 relative fluorescence units/mL (Figure 2). Since a batch culture protocol does not include nutrient or carbon source addition, nutrients were depleted and the culture entered stationary INTERNATIONAL PHARMACEUTICAL INDUSTRY 77


Manufacturing

Figure 2: E. coli growth curve and GFP production yields. RFU: Relative fluorescence units

phase around 7 hours, and we ended the experiment. The growth curve is typical for a batch fermentation and provides necessary strain characterisation information to begin designing a fed-batch or continuous bioprocess. Auto Culture mode allows for the optimisation of parameters based on experimental need, with the option to save a new custom recipe, which is then available in the Auto Culture menu for future use. Each time a new production strain is developed, the batch culture allows the scientist to determine the appropriate

Kevin Voll

growth parameters. In this case, our GFP-expressing strain grew satisfactorily at 37˚C and at pH 7.0. If, on the other hand, the experiment had required a custom temperature or other setpoint, those changes could be made at any time. When the experiment is finished and the ideal setpoints determined, the recipe can be saved as a custom Auto Culture mode available to be automatically employed just like the pre-loaded E. coli template. In this way, the number of available Auto Culture modes grow with experience, allowing for the creation of a library of custom recipes. REFERENCES 1. Terrific Broth. Cold Spring Harbor Protocols 2006. 2006(1): pdb rec8620. 2. Li, B. and Sha, M. Scale-up of Escherichia coli fermentation from small scale to pilot scale using Eppendorf fermentation systems. Eppendorf Application Note 306. 2016. 3. Li, B., Willard, S. and Sha, M. High cell density fermentation of Escherichia coli using the New Brunswick™ BioFlo® 115. Eppendorf Application Note 335. 2014.

Ishwarya Pabbathi

Bin Li

Eppendorf Inc., Enfield, USA Product Manager for Bioprocessing products at Eppendorf. He has previously worked within the field of pharmaceutical manufacturing before moving to Eppendorf. Kevin has eight years of experience of product management and service for Eppendorf bioprocess equipment.

Software engineer at Eppendorf Manufacturing Corp. She was jointly responsible for the implementation of the Auto Culture modes into the Eppendorf bioprocess software. Ishwarya completed her Masters at the University of New Haven in Connecticut and graduated with a major in computer engineering.

Eppendorf Inc., Enfield, USA Bioengineer at Eppendorf Inc. There he tests new bioreactors and develops and optimises bioprocess protocols. Before moving to Eppendorf he worked at Green Biologics, Inc. He earned his PhD from University of Toledo in the field of Bioengineering.

Stacey Willard

Ulrike Becken

Eppendorf Inc., Enfield, USA Director of Technical Applications at Eppendorf Inc. Among other responsibilities, he heads the Application Development Team in Enfield, whose experience and expertise led to the new Auto Culture modes. Ma received his PhD of Biochemistry from the City University of New York and conducted extensive postdoctoral research at The Rockefeller University and at Harvard University Medical School. Ma has over 20 years of experience in the field of biological sciences, including cell culture and fermentation process development.

Eppendorf Inc., Enfield, USA Senior technical application specialist. Stacey has over 15 years' experience in cell culture applications in both academia and industry. After her postdoctoral work at Johns Hopkins Medical School, she spent time at a startup drug discovery company and a large cancer institute before joining Eppendorf. As part of the Global Bioprocess Applications team at Eppendorf, she specialises in high-level problem-solving for customers, training, and product development.

78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Eppendorf AG Bioprocess Center, Juelich, Germany. Scientific Communication Manager at the Eppendorf AG Bioprocess Center in Juelich, Germany. Amongst others she is responsible for authoring application notes in cooperation with customers and the Eppendorf Applications Team. Ulrike earned her PhD from the RheinischeFriedrich-Wilhelms University, Bonn, in the field of cell biology. becken.u@eppendorf.com

Ma Sha

Spring 2017 Volume 9 Issue 1


Leading you through the process We engineer solutions to suit your process requirements, from laboratory and R&D, up to production scale.

All NEW

Exclusive! Technical Presentation at Interphex: TAKING VIRTUAL REALITY TO REALITY Presented by process expert Michelle Frisch. Tue. March 21, 2017 4pm to 5pm


Packaging

Innovative Glass Production for Pharmaceutical Packaging Why is glass still the first choice of primary packaging for most pharmaceuticals today and how much high-tech do you need to manufacture a glass container that has good filling properties and keeps the content safe? IPI Media director, Anthony Stewart, visits Gerresheimer`s pharmaceutical glass facilities in Lohr and Wertheim, Germany and learns about the production of moulded glass and ampoules.

According to recent surveys, when it comes to pharmaceuticals, glass packaging is still the first choice for most drugs, reveals Jens Kuerten, Director Communication and Marketing at Gerresheimer. He explains that the reason Gerresheimer is one of the market leaders in America, Asia and Europe is because pharmaceutical glass packaging development and production is one of its traditional specialist fields. The actual moulding process starts off with a simple “gob” of glass, a hot lump of molten glass. To make the molten glass, quartz sand is mixed with limestone and soda ash and melted in a furnace at around 1500°C to obtain a homogenous mixture. “Glass is still made of the three raw materials of sand, soda and lime, as well as the used glass cullet which is added to the batch. This was actually the first method of recycling ever to be introduced,” points out Andreas Kohl, Senior Plant Director at Gerresheimer Lohr. But, other than that, everything has changed at the present day, ultra-modern plant Gerresheimer Lohr. At Gerresheimer Lohr, one of the most innovative plants in the Gerresheimer Group, production runs in continuous 24/7 operation with modern IS machines and sophisticated melting equipment. Today`s glass process engineers work with stateof-the-art machines and even batchmixing is computer-controlled. 80 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Around 1 billion units of type III glass in different colours, designs and filling capacities are manufactured at the Lohr facility every year. Tablet jars, syrup bottles, dropper bottles and acid-resistant chemical bottles; the moulded glass range includes some 600 different articles ranging in size from 3ml to 4l for the pharmaceuticals. Gerresheimer Lohr today heats up its melting furnace with eco-friendly natural gas, says Kohl, using an ultra-modern electrical filter system for dust and sulphur flue gases in both furnaces, which also contributes to keeping the environment clean. The plant has two regenerative furnaces and nine IS machines. The production lines for pharmaceutical glass products leads into a certified cleanroom (ISO class 8, ISO 14644-1 certified) that conforms to the pharmaceutical requirements. In the cleanroom, which is next to the hot end of the production facility, the air is automatically exchanged 35 times an hour and cleaned with state-of-the-art high-performance filters. At the cold end, each single product is inspected in a fully automated process. State-of-the-art visual inspection systems take up to 12 images of each product for computer analysis. The pharmaceutical bottles are packed in a vacuum method and hermetically sealed with Safepack machines for contamination-free delivery to the filler. Frank Egert, Vice President of Moulded Glass sales in Europe at Gerresheimer Lohr is keen to stress “Gerresheimer is responsible for ensuring the safety and reliability of every single one of its pharmaceutical packaging products when they are used by patients. Every product is inspected in a fully automated process with state-ofthe-art inspection equipment for all theoretically possible non-

conformities to specification. Questionable and defective products are rejected in this process, ensuring that only defect-free products are packaged for shipment to the customer.” The international pharmacopoeia categorise glass types that are used in pharmaceutical applications into different hydrolytic classes on the basis of resistance against the leaching of alkaline glass components, and Gerresheimer can supply the entire spectrum of different glass types, says Andreas Kohl. “Our customers want lightweight yet stable products and to meet their requirements we use simulation software that was especially developed for the moulded glass production process. It optimises the designs of the moulds and the moulding process by taking the entire chemical and physical parameters of the glass into account,” explains Philip Amrheim, New Product Development and Mould Design Manager at Lohr. In the past, lengthy empirical tests were necessary to achieve a stable production process. Today, simulation software performs the same task in a matter of minutes. “The simulation software shortens mould development time by up to 70%,” Amrheim adds. A finite element analysis (FEA) is a numerical method of calculating the stresses that the glass container will be exposed to, on the basis of product specifications.

Spring 2017 Volume 9 Issue 1


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 81


Packaging The results of the FEA help to eliminate weaknesses even before the product drawings are finished. A Zero-defect Production Strategy for a Demanding Market Around 700 million ampoules are manufactured in Wertheim every year. A type of primary packaging that allows the pharmaceutical drug to come into contact with only the inert and gas/vapour-impermeable material of glass, ampoules have been competing with vials (and increasingly also with pre-filled syringes) for quite some time now. However, completely tamper-proof ampoules are still the number one choice for primary packaging for injectables. “Although demand has slowed down for ampoules in developed nations, this trend is offset by clear growth in demand in the cost-sensitive growth markets of emerging countries,” states Lothar Haaf, General Manager of Gerresheimer Wertheim and Senior Product Manager for Ampoules in Europe Tubular Glass Converting. “Most ampoules are manufactured in accordance with the DIN ISO EN9187-1/2 standard in straightstem, funnel-type and sealed designs. All types can have various opening systems that make it easier to break off their tips. Each opening system is associated with specific ergonomic and particulate contamination characteristics and the most popular opening system today is the OPC (one point cut) system; it is very easy to control the break on OPC ampoules and glass particle contamination is very low,” states Haaf.

are being formed. An additional ammonium sulphate treatment inhibits alkali ion leaching, very important when the ampoules are being used as primary packaging for sensitive pharmaceutical formulations. Also, a silicone coating is often applied to the inside surface of the ampoule to make it hydrophobic. This prevents high-viscosity products from sticking to the surface and allows the entire contents to be emptied out. Ampoules are manufactured from thin-walled type I borosilicate glass and high-quality, precisedimensioned glass tubing with a low incidence of cosmetic defects is essential to the manufacturing of defect-free ampoules. Laboratory tests involving the destruction of the products are regularly performed on random samples taken from the production lines. They serve to check ampoule break force in the opening process, for instance. The hydrolytic resistance of the ampoule`s inside surface is also tested in the lab. Gerresheimer`s optimised process control enables it to manufacture ampoules with hydrolytic resistance values that are between 30 and 50% lower than the values stipulated in the ISO standard. Total Quality Control Every ampoule manufactured is inspected in detail by automated camera systems before the packaging process takes place. They are rotated in front of the camera to ensure that non-conformities and defects can be detected on the ampoules` entire surface area. “Advanced image processing technology not only ensures uncompromising quality,

but also improves production process efficiency by substantially reducing the number of false rejects,” explains Dr Volker Rekowski, Quality Director Europe & India Tubular Glass Converting. According to Rekowski, the inspections cover up to 28 different parameters, including the compliance to specification of all exterior dimensions, the correct positioning of the code rings, the OPC dot and the break ring. “To exclude the risk of the wrong products being filled into the ampoules, an increasing number of customers are having their own inspection equipment on the production lines to check code ring colour combinations. The length of the score on OPC ampoules is also checked, because this information can be used to calculate its depth and whether the break-force conforms to specification.” No doubt, one of the most important prerequisites for high production quality is the highly automated production and inspection processes. The elimination of human intervention in production processes, other than in exceptional circumstances, also eliminates a key source of defects. “Medical technology products quite rightly have to meet steadily increasing quality requirements. Gerresheimer`s quality management system drives for defect-free products following a product by process. Nevertheless, in case of any internal deviation, the 100% inspection is our safeguard to guarantee pharmaceutical requirements and satisfy our consumers,” says Rekowski.

At Wertheim, customised packaging solutions are available for pharmaceutical drugs with challenging requirements: dimensions and glass quality can be tailored to the specific requirements of the drug itself and to the filling process. For example, the hydrolytic resistance of the glass can be increased by controlling the temperature when the ampoules 82 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Spring 2017 Volume 9 Issue 1


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Packaging

The Advent of Patient-Centricity: What does it actually mean? There is a lot of buzz in the pharmaceutical and healthcare industry right now around the concept of ‘patient-centricity’. The term can mean many different things to a lot of different factions within the healthcare space. With high-profile headlines about drug pricing in the market, the industry is coming around to the enlightening thought that it ought to be more overtly focused on the patient. This is now borne out in many facets of the business.

Pipeline development is one leading indicator of where the industry’s focus resides. Market factors have driven pharmaceutical and biotech companies to pursue therapies in increasingly specialised therapeutic areas. With the advent of priority review programmes by the FDA, companies are increasingly focusing on areas such as oncology, as well as diseases where there is long-standing unmet or underserved need. These areas are attractive for pharmaceutical companies due to the expedited and largely assured regulatory approval, as well as attractive premium pricing and patent protection. It is interesting to follow the role of patient advocacy groups for these rare diseases. This was evidenced recently in the approval of a prominent muscular dystrophy drug, where patient testimony seemingly played a substantial role in the ultimate approval of the drug, despite reservations from the FDA review panel regarding its perceived effectiveness. Regardless of one’s perspective, it was clearly a win for the patients who, up until that point, faced no currently available treatment and potentially life-limiting prospects. Drug delivery In the drug development space, we are seeing patient-centricity borne out in formulation development and drug delivery. For oral solid delivery forms, the advent of more patientfriendly technologies can offer a more 84 INTERNATIONAL PHARMACEUTICAL INDUSTRY

palatable, increasingly biologicallyeffective and better, faster-acting product. Technologies such as soft gels, liquid gels and liquid-filled capsules, rapid release or quick dissolve formulations, dissolvable thin strips, as well as multilayered or multiformulated tablets for drug combinations to reduce pill burden, all bring smarter and more consumerfriendly solutions to the patient. For parenteral delivery forms, we are seeing increasing technologies to reduce the complexity of drug delivery. Traditional vials and syringes are making way for advanced prefilled syringes with refined safety technologies, as well as the advance of highly-engineered and even multi-use autoinjectors. Further developments are seen in topical deliveries, transdermal technologies, inhaled therapies and even discreet wearable infusions and electronics. As a shining example, while it took many years and considerable persistence to reach the market, the novelty and convenience of MannKind’s Afrezza® inhaled insulin product has brought a significant step-change for patients suffering from diabetes.

Packaging focus Integral to drug delivery is drug packaging. Often maligned due to the encumbrance brought on by the need for child-resistant protections, drug companies have made considerable strides in commercialising medicines with more patient-centric approaches to the packaging that delivers the therapy. Providing patients with medicines that are packaged not only for protection, but also for discretion and convenience, is a notable turning point for the industry. The FDA has helped inch the industry along with its requirements for human factors studies, forcing companies to take the time and effort to engage focus groups and ensure the voice of the customer is reflected in the ultimate packaging. Patient compliance and adherence is another element of patientcentricity that is an increasing area of focus for the industry. Holistic adherence programmes engage patients in a variety of ways, such as patient enrolment and support p ro g ra m m e s ; p hys i c i a n a n d pharmacist engagement; followon remote monitoring; nursing Spring 2017 Volume 9 Issue 1


Packaging

engagement and intervention; patient education; and many other touchpoints to encourage positive health outcomes. Within the packaging segment, published studies have identified that simple unit dose calendarisation has considerable impact on both patient adherence as well as persistence, supporting patients to take medication consistently and effectively, engendering patient behaviours - resulting in staying on therapy longer and reducing fall-off. Increasingly, pharmaceutical companies are leveraging this methodology and also addressing other elements of non-adherence through packaging. For example, incorporating tools for cost mitigation and reimbursement instruction; patient education and disease state education; side-effect education, lifestyle tips; goal-setting tools; and many others in a coordinated adherence strategy that leverages packaging as the primary ‘direct-topatient’ channel. Such patient-centric design is evidenced in the Vertex Pharmaceuticals Orkambi® Cystic Fibrosis treatment, a recipient of the Healthcare Compliance Packaging Council’s (HCPC) Compliance Package of the Year award in 2016. Considerable research and patient feedback helped guide the development and commercialisation of the product and its outstanding packaging, www.ipimediaworld.com

clearly reflected in the consumerfriendly design. Patient-centricity in clinical study For many years, industry focus in clinical trials was concentrated all around the data. As the industry has evolved, so has the realisation that the quality of the data is contingent upon the patient’s engagement with the investigational drug product. If the patient fails to take the medication properly, ultimately the success of the drug product is compromised and generates false or unusable trial data. Worse yet, non-adherent patients are lost, at significant expense to financial and

trial duration goals. Increasingly, sponsor companies are utilising packaging and adjacent technologies to facilitate patient engagement and feedback, in addition to spurring effective adherence, ultimately leading to better data capture and analysis. Specifically for packaging, sponsor companies are opting not to take the traditional ‘just throw it in a bottle’ approach, but devoting the resource to develop packaging that helps facilitate a positive user experience and supports patient adherence.This may actually include packaging that captures information about when patients dose their medication, or may even potentially provide some level of interactivity, such as a prompt to the patient to take their medication; prompt for a response as to how they feel or what they are experiencing; or further connecting the patient to interactive communication tools as part of the study. Similarly, the structure of the study itself may be more patientcentric in its logistical approach. As the name implies, direct-to-patient studies offer a way to engage study participants and reduce the burden for participants to travel frequently to clinics. These new logistical models provide a different dynamic to bring focus to the patients, their needs and lifestyle realities, and ultimately a better and more effective treatment.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 85


Packaging Technologies such as these can d r i v e v e r y p o s i t i v e p at i e n t behaviours – including diet and exercise, adherence to medication, real-time health monitoring and potentially data-sharing if incentivised by healthcare providers, employers and insurers. Continued development in virtual reality or augmented reality opens a whole new horizon for people to manage their health, if done in a way that demonstrates value to them as the patient.

Anti-counterfeiting and supply chain security In the developed world, patients rarely ponder whether they are receiving authentic or unadulterated medicines. However, in less developed countries, the reality of receiving ineffective, improper or even harmful medicines can be a daily reality. Studies have demonstrated that in some Latin American or African countries, counterfeit medicines can comprise an estimated 30-70 per cent of the supply. This has led to the need for new authentication technologies to assure everyday patients that they can be confident in the medicines they are taking, increasingly leveraging the prominent use of cellular connectivity. In the United States and Europe, major effort has been made to provide serialised medicines that in principle should help authenticate the security of the pharmaceutical supply chain. Technologies are being implemented to provide registered data that can be monitored and verified. Furthermore, anti-counterfeiting technologies contained within the packaging help provide a robust and multilayered strategic approach to ensuring that the drug and its packaging are authentic and also not adulterated. These initiatives will provide a foundation for extending product assurance to emerging markets and developing countries in a patientfocused approach. 86 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The future of patient-centricity With the rapid advances in consumer technology, one has to wonder how these breakthroughs will find their way into the healthcare continuum in a way that is truly patient-centric. Published news has shown promise in interesting applications such as smart pills, providing real-time information as they travel through the body. Technologies such as these may not be patient-centric in the eyes of some people, however, who may find the idea of ingesting a small robot disturbing. Conversely, the broad appeal of Fitbit-style technologies and Apple smartwatches demonstrate that health technology can be engaging to the patient when it has a perceived value or benefit to them.

It’s about the patient What is clear is that when companies take a measured and focused approach to understanding patient's their needs and circumstances, positive outcomes are realised. The industry is changing and we should be encouraged by its focus on driving positive and sustained change towards a patient-centric outcome.

Justin Schroeder Executive Director, Marketing, Business Development & Design at PCI Pharma Services. Mr Schroeder is responsible for new account development, global marketing, and creative package design with a focus on the development and commercialisation of unitdose and compliance-prompting packaging. He holds a Bachelor of Science from the School of Packaging at Michigan State University, and a Master of Business Administration in Marketing from Northern Illinois University. Mr Schroeder has been at PCI/Anderson since 2000, holding positions including Process Development / Packaging Engineer, Customer Project Manager, Director of Project Management and Planning, and most recently Senior Director, Marketing & Development Services. Previously, Mr Schroeder held package engineering positions with Hershey Foods Corp and at the J.M. Smucker Co. (Smucker’s). Mr Schroeder is a Certified Packaging Professional from the Institute of Packaging Professionals (IoPP) and is the Vice Chairman of the US Healthcare Compliance Packaging Council (HCPC). Email: justin.schroeder@pciservices.com

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 87


Packaging Ensuring a Carefully Designed and Executed Product Packaging Interaction Study for Concise, Cost-effective Evidence in Support of New Drug Product Development The U.S. Food and Drug Administration (FDA) Guidance for Industry document, ‘Container Closure Systems for Packaging Human Drugs and Biologics’, addresses the review and evaluation of packaging requirements. According to this document, each new drug application (NDA) or abbreviated new drug application (ANDA) should contain sufficient information to demonstrate that a proposed container closure system and its components are suitable for its intended use.1

There is a regulatory requirement for pharmaceutical companies to investigate the potential interaction between a dosage form and the primary closure and transfer system employed, hence comprehensive leachables and extractables studies are essential. In order to do this, it is becoming increasingly important to design and implement bespoke product packaging interaction (PPI) studies. The complexity of packaging materials and the advanced technological nature of medicinal products mean that interaction between container components and active pharmaceutical ingredients, excipients and solvents in dosage forms is more likely.2

A carefully designed and executed PPI study provides concise, costeffective evidence to support product efficacy and regulatory submissions. There are a limited number of guideline documents available to both the experienced and inexperienced practitioner in this field. However, there is still the potential to waste an extensive amount of resource, time and budget by putting in place an extractables and leachables (E&L) programme that is not fit-for-purpose. Getting this critical stage of the development programme correct is essential to ensure these pitfalls are avoided. Extractables and Leachables: E&Ls can affect stability, alter impurity profiles, inactivate the active ingredient, alter the smell, taste or colour of the product, and cause it to fail quality-control assays. Leachables are typically considered a sub-set of extractables, and it is important to distinguish between these two material groupings: • Extractables are chemical compounds that migrate from any product-contact material (including elastomeric, plastic, glass, stainless steel, or coating

components) when exposed to an appropriate solvent under exaggerated conditions of time and temperature. • Leachables are chemical compounds that migrate into a drug formulation from any product contact material as a result of direct contact under normal process conditions or accelerated storage conditions.

Any material in direct contact with a drug can potentially cause contamination through leaching. This change in the product’s composition can impact its safety and/or therapeutic effectiveness. Correctly assessing the potential sources of these compounds is vital to a development programme. Designing and implementing an E&L programme can save significant time and cost in development. Levels of Regulatory Concern The management and control of leachables is important to pharmaceutical and biotechnology/ biologic product manufacturers and regulatory authorities, as certain leachables that appear above specific concentrations can present

Figure 1: Examples of regulatory concerns for common classes of drug products 88 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Packaging safety concerns for patients and/or compatibility issues for drug product formulations. During the 1980s, the FDA began to formally and comprehensively address leachables in drug products, in light of instances of patient sensitivity induced by leachables and other related potential safety concerns. Since then, control of both E&Ls for packaging systems and final drug products has become an important part of pharmaceutical development and regulatory submissions for many dosage form types. This is particularly the case for those seen as relatively high risk for dosage form interaction with the packaging system, along with a relatively high safety risk related to the route of administration. The new chapters USP (1663) and (1664)3, 4 present frameworks for the assessment of E&Ls based on the recommendations of the Polymer Quality Research Institute5, a non-profit consortium working in collaboration with the pharmaceutical industry. A risk-based approach is taken in designing an E&L programme and consideration must initially be given to the formulation type and delivery platform, as this will determine the potential for leachables formation. Figure 1, above, summarises the levels of regulatory concern associated with various drug products.6 Products such as inhaled aerosols attract the greatest regulatory concern, due to their high potential to produce leachables combined with the risks associated with direct delivery of the drug product to the lungs. It is important to note that even low-risk dosage forms present a level of concern which requires an appropriate and considered approach to the assessment of leachables. Applications/Techniques for Consideration in Extractables and Leachables Studies Identification and quantification of E&Ls covers a broad range of extraction and analytical techniques. The scope of an E&L study includes understanding the materials of construction, which begins with an 90 INTERNATIONAL PHARMACEUTICAL INDUSTRY

extractable study. This is followed by the analysis of the drug product stored in the final delivery system. The overall aim is to detect and measure leachables present in the final drug product formulation and interpret the data with regard to safety risk based on total daily exposure and alerts for incompatibility. The totality of the extractable data will lead to the leachable analytical target profile. Leachable methods will often use the same techniques as those used for extractables. In most cases, the techniques need to be optimised to eliminate interferences and achieve appropriate sensitivities based on the exposure of the patient to the final drug product. Below are a number of study packages and associated techniques: Services •  Devise strategies for testing polymeric materials •  Full analysis of leachables and extractables on various delivery systems, including inhalers, injectables, blister packs and other medical devices •  Extractables screening, leachables monitoring •  Method development, validation and technology transfer of analytical methods for product testing and quality control •  Stability testing Techniques •  Solvent extraction including ultrasonication, microwave, ASE (automated solvent extraction), Soxhlet and Soxtect •  Gas chromatography (GC) coupled to mass spectrometry (MS) or flame ionisation (FID) detectors, also available with headspace injection •  High-performance liquid chromatography coupled to diode array UV detector and tandem mass spectrometry (HPLC-DAD- MS/MS) •  Spectroscopy with Fourier transform infrared (FT-IR) and nuclear magnetic resonance (NMR) •  Inorganic analysis with inductively coupled optical emission spectroscopy (ICPOES), inductively coupled plasma mass spectrometry (ICP-MS) and atomic absorption spectroscopy (AAS).

There are a wide range of sophisticated analytical technologies that can be employed for E&L testing. While all-purpose generic methods can be used as a starting point, methods such as these will not address all applications. Through an understanding of the materials and their intended use, the appropriate extraction and analytical methodologies can be selected. Product Packaging Interaction (PPI) Studies PPI studies are typically used in the consumer healthcare sector to provide a direct assessment of the potential impact of changes in product delivery and storage devices. These changes may involve substitution or modification of individual components, or the implementation of a completely new device. Packaging and combination product medical device components can also potentially be in direct contact with a patient's mouth, nasal passage, or other body tissues during normal administration of the final product. Devices include pump dispensers, laminate sachets and transdermal patches, among others. Patients are potentially exposed to chemical entities by direct contact from such components. Assessment of patient exposure in such direct contact scenarios is best accomplished with appropriate studies and protocols. PPI Study Protocol The PPI approach utilises a more pragmatic alternative to a full assessment of device extractables and associated leachables. The device components are subjected to a forced extraction, and the results of the analysis are then used to target potential leachables in product samples stored in the final packaging. In addition to the forced extraction of the device components, a PPI study introduces the idea of carrying out leachables testing under accelerated ageing conditions to determine which of the extractables detected actually impact on the final product. Typical product samples tested following this particular approach include toothpastes, mouthwash, ophthalmic Spring 2017 Volume 9 Issue 1


Packaging solutions, skin creams and topical products. The basic approach used for PPI-type studies includes the following aspects; • Forced extraction of device components using exaggerated conditions to characterise • Organic extractable compounds (non-volatile, semi-volatile and volatile) • Inorganic extractable species (ICHQ3D) • Analysis of final product formulation samples, including accelerated stability samples, for potential presence of identified device-related leachables • Analytical techniques employed • High-performance liquid chromatography coupled to diode array UV detector and tandem mass spectrometry (HPLC-DAD- MS/MS for the analysis of non-volatile organic components) • Inorganic analysis with inductively coupled plasma mass spectrometry (ICPMS), inductively coupled plasma optical emission spectroscopy (ICP-OES), and atomic absorption spectroscopy (AAS) for the quantification of elemental components • Gas chromatography (GC) coupled to mass spectrometry (MS) or flame ionisation detection (FID), also available with headspace (HS) injection (for the analysis of volatile and semi-volatile organic components).

Summary Due to increased regulatory pressure on pharmaceutical companies to investigate the potential interaction between a dosage form and the primary closure and transfer system employed, leachables and extractables studies are essential. PPI studies are implemented to provide supporting evidence of regulatory compliance. These studies are designed based on sound experimental design and a thorough knowledge of the relevant associated risk factors. Designing a fit for purpose approach to E&L testing to ensure compliance is a process that needs to strike a balance between sound science, prudent resource allocation and effective risk management, with an emphasis on patient safety. Consequently, sponsors are increasingly turning to specialist external service providers who are able to use their regulatory knowledge and extensive analytical expertise to design and implement a robust and defensible E&L testing programme. This includes pre-developed screening methodologies for the assessment of volatiles, semivolatiles, non-volatiles and inorganic extractable components, as well as validating methods specifically for use with a company’s product, following the extractables analysis. REFERENCES 1. FDA, 2002. Guidance for Industry - Container Closure Systems

2.

3.

4.

5.

6.

for Packaging Human Drugs and Biologics (Internet) http:// www.fda.gov/downloads/drugs/ ecomplianceregulatoryinformation/ guidances/ucm070553.pdf [Accessed 14/11/2016] World Health Organization (WHO), 2002. Guidelines on packaging for pharmaceutical products (Internet) http://apps.who.int/ medicinedocs/documents/ s19638en/s19638en.pdf [Accessed 14/11/2016] (1663) Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems (Internet) http://www.usp.org/ sites/default/files/usp_pdf/EN/ meetings/workshops/m7126.pdf [Accessed 14/11/2016] (1664) Assessment of Drug Product Leachables Associated (Internet) http://www.usp.org/ sites/default/files/usp_pdf/EN/ meetings/workshops/m7127.pdf [Accessed 14/11/2016] Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products: An Overview of the PQRI Recommendations Pharmaceutical Research April 2008, Volume 25, Issue 4, pp 727–739 FDA, 1999. Guidance for industry: container–closure systems for packaging human drugs and biologics. Rockville, MD: FDA.

Mike Ludlow Technical Study Manager for LGC’s CMC analytical services. Mike specialises in the area of extractables and leachable testing. Mike works with a team of scientists delivering high-quality analytical services to pharmaceutical clients, providing support to all stages of the drug development process. The team specialises in trace-level organic and inorganic analysis, with a primary focus on extractables and leachables testing of drug delivery systems, packaging and the characterisation of pharmaceutical impurities. Email: mike.ludlow@lgcgroup.com

www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 91


Exhibitions Previews and Reviews

20 Years of Innovation, Drug Delivery, and Pharma Packaging – A Review of Pharmapack 2017 This year was the 20th anniversary of Pharmapack Europe, which returned this past February to Paris. The event gathered a record 5290 pharma professionals and over 411 exhibiting companies from more than 100 countries. As well as present opportunities to meet new partners, attendees learnt about the industry trends and discussed the ideas of tomorrow.

Over the last 20 years, many of the developments and products that are beneficial to patients have had their origins in meetings that began at Pharmapack. The relationships that have been forged across national boundaries and cultures are integral to pushing forward drug delivery and packaging. Since the very first Pharmapack, a set of common values was established: innovation, education, and networking. Shared beliefs and a spirit of innovation have also remained core assets that mark Pharmapack out as being a truly unique event. Two decades later, these remain true as the community has changed and progressed, adding an exhibition, awards and new products to complement these themes. The 2017 conference programme was based on three sessions focused on ‘Innovation and Compliance’, ‘Patient Adherence: New challenges, New Oppor-tunities’, and ‘Impact on Patient Centricity and Biologics on Packaging and Device Development’. A special emphasis was placed on the emerging importance of the ‘human factor’ – which is defined as patient-centricity, adherence and/or compliance – particularly with the current trend of self-administered drugs. Central to the content platform too was Pharmapack’s Serialisation and Track & Trace symposium, which 92 INTERNATIONAL PHARMACEUTICAL INDUSTRY

outlined the industry’s efforts to overcome pharmaceutical counterfeiting, putting traceability solutions and serialisation strategies at the forefront of the agenda. With the impending deadline looming over manufacturers, a special session also provided guidance on the EU Falsified Medicine’s Directive. Additionally, the symposium featured case studies and practical examples of traceability application and compliance for attendees. Outside of the conference agenda, this year’s Pharmapack Europe also included a first-ever media debate (held on 1st February), with industry experts predicting future innovations to mark 20 years of the event. Pr. Philippe Arnaud (Hospital Bichat-Claude Bernard AP-HP), Dr Pascale Gauthier (Biopharmaceutical Department, Faculty of Pharmacy, Auvergne University), Lionel Jeannin (Device and Packaging Expert at Novartis), and Jean-Marc Bobee (Director Industrial Anticounterfeiting Strategy at Sanofi) shared their t h o u g h t s o n t h e i n d u s t r y ’s evolution in the past 20 years, and the upcoming trends. Chaired by Jim Chrzan (Group Publisher for Healthcare Packaging Magazine, PMMI), the debate discussed digital integration, packaging individualisation, medication/ device synergies and serialisation. All experts highlighted digital integration as a key development. According to Dr Gauthier, ‘technology is becoming more integrated with packaging, particularly as solutions move towards greater patientcentricity, in terms of screen integration, signal transmission and data-sharing’. Digital integration is also indispensible for packaging of cold chain biopharmaceuticals, helping maintain safety and enabling proper use and storage of products. Prof. Arnaud suggested that in order

to advance in the industry, we must look at the future of pharma packaging, both in terms of the environment and the patient population. Individualisation has been at the forefront of innovation, particularly with regard to small populations and the elderly. Innovation in packaging should also help maintain long-term compliance and adherence, with clear directions for patients about the dosage, adherence and the API. With device development being fast-tracked by many authorities, Mr Jeannin commented that the interaction between medication and devices is increasingly growing across the globe, with the United States FDA at the forefront of combination products. Europe is also experiencing development in this area, with what Mr Jeannin describes as ‘borderline products’ – either medical device or drug products, which can be embedded into medical devices. He added, “What is interesting is that the integration of human factor engineering has become a lot more advanced”. The experts argued that in the last 20 years lots of products have had issues with anti-counterfeiting and traceability in the increasingly complex supply chain. Mr Bobee stated packaging is the key element in the security for patients and products, with tamper-evidence now expected to be an essential requirement in the future. Authentication and secondary packaging will also be important, with traceability elements, such as the serial number, aiding anti-counterfeiting initiatives. Pharmapack Europe 2017 also saw the return of the Innovation Gallery and Innovation Tours, presenting the most innovative products in the pharma packaging and delivery device industry through dedicated guided tours. Another Pharmapack Spring 2017 Volume 9 Issue 1


Exhibitions Previews and Reviews first was the introduction of the new Pharmapack Start-up Hub – the newest addition to the show floor, which highlighted groundbreaking young pharma companies as the most innovative in the exhibition. Anne Schumacher, Brand Director at Pharmapack Europe, commented: “This year’s event was an amazing celebration of our industry, 20 years is a reason to proudly celebrate what we have achieved in this time. Innovation has been the driving force of both Pharmapack and the industry in the past two decades, moving the industry closer to patients, and increasing compliance and traceability. During the conference, we got a view on how the industry is synergising with the patient and looking to individualise packaging. With over 5290 attendees, Pharmapack is a community hub of pharma leaders, and many of the deals completed this week are the starting points for the developments of tomorrow.” A vital aspect of Pharmapack Europe, the Pharmapack Awards commemorated the most exciting innovations in the industry, choosing the best exhibitor innovations and health products – with the winners of both awards categories announced on February 1st during the prestigious Pharmapack 20-years party. In the Exhibitor Innovation category, the winners were: August Faller GmbH & Co. KG - Pharma Compliance Pack for “patient compliance”; EVEON Intuity®Ject for “ease of use and patient compliance”; Multi-Color Corporation – SMART Packaging Solution for “patient safety”; and Nemera – Safelia ® for “patientcentricity and customisation”. In the Health Product category two winners received recognition: Celgene’s OTEZLA (apremilast) Titrition Pack for their contribution to “patient compliance”, and Sanofi Pasteur & Campak for “Eco-Design” with the Compact Box. OTEZLA (apremilast) Titrition Pack by Celgene was recognised for its design that maximises patient compliance to titration-dosing schedule. Containing three different strengths of Otezla® www.ipimediaworld.com

pills (10mg, 20mg, 30mg) and easy to read and understand instructions, it promotes patient adherence and compliance to the Otezla® titration dosing regimen.

It also works with viscous drugs and can monitor batch numbers, date/time and volumes delivered – transmitting this information to patient or healthcare professional.

The Compact Box, created by the partnership of Sanofi Pasteur and Campak, simultaneously improves environmental footprint, customer convenience, supply chain costs and industrial performance. The breakthrough enables packaging volume to be reduced by 50% and eliminates the need for PVC blisters. Reduction is achieved through using continuous motion technology, and cold chain benefits include a 30% improvement in distribution costs.

Best Exhibitor Innovation for “Patient Safety”, the Multi-Color Corporation’s SMART Packaging Solution transforms standard packaging into effective, interactive touchpoints for use throughout the drug supply chain. This means you can communicate with various users, whilst also offering security and logistics management for traceability and tamper-evidence. The innovation includes copy proof QR code, NFC/ RFID technologies, proof of purchase and an analytics dashboard.

“The entire event is dedicated to innovation, from the products on the show floor through to the content sessions, but the awards provide international recognition and are very much the crowning glory of Pharmapack Europe each year. All the exhibitor awards’ finalists are featured in the Innovation Gallery and Innovation Tours. But beyond this, we also introduced the new Pharmapack Start-up Hub, to showcase the most cutting-edge early-stage innovations”; commented Schumacher. The Pharma Compliance Pack by August Faller GmbH & Co. received the Best Exhibitor Innovation for “Patient Compliance”. This unique innovation – which also features authenticity protection – guides the patient easily through the medication by incorporating perforated tabs, that are removed before a tablet is taken, meaning blisters can only be withdrawn in “portions”. As a result, the patient takes their medication at the right time, in the correct order, and in the prescribed amount – promoting much-improved treatment adherence.

Finally, Nemera’s Safelia ® was bestowed the award for Best Exhibitor Innovation for “Patientcentricity & Customisation”. An innovative autoinjector used for the delivery of 1ml and 2.25ml prefilled syringes, it is able to administer both high volumes and high viscosities through thinner needles. Providing automatic needle insertion, injection and needle retraction, Safelia® can be customised to specific patient cohorts and formulations – including the most difficult ones (viscous, fragile, non-Newtonian behaviour). The 20th year of Pharmapack brought insights into the most pressing issues in the industry and the future trends to expect in the coming years seeing digital integration, compliance, and above all, the importance of the ‘human factor’ as the key factors for the continued evolution of the industry. Pharmapack Europe will return to Paris Expo Porte de Versailles, hall 7.1 on 7th–8th February 2018.

Intuity®Ject by EVEON was selected as the Best Exhibitor Innovation for “Ease of Use & Patient Compliance”. This is an industry first; it’s the only fully automated injector that adapts to vials. The all-in-one platform provides automated preparation and administration, with a modular design to adapt to primary containers. INTERNATIONAL PHARMACEUTICAL INDUSTRY 93


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Eurofins BioPharma Product Testing

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LogiPharma

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Owen Mumford Ltd

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Powder Systems Limited (PSL)

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Research Quality Association Ltd

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Sartorius Stedim Biotech

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Sulzer Mixpac Ltd

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Therapure Biopharma Inc.

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TP3 Global Ltd

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va-Q-tec Ltd

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Valsteam ADCA

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Vetter Pharma International GmbH

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Wickham Laboratories Ltd

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World Courier

Volume 9 Issue 1 - Spring - 2017

Volume 9 Issue 1

International Pharmaceutical Industry

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

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MALDI Mass Spectrometry in Drug Discovery Gaining A Deeper Understanding

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Three Ways to Mitigate the Risk of

Late-Stage Failure in CNS Drug Development

Data

The Foundation of Clinical Trials www.ipimedia.com

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96 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Temperature Management Keep Your Cool

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Spring 2017 Volume 9 Issue 1


When it’s

YOUR

compound, every step matters.

www.pfizercentreone.com API www.ipimediaworld.com

STERILE INJECTABLES

HIGHLY POTENT SOLIDS

PC1-16-0005/R2-8x10.75in © 2016 Pfizer Inc. All rights reserved. Pfizer CentreOne is a Trademark of Pfizer Inc.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 97


Revolutionizing Automation Assembly - High Precision Dispensing - Quality Control

From standard products to fully customized systems, Ginolis offers an extensive range of production automation solutions for diagnostics and medical device manufacturing.

Ginolis Ltd Automaatiotie 1, 90460 Oulunsalo, Finland T +358 10 315 3600 E sales@ginolis.com

www.ginolis.com

IPI - Spring 2017  
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