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Volume 8 Issue 2

Peer Reviewed International Pharmaceutical Industry

Supporting the industry through communication

Regulatory Focus on Nanomedicines In US and Europe Data Driven Drug Pricing Technology Solutions that could Change the Paradigm MES Adoption in Pharmaceutical Manufacturing A Changing Landscape Serialisation The Bigger Picture

Contents 06 Editor’s Letter REGULATORY & MARKETPLACE

International Pharmaceutical Industry

Supporting the industry through communication

DIRECTORS: Martin Wright Mark A. Barker EDITOR: Orsolya Balogh EDITORIAL ASSISTANT Veronica Tomasiello BOOK MANAGER: Anthony Stewart BUSINESS DEVELOPMENT: John Donalds DESIGN DIRECTOR: Fiona Cleland CIRCULATION MANAGER: Dorothy Brooks FINANCE DEPARTMENT: Martin Wright RESEARCH & CIRCULATION: Heather Bayran COVER IMAGE: iStockphoto © PUBLISHED BY: Pharma Publications Unit J413, The Biscuit Factory Tower Bridge Business Complex 100 Clements Road, London SE16 4DG Tel: +44 (0)20 7237 2036 Fax: +44 (0)01 480 247 5316 Email: All rights reserved. No part of this publication may be reproduced, duplicated, stored in any retrieval system or transmitted in any form by any means without prior written permission of the Publishers. The next issue of IPI will be published in September 2016. ISSN No. International Pharmaceutical Industry ISSN 1755-4578. The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright. 2016 PHARMA PUBLICATIONS Volume 8 issue 2 - Summer - 2016

08 The NHS Must Invest in Order to Drive Efficencies The NHS needs to embrace technology for the management of medication and supplies throughout hospitals if it wants to realise the cost savings detailed in the recent Lord Carter report, and meet GS1 standards. Lord Carter’s report highlighted that in 2012/13, expenditure on hospital medicines showed a staggering 11% increase on the previous year, to £6.5 bn. Lord Carter believes that there are greater savings to be had by managing the demand for medicines via better inventory management systems. He went on to state that all trusts should have key digital information systems in place, fully integrated and utilised by October 2018. Paul O’Hanlon, Managing Director at Omnicell Ltd, UK & Ireland, shares his thoughts on the NHS. 12 Incorporating the Patient Perspective: The Critical Role of Human Factors and Usability in Improving Medication Adherence Although we may not always notice it, the products we use in our daily lives continually evolve as manufacturers keep a close eye on consumer behaviour. Typically, they’re constantly adjusting and improving those goods based on feedback from surveys, focus groups and, of course, online commentary and criticism. Chris Evans, Vice President, Global Innovation at West Pharmaceutical Services, highlights the critical role of human factors from the patient’s perspective. 16 The Great Brain Drain The life sciences industry is drowning beneath a sea of new regulations and directives. As well as being immensely demanding from a risk management perspective, the associated administration is detracting from core activities. Even basic administrative tasks, such as checking updates to labelling, consume hours of PhDqualified staff time – capacity firms cannot afford. This is having an effect on professionals’ morale. Organisations should take heed, or risk losing valued experts at a time when experienced regulatory and QA personnel are in short supply, warns Dr Jutta Hohenhörst of Schlafender Hase. 20 Adelaide is the Ideal Life Sciences Location Creating an attractive city for health and life sciences companies happens through executing a well-designed strategy backed by a clear vision. Global companies are now discovering Adelaide, a city which is being transformed into the ideal location for clinical trials, research and development, medtech manufacturing, and distributing in Asia. Marco Baccanti, Chief Executive at Health Industries South Australia, reflects on a specific area – Adelaide – and explains why this city is ideal for life sciences. DRUG DISCOVERY, DEVELOPMENT & DELIVERY 24 Regulatory Focus on Nanomedicines in US and Europe This article aims to produce an overview of nanotechnology and its drug delivery systems, as well as the regulatory approach for the approval of nanomedicines in regulated markets like the United States and Europe. The use of nanoscale technologies to design novel drug delivery systems and devices is a rapidly developing area that promises breakthrough advances in therapeutics and diagnostics. Nanomedicine is one area of nanotechnology, and the goal of nanomedicine is to provide the most effective treatment without side-effects. Vidhya Sabbella, Valluru Ravi, Prof. T. M. Pramod Kumar and Sreekanth Reddy Kaja at JSS College submit a new white paper on the regulatory focus on nanomedicines in the US And Europe. 28 Innovations in the PASS Concept Opening the Door to Real-world Data The role of data collected during post-marketing surveillance has recently been widely recognised as being of great value in terms of providing real-world evidences, as long as the credibility,


Contents quality and transparency of data is maintained. In parallel with the dynamic increase of requirements and challenges concerning PostAuthorisation Safety Studies planning, conduct and assessment, the European Medicines Agency offers flexibility and firm scientific assistance to marketing authorisation holders. Magdalena Matusiak, MPharm, Clinical Development Manager at KCR, focuses on the PASS concept. 32 Pre-fillable Syringes for the Biotechnological Requirements of the Present and Future Pre-fillable syringes are both pharmaceutical primary packaging and drug delivery devices. End users, drug administration agencies and the pharmaceutical industry are imposing increasingly stringent quality requirements on pre-fillable syringes in both these functions. Optimised production and inspection processes ensure that the syringes can meet these requirements. Although siliconisation is crucial as lubricant to the proper function of the plunger in the syringe body, it has to be reduced to the minimum in syringes used for innovative biotech drugs. Bernd Zeiß and Claudia Petersen at Gerresheimer look into the world of pre-fillable syringes. CLINICAL RESEARCH 40 Three ‘Ps’ for Implementing an Effective eCOA Strategy: People, Processes, and Plan Clinical scientists have proven that the collection of clinical outcome assessment data with an electronic device improves patient compliance and delivers higher quality and more reliable data. The value of electronic clinical outcome assessment data for clinical trial claims, post-marketing safety studies and patient registries has become increasingly recognised by various stakeholders, including regulatory authorities and health economics outcomes research experts. D. Eek, C. Hall, S. Hooper, F. Wald and M. Wurm at ERT. LABS AND LOGISTICS 44 Maintaining Cold Chain Integrity for Pharmaceutical Products Almost 30 per cent of scrapped sales at pharmaceutical companies can be attributed to logistics issues. As most medical and biological products require a temperature-controlled environment at all stages of manufacturing and distribution, the control of storage and transportation temperatures is vital in maintaining the quality and effectiveness of medicines and is critical for its manufacturers and for public health and patient safety. Essangui Mbaitjongue at Thermo King deals with cold chain integrity for pharmaceutical products. 48 Understanding How New Data Integrity Regulations Apply to Your GDP Temperature-controlled Pharmaceuticals The 2015 UK Data Integrity Guidance states raw data must be “legible and accessible, retained in the format in which it was originally generated, throughout the data lifecycle”. From a business perspective, we know that raw data generated in the supply chain is valuable to understanding its performance - if handled correctly. But how? It’s more efficient to ensure raw data is connected to the original data record, which can be done using a relational database. If you’re manually processing flat files, it can be resourceintensive to review numerous spreadsheets, for example, and more subject to error when archiving and storing paper records or flat files. Courtney Becker-James, Strategic Marketing Director at Elpro, helps to understand how new data integrity regulations apply to your GDP temperature-controlled pharmaceuticals.

this level of inefficiency can put patient safety at risk and increase pressure on healthcare professionals, and that the NHS wastes billions of pounds on these preventable errors. Glen Hodgson, Head of Healthcare at GS1 UK, draws up the vital role of standardisation for the NHS’s future. TECHNOLOGY 56 The Future is Bright for BYOD but is it Always the Best Approach? Technology is well and truly embedded within the lives of people of all ages, geographic locations and economic backgrounds, ultimately driven by the increasing sophistication and associated reduction in cost of using emerging technology for all kinds of applications. In line with this, the ownership and use of smartphones has become extensive - in fact, it is estimated that by the end of 2016, the number of smartphone users worldwide will exceed two billion. With increasingly tech-savvy consumers, the pharmaceutical industry has reached a point when it can finally begin to consider utilising the low-friction, rich, real-time data that can be captured using patients' own devices. Paul O'Donohoe, Director of Health Outcomes at CRF Health, answers the question: is BYOD always the best approach? 58 Data-driven Drug Pricing: Technology Solutions that could Change the Paradigm With the global pharmaceutical industry expected to be worth £800bn by 2020, the pressure is on to improve efficiency and decision-making in drug research. New drug pipelines are dwindling and the cost of failure is high. The estimated cost of taking a single drug to market is $350 million, and with regulatory agencies demanding more, larger and longer studies due to the increased desire for niche therapies, this figure is only going to increase further. Elliott Frodsham, Business Development and Operations Assistant at Datatrial, shares his thoughts on datadriven drug pricing. MANUFACTURING 62 Safe, Fast and Compliant: The Raman Advantage for Pharmaceutical Manufacturing The contamination or incorrect measurement of raw materials used in the manufacture of pharmaceutical and healthcare products poses a significant risk to patient safety. As a result, regulatory requirements for raw material identification and QA/ QC manufacturing process have become increasingly stringent and manufacturers are faced with the challenges of meeting these requirements while simultaneously trying to improve productivity, reduce costs and deliver innovative products to market. Suzanne Schreyer, Sr. Applications Scientist at Rigaku Analytical Devices, focuses on the Raman advantage for pharmaceutical manufacturing.

52 Standardisation is Vital for the Future of the NHS Standardisation can make a difference in healthcare. And while standardisation might not make headlines very often, what happens when it’s missing – especially in the NHS – often does. The pressure on the NHS to deliver more for less increases in line with the stories we hear about mistakes made in the operating rooms, mis-medication and the hours wasted looking for recalled devices, medicines or equipment. We hear time and time again that


Summer 2016 Volume 8 Issue 2


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Contents 66 MES Adoption in Pharmaceutical Manufacturing – A Changing Landscape Manufacturing execution system solutions have the potential to improve productivity and simplify compliance within the pharmaceutical manufacturing industry. However, factors such as cost and lack of specialist expertise have proven a barrier to many small and mid-sized pharmaceutical companies. Siobhan Fleming, Business Development Executive and Manufacturing Software Specialist at LZ Lifescience, discusses the role of MES solutions in the pharmaceutical sector, typical barriers to adoption and the increasing use of the technology as it becomes more accessible to a wider part of the industry. 68 Why is Good Tablet Design so Important and How Can it be Achieved? Detailed design of pharmaceutical and nutraceutical tablets is essential in order to produce robust tablets with bespoke designs. Tablet manufacturers should not overlook tablet design because it is key to the quality of the end product. Good tablet design is extremely important; it has an impact upon anti-counterfeiting, tooling strength, tablet coating, durability and functionality. Good tablet design helps to avoid downstream manufacturing problems such as tablet sticking, picking, lamination, capping and premature tooling failures. I Holland’s Product Design Manager, Steve Osborn explains why good tablet design is so important. 74 Cleaning and Coating: How to Overcome Challenges in Device Design and Manufacturing Cleaning and coating methods can significantly affect the consistency and quality of medical device performance. However, many design engineers and manufacturers are unaware of this fact. It’s important to keep in mind device cleaning and coating considerations at every stage of design and manufacturing for optimal performance once the device is in a doctor’s use. Read on for four of the top challenges and solutions design engineers and manufacturers experience regarding cleaning and coating during medical device production. Within this article, Jay Tourigny, Senior Vice President at MicroCare Medical, presents more information on cleaning and coating. PACKAGING 78 Serialisation – The Bigger Picture Preparing for all Requirements with a Scalable Machine and Software Concep Whether potency pills or even life-saving pharmaceuticals such as heparin – the trade in counterfeit medicine is still booming. Accordingly, drug producers and contract packers are shifting their focus to serialisation of pharmaceutical packaging. Time is pressing, as numerous laws and guidelines have already or will come into force all over the world in the coming years. Companies concerned are facing the challenge of finding and implementing appropriate technologies, and connecting them with their manufacturing and packaging processes. A scalable machine and software concept undoubtedly is the safest option. Daniel Sanwald of Bosch Packaging Technologies looks into the topic of serialisation. 82 The Key to Successful Design: Understanding the Patient’s Needs The key to delivering medicine to patients effectively is quite simple; effective design starts with the need to truly understand the patient’s needs. This declaration may seem provocative and overly simplistic. Of course we need to understand the patient’s needs. In the real world, packaging is often complicated, particularly packaging for medicinal products. There are complex and often conflicting factors such as shelf life and barrier property concerns, child-resistance requirements, the need to protect product in the distribution environment, factors for logistical cycle times, complexity from regulatory and labelling requirements, and most certainly cost pressures. Paul Smallman and Victor Gherden of PCI Pharma Services reflect on the patient’s needs.


Summer 2016 Volume 8 Issue 2





Editor's Letter The impact of the UK’s vote to leave the EU could have major implications for healthcare and the pharmaceutical industry. Not at least because it has conducted in a period of significant economic and political uncertainty at a time when the health system is facing huge operational and financial pressures. While the impact on healthand patient care services of leaving the EU is impossible to forecast, it is clear that a number of important issues will need to be resolved. Currently the European Medicines Agency (EMA) can grant pharmaceutical companies a single marketing authorisation, providing faster access to the whole of the EU market – half a billion potential patients. However, the main focus of this edition is not the poll results; our authors are still keen to inform the business about the industry’s newest trends, researches and developments. Nanomedicine is an area of nanotechnology, with the goal of providing the most effective treatment without side-effects. It is likely to have a wide impact on medical devices and medicinal products, with the potential for the development of new therapies, such as smaller implantable devices or improved dosing and targeting of medicines. IPI’s well known JSS College team from Mysore, India focuses on the

regulation of nanomedicines in the US and Europe. With the global pharmaceutical industry expected to be worth £800bn by 2020, the pressure is on to improve efficiency and decision-making in drug research. New drug pipelines are dwindling and the cost of failure is high. The estimated cost of taking a single drug to market is $350 million, and with regulatory agencies demanding more, larger and longer studies due to the increased desire for niche therapies, this figure is only going to increase further. Elliott Frodsham, Business Development and Operations Assistant at Datatrial, submits a white paper to the Technology topic of IPI Summer.

We are happy to welcome Bosch on board again. Within their article, they paint the bigger picture of serialisation, explaining the requirements for a scalable machine and software concept. Pharma Publication team wishes you a pleasant summer. We are all gearing up for CPHI/ICSE 2016 – Barcelona. Hope to meet all of you at the event. Orsolya Balogh Editor

Manufacturing execution system (MES) solutions have the potential to generate efficiencies, improve productivity, and simplify compliance within the medical device manufacturing industry. Used to manage production activities, this class of software typically provides the ability to schedule activity, deliver instructions to operators, synchronise manual activities with automated processes, and integrate with manufacturing computer systems to enable quality control, deviation management and effective enterprise resource planning (ERP), equipment management, and the documenting of floor activities for monitoring and reporting purposes. Siobhan Fleming, at LZ Lifesciences, explains MES adoption in pharmaceutical manufacturing.

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

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

Catherine Lund, Vice Chairman, OnQ Consulting

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

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

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

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

Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

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Regulatory & Marketplace

The NHS Must Invest in Order to Drive Efficiencies The NHS needs to embrace technology for the management of medication and supplies throughout hospitals if it wants to realise the cost savings detailed in the recent Lord Carter report and meet GS1 standards. Lord Carter’s report highlighted that in 2012/13, expenditure on hospital medicines was a staggering 11% increase on the previous year to £6.5 bn1. Lord Carter believes that there are greater savings to be had by managing the demand for medicines via better inventory management systems. He went on to state that all trusts should have key digital information systems in place, fully integrated and utilised by October 2018. He also highlighted that trusts spend around £9bn on procurement of goods and services, £6bn of which is spent by the acute sector2. Around a third of this is spent on medical consumables and a third on high-cost medical devices. The report stated that “very few trusts are able to demonstrate even a basic level of control or visibility over total inventory or purchase order compliance that is common practice in other health systems and industry sectors such as retail”. Lord Carter believes that there are greater savings to be had by managing the demand for products via better inventory management systems. It went on to suggest that a target saving of £700m to 1bn savings on the £9bn procurement spend was realistic. While some of the annual fiscal increases highlighted in the report can be attributed to an ageing population and advances in treatments, cost savings and efficiencies do need to be made to ensure a real, sustainable future for our prized NHS. At our company, we believe the answer lies in technology and automation, which will help to transform the way hospitals operate by driving down costs, maximising the time nurses and clinicians spend with patients and improving patient safety. Hospitals hold many weeks or even months of medication and supplies stock, and a current lack of automated systems and data for managing the distribution of this throughout hospitals is contributing 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to ever increasing costs. On top of this, outdated manual counting, reordering and searching for drug cupboard keys is consuming vast amounts of valuable clinicians’ time and having a detrimental effect on operational efficiency. Most importantly, the lack of control, accountability or traceability at the pointof-use is putting patients’ lives at risk due to medication errors or availability of stock. This lack of control, accountability and traceability has not only been highlighted by Lord Carter, but is a key factor in the Department of Health’s eProcurement strategy which mandates the use of GS1 standards in every NHS acute trust. It’s great to see the government placing such importance on processes that will enable the unique identification of information to be exchanged across a hospital, a trust and between different care providers and systems, no matter where or when a patient receives care. Adopting GS1 standards in every NHS trust will improve patient safety, deliver greater regulatory compliance and drive operational efficiencies along the entire patient pathway. If implementation is successful, it could put an end to nurses spending two hours of their shift looking for supplies3 and will make it easier to track down affected patients in the event of another major healthcare scandal like PIP breast implants. We know there is a lot of wasted money in the healthcare service, and the GS1 programme can help to liberate that cash. Lord Carter believes the introduction of these GS1 standards will allow every NHS hospital in England to save an average of £3million each year while improving patient care. We share Lord Carter’s view that hospitals need to make greater use of technology such as electronic systems to automate ordering, storage and tracking of medicines and supplies at an individual patient level. It’s something all hospitals in England will need to embrace if they are to meet the GS1 standards. As Lord Carter himself said in his report – ‘the best performing hospital systems around the world have real-time data at their fingertips enabling them to make decisions on a daily, weekly, monthly

basis to improve performance’ – isn’t this what we should be aspiring to here in the UK? Evidence is widely available for both supplies and medicines that demonstrates how: •

something as simple as replacing traditional drugs cabinets with automated dispensing cabinets really does offer hospitals a great opportunity to improve the way they work, save money, free up staff time and improve patient safety, automating theatres and the wider hospital will significantly reduce stock levels, cut spending, release clinical staff time and deliver accurate patient costing and data that can be used to benchmark hospitals against others.

As a GS1 accredited partner and the only partner that can provide hospitals with a solution for both hospital supplies AND medication management, we’ve seen time and time again through our partnerships with the NHS how harnessing such technology can bring about real cost savings and free up clinician, nursing and pharmacy time, allowing it to be redirected back into face-to-face patient care. Our systems and solutions have already saved the NHS £50million over the last five years. This tried-andtested technology is now helping 100 UK hospitals to drive efficiencies, reduce costs, spend more time on face-to-face patient care and improve patient safety and patient experience. More and more hospitals are beginning to realise the importance of automation and the benefits it can bring. We’re seeing engagement from trusts’ clinical and executive teams, and this will be key going forward, if implementation of GS1 and the recommendations outlined by Lord Carter are to be successful and have the desired impact. Following the publication of the Lord Carter report, a shift in culture is already evident, as can be seen in our recent contract wins with no fewer than five hospital trusts. The five new business contracts will see automated medical supply systems being installed in Summer 2016 Volume 8 Issue 2










Regulatory & Marketplace

Chapter Title recommendations outlined in Lord Carter’s report. Because we are passionate about what we do, we’re committed to being a long-term partner for the NHS. We support trusts throughout their automation process – from developing the business case to feeding into hospital pharmacy and procurement transformation programmes, and from successful rollout across the hospital to ongoing service and support, we’re with trusts every step of their journey.

Wye Valley Trust (Hereford), Maidstone & Tunbridge Wells, Southampton, Burton and Gateshead, where our automated systems will manage a combined total of £20m of stock. All five installations will go live in the coming summer. The solutions include secure closed cabinets and open scanning systems which track inventory in real time and cost product usage to patients, healthcare consultants and procedures. This data provides trust management teams with visibility of patient-costing, and allows them to benchmark and analyse hospital costs. In addition, clear visibility of stock levels ensures that hospitals only order what they really need rather than what they think they need. We frequently see hospitals save hundreds of thousands of pounds in both stock-holding levels and the consumption of medical supplies by automating their inventory management systems. On top of this, trusts are also able to rationalise storage space, helping to meet some of Lord Carter’s recommendations around estates, and save clinicians valuable time which can be redirected back in to face-to-face patient care. It’s great to be helping these five trusts to implement and realise their GS1 vision. One of these hospitals, Gateshead, already use medication dispensing cabinets so it’s fantastic to see them taking the next step and using our service for their total solution when it comes to managing medication and supplies throughout their hospital. Another hospital already using our total solution is

Guy’s and St Thomas’ Hospital in London – the hospital was recently held up as a model of best practice for procurement and inventory management by Lord Carter. The Trust was looking to increase patient safety and to reduce unnecessary waste of both medication and supplies. They knew the answer lay in a safer, more controlled and more efficient system. The cabinet systems for automating the ordering and control of medicines were installed across 80 wards and A&E at Guy’s and St Thomas’ Hospital. The systems are integrated with their ePMA system, Medchart. In addition, the trust installed 219 inventory management systems across all their main clinical areas from theatres to wards. The systems manage over £25m per annum of supplies spend, and generate approximately 440 orders per day, which can be tracked at a per-patient level. The large-scale installation of cabinets has seen some impressive results, including: • • • • •

reduction in theatre spend of 5%, reduction in medication spend of over 10%, 35% reduction in non-moving inventory, 100,000 nursing hours freed up, which is now directed back into face-to-face patient care, speedier discharge of patients from hospital wards.

Our expertise in automation means we are the perfect partner to guide hospitals through implementing the key pharmacy and inventory management

We recognise that there is a long way to go to meet the recommendations of the Lord Carter report, but we look forward to working with more trusts to drive up efficiency through innovative technological solutions. In a day and age where we use technology in nearly everything we do, isn’t it time we started to embrace technology in the same way across the NHS? For more information: 0330 024 0850 References 1. Operational productivity and performance in English NHS Acute Hospitals: Unwarranted Variations – Lord Carter 2. Operational productivity and performance in English NHS Acute Hospitals: Unwarranted Variations – Lord Carter 3. Nursing Times

Paul O’Hanlon, Managing Director, Omnicell Ltd, UK & Ireland. A pharmacist by profession, Paul is Managing Director of Omnicell UK & Ireland. Founded 24 years ago in the US, today Omnicell is a leading provider of medication and supply management solutions to the global healthcare market, with more than 4000 customers worldwide. The company specialises in improving the medication and supply distribution process from hospital to home. Email: INTERNATIONAL PHARMACEUTICAL INDUSTRY 10

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Regulatory & Marketplace Incorporating the Patient Perspective: The Critical Role of Human Factors and Usability in Improving Medication Adherence Although we may not always notice it, the products we use in our daily lives continually evolve as manufacturers keep a close eye on consumer behaviour. Typically, they’re constantly adjusting and improving those goods based on feedback from surveys, focus groups and, of course, online commentary and criticism. The roads on which we drive every day are analysed and regulated with systems of signs and stoplights designed by traffic engineers, whose first intent is to keep us safe and aware – but then alter their plans to optimise the flow of traffic. Computer, smartphone and tablet applications begin with human factors analysis and usability testing that determines not only how we interact with the software, but also the look and feel of the interface – and even the icons used to navigate. When publishers find that magic intersection of minimalist elegance and natural intuitiveness, everybody benefits and a popular app is born. All of these illustrations have one thing in common: Appealing design, efficiency and usability rank as the top priorities. More importantly, however, satisfying end-user needs outranks them all. Drug delivery systems benefit from this ideology, too. That is one of the things we are doing as we seek continuous improvement in our manufacturing and design processes: Taking human factors into account from the very beginning, and testing them over and over along the way. We do this for several reasons: •

First, today’s cutting-edge analysis tools allow us to gain deeper insights into user wants and needs more than ever before. Second, it’s a way of putting the patient first, which should be every healthcare company’s prime directive. Third, with healthcare trending in the direction of self-administration, packaging and device manufacturers


can help enable these at-home treatments by making them less unpleasant and reducing potential errors through designing and producing more eminently usable delivery systems. Fourth, if we can help our pharmaceutical partners increase medication adherence – especially for patients with chronic diseases – we not only increase the quality of life for the patients they serve; we help them better execute their commercial goals and mitigate the negative financial impact non-adherence has on the entire healthcare system.

By focusing on human factors from the very beginnings of product development, we can effect better quality healthcare for the patients who count on us. The Evolution of Patient-centred Drug Delivery We are seeing earlier collaboration between pharmaceutical companies and drug packaging and delivery system manufacturers in the drug development process. A decade ago, the choice of system to deliver a medication was often the last piece of the puzzle for the drug manufacturer; almost an afterthought. In the same way, drug packaging manufacturers often concentrated on developing new systems based on new technologies and better performance, seeking the majority of their customers after drug products were brought to market. With today’s biologics, it has become clear that higher and higher protein concentrations and larger doses of medications present challenges that require more interaction between pharmaceutical and biopharmaceutical companies and their packaging and delivery system partners to ensure the safety of patients and the efficacy of their medications. For companies like ours, it became abundantly clear some time ago, that — instead of first creating a product or compelling technology, and subsequently identifying customers it could serve —

we need to focus on identifying unmet patient and market needs by creating/ conceiving appropriate delivery systems, feature-sets, training programmes, adherence improvement methods and even software and digital interfaces, together as an ecosystem to enhance the user experience. This a commonsense notion, but still one to which many technically-driven companies often fall prey. Guidance from regulators, such as the US Food and Drug Administration, also points to growing requirements for due diligence in human factors research and user-centred design to help build the case for combination product (drug or biologic and device) approvals. Design for Affinity What does user- or patient-centred design mean—in practical terms? For us, it includes: •

Talking to users several times before even prototyping an injectable drug delivery system to understand and characterise their needs as a basis for learning how to meet them. Understanding how patients feel about their journey from diagnosis to ongoing treatment, and understanding how to make a delivery system that will both enhance the therapeutic experience and improve medication adherence. Creating delivery systems that are intuitive for patients to use correctly without inhibiting their lifestyle. These are delivery systems that are not only convenient, but are also driven by research and device training that has been validated and improved through meaningful, comprehensive user data.

This kind of development costs more than traditional approaches, and may take a bit more time at first, but when built into the overall timeline of drug development and thoughtfully considered, we believe this approach pays dividends by yielding medications with delivery systems that patients not only can use, but want to use. This helps promote patient Summer 2016 Volume 8 Issue 2

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Regulatory & Marketplace adherence and ultimately, contributes to improved chronic disease management and outcomes.

to keep them from going off their critical medications — and the reasons they have for doing so.

Connected Health As we developed our own human factors and user research team’s capability and leveraged our existing partner in this area, Insight Product Development, we knew we needed to also find a partner on the software side to help create a digital health ecosystem to enhance the patient experience for those using self-injection systems. We chose HealthPrize, a platform on which patients are rewarded for reporting data around medication adherence and taking advantage of disease-state-specific, self-education opportunities. In the future, we hope to expand these capabilities to track more details about patient behaviour and adherence, as well as confirm proper device operation via sensors in the injector or delivery system.

Connected health programmes such as HealthPrize and other systems that incorporate a positive and social patient ‘environment’ into treatment regimens – and offer physicians and nurses the ability to monitor patient data and medication adherence – show promise in giving patients additional reasons to help care for themselves, in both incentive and accountability.

Through HealthPrize’s reward programmes and gamified environment, we offer both extrinsic and intrinsic motivation for patients to effectively interact with and adhere to their prescribed drug delivery system and therapy. As a concept, gamification has made inroads in online marketing by applying elements of game playing – such as scoring points, competing with others, setting a hierarchy of rules and, of course, reaping rewards for success. This approach is now also showing promise in other sectors such as business, fitness and even healthcare, too. This expansion has provided patients with chronic conditions a new tool to help them meet the daily challenges of managing their illnesses. Patients with chronic conditions, such as diabetes, may be asymptomatic or experiencing only mild symptoms, and may feel all right – even though that may not actually be true. This can be one of the main reasons they skip medications. Speaking with patients to understand their journey — keeping in mind that some live with diagnoses for months, years and even decades — is key to developing medication self-injection systems that help patients better manage their health. One size may not fit all patients, at all points, in different stages of different diseases. But learning how patient attitudes toward their diagnosis evolve, and how their needs change as they progress through the various stages, will lead to better understanding of how 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Such technology options allow drug packaging partners to team up with pharmaceutical companies to add these medication adherence benefits to drugs and delivery systems in development, as part of a pipeline to market that is more patient-focused than ever before. Looking Forward: It’s Here to Stay Drug packaging and delivery system manufacturers, partnering with drug companies, can help influence patient behaviour in a positive way by following the example of the consumer products and software industries. The look and feel of the medication experience – which hasn’t been commonly explored using this approach, at least in the context of injectables – can be improved by thinking about these factors. We can also potentially streamline development cycles by looking at other markets for areas of optimisation. Software developers use the agile “scrum methodology” to manage product development, with each iteration called a “sprint” governed by planning meetings, time limitations and review processes. Each team member understands his or her role in achieving a common goal called “definition of done.” This method leads to better, faster development. The healthcare industry is also trying these methods on for size and adapting them to their own product development processes, particularly in drug delivery systems. While healthcare must be deliberate and conservative in developing their own new agile methodologies, we are seeing it happening across our customer universe. It can take more than 10 years to bring a drug to market, and three to five to develop an injectable delivery system. In other industries that’s an

eternity – think about how the iPhone has evolved over the eight years since its debut. Of course, it’s not appropriate to compare the timeframe for smartphone development with that of lifesaving drugs or delivery devices. However, the principles of assimilating usability, human factors, better training programmes and adherence improvement tools into a drug-delivery ‘ecosystem’ to enhance the patient experience, certainly offers potential to compress the overall development process as opposed to considering all the elements separately. Although a growing topic of conversation and excitement at industry conferences, it will likely take years before we see the fruits of integrating better user research into real-life medications and delivery systems. But, just as monoclonal antibodies and protein therapeutics arose from a traditional drug ecosphere in a few decades, “everybody engaged in healthcare will inevitably find themselves in the behavioural change business,” to paraphrase a favorite quote I read in an Ernst & Young report a few years ago, and still use in my presentations at conferences internationally. While it might seem new, and even intimidating to some companies, we embrace this trend. It’s a powerful tool to improve the lives of patients. In the next five years, the companies who take this holistic view toward product development will be the trailblazers; those who act now will separate themselves as leaders from the followers. As a company that is investing more and more into usability, human factors research and enhancing the patient experience, we look forward to this evolution of healthcare.

Chris Evans Vice President, Global Innovation Pharmaceutical Delivery Systems West Pharmaceutical Services. Chris has been in product development for over 20 years, primarily in healthcare packaging and device development. He is the holder of 19 U.S. patents with several more pending.Chris is now responsible for new product & technology development, focusing on device usability and enhancing the patient experience. He also manages West’s Connected Health Initiative and the resulting partnerships and alliances brought together to assemble a ‘patient engagement ecosystem’.

Summer 2016 Volume 8 Issue 2

WE’RE SOARING TO NEW HEIGHTS End to End Services for Patient Recruitment and Retention

THE PATIENT RECRUITMENT-RETENTION REVOLUTION “Over MediciGroup’s 24 year history, the last 4 years has witnessed more change than the previous 20 years. The speed of change is unprecedented as more than 85% of patients and families obtain health and clinical trial information online. Medici is proud to be at the forefront of this digital revolution, spearheading more than 30 global online patient communities, and leading in the delivery of successful patient recruitment through digital and social media on a global scale.” Liz Moench, President & CEO MediciGroup® Inc.

Accelerating Enrollment

Digital Marketing

Locating Lost Patients

Regulatory & Marketplace

The Great Brain Drain The life sciences industry is drowning beneath a sea of new regulations and directives. As well as being immensely demanding from a risk management perspective, the associated administration is detracting from core activities. Even basic administrative tasks, such as checking updates to labelling, consume hours of PhD-qualified staff’s time – capacity firms cannot afford. This is having an effect on professionals’ morale. Organisations should take heed, or risk losing valued experts at a time when experienced regulatory and QA personnel are in short supply, warns Dr Jutta Hohenhörst of Schlafender Hase. In life sciences, it can seem as though new regulations are being announced or coming into force every few weeks. On top of the authorities’ need to safeguard patients, consumers expect more transparency – about a product’s contents, origins and processes. All of this is creating more red tape for the industry: requirements that need to be serviced and managed. The more rules there are, and the more frequently these change, the greater the risk of something going wrong. Similarly, the more products, variants and markets a company is dealing with, and the shorter the release cycles, the greater the controls needed across documentation, packaging and labelling to ensure nothing slips through the cracks. The media archives are laden with examples of big names that have fallen foul of regulations, by simply failing to spot a misprint until it’s too late, or neglecting to meet new guidelines in a particular market. From children’s cough medicines to dietary supplements, the simplest error in how consumers should store or take the product could result in illness, harmful side-effects or even death. Errors can creep in so easily. People make mistakes, especially if they’re tired, busy or stressed. In life sciences, the difference between “store this product at 2-8°C” and “store this product at 28°C”; “take 1-2 a day” and “take 12 a day”; or “do not chew and swallow” and “do not not chew and swallow” could be a matter of life and death. 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Guarding against this kind of exposure is a full-time job, and a significant part of risk management in an industry where the smallest mistakes can be fatal. Even where companies have the most extensive and comprehensive regulatory affairs and quality assurance departments, the strain is being felt. The slightest change in regulatory requirements can create the biggest administrative backlogs, and increase the company’s vulnerability – e.g. to product recall, or worse. Soaring Stress Levels All of this extra work and responsibility is taking its toll on RA and QA teams. In many cases, it is highly qualified professionals – people with doctorates, and years of experience – who are being called up to check amended labels and patient literature to ensure it is compliant with the latest guidelines. Are the right details included in the right way, place and format to ensure up-to-date conformance? Is everything accurate and consistent? At the same time that these administrative requirements are being increased, so too are regulatory and quality assurance professionals’ broader workloads. RA and QA teams have never been busier or as overstretched. Unsurprisingly, a 2014 survey of European recruitment and staffing trends in the life sciences sector (Recruiting & retaining a competitive workforce: Pharma, biotech & medical devices by Real Staffing: http://assets.realstaffing. com/images/site/Recruiting_and_ retaining_a_competitive_workforce.pdf) found that quality assurance, regulatory affairs, along with sales & marketing, and research & development, are now the main growth disciplines. Regulatory affairs was the primary growth area for more than half of medical devices organisations, which has been subject to increased regulations in recent years; RA was similarly a major focus for pharma and biotech organisations across Europe. But the same survey also identified a gap in the available talent pool. A third of firms across all three sub-sectors felt the size of the available talent pool had decreased. Close to half of companies cited a lack of available skilled talent,

and in particular a lack of local talent. Deeper analysis revealed a growing concern among life sciences employers that failure to keep employees stimulated and motivated could result in key people moving on. Poor Resource Management Manual tasks are unrewarding, demotivating and a poor use of qualified professionals’ time. So it is far from ideal that the life sciences industry is using scientific writers with PhDs to check over content for regulatory/QA purposes, at great expense to the business. Avoiding a product recall or safety scare is clearly in everyone’s interests, but there must be a better way. The cost per hour of work from the employee doing routine proofreading (e.g. checking that updated labels meet all the new regulatory criteria for a market, and are correct and consistent) doesn’t just include that person’s salary. It also includes tax, benefits, insurance, holidays, office space, training, recruitment costs and so on, which can more than double the gross salary figure. If graphic designers have to get involved, there may be additional fees for re-work if the resource being used is external. When budgets are tight, and skills in regulatory affairs and quality assurance are at a premium, it isn’t very astute to be using experts to do menial tasks, however vital the outcome. In the worst cases, people who feel unchallenged or under pressure to do extensive manual tasks on top of already demanding workloads, will leave the organisation. Studies suggest that losing a salaried employee can cost as much as twice their annual salary, especially for a highearner. Adding to employees’ faltering morale is the stress caused by being at fault for an error – errors that are very easy to make, yet equally easy to avoid. Retention Challenges Research by TalentKeepers (The Dirty Truth: Employee Turnover Costs, 2015 - h t t p s : / / w w w. t a l e n t k e e p e r s . c o m / wp-content/uploads/2015/03/ Talentkeepers-The-Dirty-Truth-EmployeeSummer 2016 Volume 8 Issue 2

Manufacturing Regulatory & Marketplace Method A – Membrane Filtration The method calls for the routine use ofsuggests positive and negative controls. Turnover-Cost-Whitepaper.pdf)

that morale and culture have risen to

Test method: For aqueous solutions: going to feel like an unwelcome burden. Aseptically transfer a small quantity of fluid A on to the membrane and filter it. Transfer aseptically the combined quantities of the preparation translation and under examination prescribed in the two media onto one membrane.

Apparatus: become the largest casualty of employee Then again, Cellulose nitrate filters are used for aqueous, oily and weakly alcoholic turnover and a lack of engagement, proofreading of labelling requires a solutions, and cellulose acetate filters are recommended for strongly followed by productivity, team completely different set to under manyexamination Technology Raises its Game Ifskill the solution has antimicrobial properties, wash the alcoholic solutions. performance and stress. Service quality other regulatory tasks. Most RA Although software canthan never the membrane(s) by filtering through it (them) not less threetake successive can also suffer people’s hearts aren’t in officers are scientifically minded of a human quantities, each and of 100 place ml, of sterile fluid A. expert in its ability to Diluting Fluids: (IP,ifBP): the task, which is1the thing firms don’ttissue necessarily Fluid A: Dissolve g last of peptic digestneed of animal (such as have well-developed spot subtle variances in meaning, it can Do not toexceed a washing cyclethe of five timesofor proofreading 200 ml, even if– it bacteriological peptone) or its in (A water communication to make 1 litre, filter when attention to detail is equivalent everything. skills needed talk about reduce rounds has been demonstrated during validation a cycletodoes orlast-minute centrifuge tore-work clarify, adjust to pH 7.1 ± 0.2, dispense into flaskstoin non-scientists of a revised product their products (hence releasing time for that the such specialists focusnot eliminate the antimicrobial The quantities of fluid used 100ml 121° C forlate 20 minutes. labelquantities because and of asterilize mistakeatidentified the call for usability fully testing of leaflets, on moreactivity. challenging and rewarding of a small inoculum organisms in the process takes time and could delay implemented in 2005).should be sufficient to allow tasks.growth And technology is gettingofbetter. (approximately 50 CFU) sensitive to the antimicrobial substance in the Fluid B: If the test sample contains lecithin or oil, use fluid A to each litre the production, with substantial financial In the past, attempts to automate of which has been added 1 ml of polysorbate 80, adjust to pH 7.1± presence of the residual inhibitory material on the membrane. ramifications.) Similarly, proofreading can be proofreading and document comparison After filtration, aseptically remove the membrane(s) from the holder, 0.2, dispense into flasks and sterilise at 121° C for 20 minutes. challenging for a subject expert who, fell wide of the mark due to technology transfer the whole membrane or cut it aseptically into two equal parts. So what is theto answer? understanding language restrictions, andfor one half toofeachlimitations, of two suitable media. Incubate the media Quantities of sample be used: Usually in although having an Transfer these situations, technology comes to what the content needs to say, may insufficient accuracy to fit the purpose. not less than 14 days. For parenteral preparations: the rescue, alleviating be trained to question it. Although Whenever possible, use the heavily-repetitive whole contents of the not container, but in any manual so quantities that skilled employees larger where companies runthetraining text comparison tools Observe containers of Traditional media periodically during the 14 relied days of case not lesstasks than the prescribed in Tablesome 3(E), diluting can useto about their 100 timemland it Ifdoesn’t on converting content format incubation. the test specimen is positive before 14 to daysPDF of incubation, necessary with talents a suitablemore diluent programmes such as fluid A. and exams, further incubation is not for necessary. products terminally sterilised by constructively. In a sensitive proofreading necessarily make sense to put everyone visualForcomparison, an approach a validated moist heat process, incubate the test specimen for not less For ophthalmic and other non-parenteral preparations: context, that hasn’t always been possible through the process. And, to return to that is inadequate for heavily-regulated Take an amount range prescribed column (A) point, of Table – there are sowithin manythesubtleties at work in the earlier giventhan the seven wide days. array of markets. Converting from one format 3(E), necessary, using thebeen contents one container, andtasks RA officers have to another can introduce anomalies, thatifcompanies haven’t ableoftomore trustthanother demanding For liquids immiscible with aqueous vehicles, and suspensions: mix thoroughly. For each medium use the amount specified in column automated solutions to make the right to contend with which do require their and the process doesn’t allow teams to Carry out the test described under for aqueous solutions but add a (B) of Table 3(E), taken from the mixed sample. judgement calls. scientific skills, proofreading is always work from original documents, which sufficient quantity of fluid A to the pooled sample to achieve rapid filtration. Sterile enzyme preparations such as penicillinase or cellulose

High purity systems require high quality products. That´s what Adca Pure is all about.




Regulatory & Marketplace This frees up expert time for higherlevel verification/decision-making and frontline regulatory/quality assurance work. Our own research has found that professionals can save two hours or more of their valuable time by using automation in the first instance. Average savings translate to five hours a week on manual proofreading/text verification. Extrapolating this against the average salary of a specialist regulatory affairs employee (estimated at $85,000 or EUR 76,000), this works out at a yearly saving/productivity increase of $13,500 (EUR 12,000) per RA user.

may be important mid-way through a drug approval process. In addition, document conversion for the purposes of comparison is a violation of GMP processes and can lead regulators to question the validity of comparisons, and the entire packaging review process. Where file conversion is taking place, or comparisons rely on certain fonts, language or specialist content knowledge, accuracy starts to suffer. And when teams can’t depend on automation for the highest levels of accuracy, their confidence in technology diminishes until they stop using the software, undermining any return on investment. But things have moved on, and it’s now possible to take a more intelligent approach to text comparison which is a lot more reliable and robust, meeting the stringent needs of life sciences. Not only can companies access the facilities costeffectively ‘as a service’ via the cloud (instead of having to pay for licences up front), the software works by comparing the underlying universal code (‘Unicode’) rather than the actual text shown on the page. This means teams can accurately compare content, irrespective of the font or language.


Using Unicode means data is retrievable with a simple keyword search in a database or document management system, and allows content to be transferred to other applications without risk of corruption. This kind of approach offers unprecedented levels of accuracy and speed. Buying Back Expert Time Automation of regulatory checks doesn’t replace the need for human oversight, but it does allow professionals to focus their time where it is needed. This is because the software is able to home in on the subtlest changes and anomalies, avoiding the need to go through entire documents manually. To give an idea, where it would take a human proofreader a week to spot all the differences between two versions of the novel Huckleberry Finn (which runs to approximately 500,000 words), and with no guarantee that all anomalies will be spotted, Unicodebased automated text comparison takes just three minutes to reliably pinpoint even the tiniest variations. A typical likefor-like document comparison will take a matter of seconds, versus 3-4 hours done manually by a human, even if the language is unfamiliar.

Improving Job Satisfaction Reducing reliance on manual processes isn’t just a risk avoidance or insurance strategy. In life sciences, the rise in merger and acquisition activity and the growing trend of smaller batch numbers and increased drug personalisation means label demands are soaring and becoming more complex to manage. Each new demand and each new regulation multiplies the burden on regulatory affairs, quality assurance and marketing to be responsive, accurate and thorough at a time when skilled employees have little or no capacity to spare. As regulatory demands continue to increase, this is a situation that is going to get worse long before it gets better, so life sciences firms need to find new ways of managing the workload if they want to hang on to skilled personnel who now command a premium on the international market.

Dr Jutta Hohenhörst has more than 19 years’ experience in the pharmaceutical business, gained across a range of departments, from Supply Chain Management to Strategic Marketing, at F. Hoffmann-La Roche HQ, AstraZeneca and Fresenius HQ. She has also worked at IMS Health, further broadening her industry knowledge via strategic consulting projects in the pharma, medical device and hospital sectors. She joined Schlafender Hase in 2012. Email: Web:

Summer 2016 Volume 8 Issue 2

Regulatory & Marketplace

Adelaide is the Ideal Life Sciences Location Creating an attractive city for health and life sciences companies happens through executing a well-designed strategy backed by a clear vision. Global companies are now discovering Adelaide, a city which is being transformed into the ideal location for clinical trials, research and development, medtech manufacturing, and distributing in Asia. Adelaide, the capital of South Australia, has a proud manufacturing history. With GM and Mitsubishi car manufacturing, and major ship and submarine building, it has been at the heart of Australia’s manufacturing base for decades. Now, like many Western countries, Australia’s economy is evolving. Several years ago, the South Australian Government made a decision to diversify the local economy. It assessed Adelaide’s skills-base and identified expertise in the health and life sciences sectors as a resource that could be used to help transform the economy. The government’s plan to grow the life sciences and leverage this hi-tech knowhow has three components: building a cluster of world-class life sciences infrastructure – Adelaide BioMed City; developing policies to deliver practical assistance to companies; and creating a government agency dedicated to helping life sciences companies establish in Adelaide — Health Industries South Australia. 1. Adelaide BioMed City In the past, hospitals were designed to deal with acute medical crises, like heart attacks or major accidents. But today, our hospitals also care for people who have multiple, complex conditions and chronic diseases like diabetes. Dealing well with these different health needs means redesigning how we care for people. At the same time, advances in technology happen quickly. Used properly, they can help record information about our health, send it electronically to health professionals and track and monitor important information like blood sugar levels, heart rate, diet and exercise levels.

planning the new Royal Adelaide Hospital (RAH). Located in Adelaide’s CBD, this 800-bed hospital is nearing completion and features hi-tech solutions, including fleets of autonomous vehicles delivering supplies and equipment. Ambulances will send patient data to the hospital ahead of patient arrival and video monitors in patient rooms will allow digital access to test results. All overnight bedrooms will be single rooms, providing patients with comfort and privacy. Another crucial component of the new RAH is the Enterprise Patient Administration System (EPAS) which will provide the foundation for delivering South Australia’s state-wide electronic health record. The new system will operate across all public hospitals in South Australia, providing a single digital repository for all patient records. EPAS data will include details of a patient’s treatment plan, their test results and information about medications they may be taking and will allow clinicians access to real-time patient records and provide the ability to order diagnostic and laboratory tests online. It will be a crucial link between administrative and clinical processes. But clinical care is only part of a life sciences cluster, and with vacant land beside the new RAH, the state government used the opportunity to begin building one of the largest life sciences clusters in the southern hemisphere — Adelaide BioMed City. The first building after the new RAH to be planned was the South Australian Health and Medical Research Institute (SAHMRI), which has become the state’s first independent

flagship life sciences research institute. SAHMRI represents an exciting new concept that brings together basic and translational research, South Australia’s three universities and the health system. This has enabled the institute to provide leadership and strengthen the collaborations and partnerships that already exist. Completed in 2014, this institute was the first building to open at Adelaide BioMed City and its central architectural proposition was a new and liberating lab typology that promotes collaboration and medical discovery to help attract the best researchers from around the world. Its forecourt, adjacent to the new RAH, encourages interaction and exchange by staff, visitors and the general public. Its striking transparent façade, inspired by the skin of a pine cone, unifies the organic diamond-shaped plan while showcasing the two atria inside the building. As part of an innovative sustainability programme, the project is the first laboratory building in Australia designed to achieve a LEED Gold rating. The iconic architecture is only the start of the innovation. It co-locates hundreds of researchers, divided into seven broad themes, including cancer, mind & brain, and cardiovascular health. The SAHMRI facility is designed to accommodate up to 675 researchers, providing nine fully flexible wet and dry laboratories to PC2 standard. The facility also provides services for bio and data analytics, as well as large and small animal laboratories, and a cyclotron to produce radioisotopes used for disease diagnosis, staging and monitoring.

Recognising the way clinical care was changing, the government embarked on 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2016 Volume 8 Issue 2

Manufacturing Regulatory & Marketplace Preparation of test solutions: at the specified wavelength in accordance with the instructions of the Solution A: Solution of the product under examination at the initial lysate manufacture. SAHMRI’s research themes were cancer. With 14 levels, it will be a clean it manages. dilution (test solution) selected based on the most important and green building, designed to meet Solution B: Test solution spiked with CSE at a concentration at or near Interpretation of results: health issues we currently face, but also LEED Gold rating. Opening in 2018, it Adelaide BioMed City is in an exciting the middle of the standard curve (PPC) The assay is valid only if their intersection with each other, and the will feature optimised solar shading on phase. is upofand the Solution C: Standard solutions of CSE in water BET covering the linear 1. The standard curve is linearSAHMRI for the range CSErunning, concentrations research collaborations they create. The the facade, use recycled materials, have new Royal Adelaide Hospital is opening part of the standard curve used; instituteD:has attracted world-class leaders a water-efficient landscape, and the roofof correlation soon, and has begun on Solution Water BET (NC) 2. The coefficient r is construction not less than 0.980; 2 in their fields to oversee each of the seven will incorporate 260m3. of solar cells. % recovery the two university-led buildings. the The mean of the added endotoxin in theBut positive Method: product control is between 50% and 150%. looking to the themes. The communal and collaborative government is already Add solution is D, already followed paying by solutions C, A, B. AddClinical lysate andcare carry and research are future. Planning has started on locating approach dividends, out the assay solution in accordance with the of theparts lysate of The with breakthroughs in areas such asinstructions important a concept life sciences the Women’s Children’s of total quality control and test refers to thehospital processinof manufacture. heart disease and infant nutrition. ecosystem, but it’s vital thattothe next a Adelaide BioMedbyCity, whichof will give striving produce perfect product a series measures



doctors, nurses and women, babies access requiring an organised effortchildren in orderand to eliminate errorstoat

Calculation: This early success has been a goad researchers are nurtured. That’s why the the most advanced acute hospital care. Calculate the endotoxin concentration of solutions A and B from the every stage in the production. In-process product testing is to action for the government, which University of Adelaide is constructing regression equation obtained with solutions of series C. Calculate the required in order to check the conformance of the product with is inpercentage the planning stages ofadded a second thebyHealth & Medical Sciences Building, With infrastructure to take compendial standards as specified in the starting pharmacopoeias. mean recovery of the endotoxin subtracting the the research institute, to be constructed will support The medical, nursing shape, embarked pharmacopoeias have the laidgovernment down the has specified limits mean endotoxin concentration in solution next A from which the mean endotoxin to SAHMRI.inThis building and around 400value upon the fall second part of its life sciencesas concentration solution B. will house 500 and dentistry students,within which the should in order to be compliant researchersofover 12 levels and will be the health sciences researchers. development. Interpretation results: per the standards. Asstrategy: the finalpolicy samples taken for the finished

site of Australia’s first proton therapy unit.

product testing is only a representative of a large batch, a

The is valid only if between SAHMRI, It assay is a collaboration The next generation of life sciences significant difference 2. stillPractical remainsPolicies because of minor variation 1.the The standard curve is linear for the range CSE concentrations government health department and ofcompanies are being fostered at Adelaide Australia already had an attractive in the specified limits in different pharmacopoeias. Since the used; University. Flinders BioMed City through markets BioSA. have This state clinical trials ecosystem. Unlike US, no opened up due to globalisation, it isthe necessary 2. The coefficient of correlation r is not greater than 0.980; government agency provides marketing investigational new drug (IND) approval for a product to comply with the standards of the place where 3. The mean % recovery of the added endotoxin in the positive A third research building is already and business development assistance to is required in Australia. However, the it is to be marketed. product control is between 50% and 150%.

under construction – The University of hi-tech companies, while also providing state government worked to speed up South Australia’s method Health Innovation access to grants, venture capital, land pharmacopoeias the ethics approval faster. End point chromogenic As the and official are process differenteven in different Building. willfollowed includebythesolutions Centre C,forA, B. forThe newchromogenic technology facilities. BioSA is co- Approvals now take 6-9 months less in Add solutionIt D, parts of the globe, there is a need for the harmonised limit Cancer and Biology, focussing on fundamental located with for more 60 companies in Adelaide than in Europe or the USA. ICT substrate lysate are added to the solution and incubated thethan within which a product should fall to meet the pharmacopoeial research relevant to the many types one the of two business incubator buildings applied to healthcare is a fast-growing recommended time. Stop reaction and of measure absorbance

Companies all around the world challenge us every day to create new products tailored to their needs. We embrace these challenges. We are engaged with




Regulatory & Marketplace sector and the government realised it had an attractive asset for researchers: 14 million hospital patient records. These are being made available to companies for their research in an anonymised form. Finally, the government has developed a new industry participation policy, leveraging government procurement to achieve economic development. In order to take advantage of the world-class infrastructure of Adelaide BioMed City and the unique policies of the South Australian Government, a new agency was created to help life sciences companies learn about what Adelaide has to offer and help them as they establish in the city. 3. Health Industries South Australia Health Industries South Australia is a state government agency, acting as a single point of contact for health and life sciences companies investing in Adelaide. It’s staffed by business professionals, with experience in areas such as pharmaceuticals, biotech and medical devices. This allows the agency to understand what companies need and provide advice on government regulations, help accessing land and introductions to the local life sciences community, from education and research through to venture capital and industry. Health Industries South Australia supports companies every step of the way as they establish and grow in Adelaide. The agency’s industry experts have also worked extensively within government to modernise policies that are good for business, including access to patient records and speeding up clinical trials approval times. The agency has already succeeded in helping companies take advantage of Adelaide, including helping Pfizer secure a lease on government land, and provided support with regulatory obligations. This helped the global pharmaceutical company establish commercial biologic manufacturing in Adelaide, with a $21 million investment. Health Industries South Australia has a clear mission and has identified six crucial factors to help attract more investment to Adelaide. a) Clinical research As well as the policy developments which make clinical trials ethics approvals 6-9 months faster than in the US or Europe, Adelaide has one of the largest and most experienced Phase I clinical trials units 22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

in Australia. This 50-bed unit recently moved into a new purpose-built facility at Adelaide BioMed City. Adelaide also has a world-class preclinical research facility, managed by SAHMRI, and facilities for Phase II and III trials. b) Cash reimbursement for R&D expenses Forty-five per cent of research and development costs will be reimbursed in cash to eligible companies with an aggregated annual turnover of less than A$20 million (approx. US$15 million). A 40% tax offset is offered to all other eligible entities. This incentive covers costs such as clinical trials, analytics, study drug manufacture and related services, and covers all phases of development, i.e. preclinical and Phases I, II and III. Companies can claim the cost of R&D activities conducted overseas in support of their Australian R&D project, when certain conditions are met. There is a solid track record of successful claims by companies headquartered overseas, such as the US, when conducting research in Adelaide. c) Automotive supply chain applied to medical devices Adelaide has decades of experience in world’s-best-practice manufacturing in the automotive and defence industries, providing highly-skilled workers and solid supply chains that are now being successfully applied to medical device manufacturing. Adelaide’s supply chain can deliver project components including optoelectronics, sensors, nanomaterials, composites, firmware, artificial intelligence, and data analytics. d) Digital health The state government is making 14 million hospital patient records available to companies for research in an anonymised form. This dataset includes 9 million in-patient records collected over 15 years, and 5 million emergency presentations collected over 10 years. Adelaide is also home to the A$88m Data to Decisions Cooperative Research Centre, where researchers and industry are brought together to create a leading provider of big data capability. The centre undertakes research, development, education and training in data intensive sectors. Adelaide has a population of 1.3 million people, with another 400,000 people

spread out across South Australia in rural and remote communities, making it the ideal location to test tele-health services and other innovative ICT healthcare solutions. e) Close to Asia Adelaide’s time zone is within two hours of Beijing, Tokyo, and Hong Kong, and has direct flights to Hong Kong, Kuala Lumpur, Dubai, Auckland, Doha and Singapore. With established domestic and international logistics for hi-tech goods, companies based in Adelaide can serve the national market and easily distribute throughout the rapidly growing Asia-Pacific markets. Adelaide’s location makes it a centre of Australia’s road, rail and air links and South Australia offers quick and cost-effective air and sea freight transport to major markets in Asia. Adelaide is the only mainland capital from which it is possible to fly to and return from all other mainland capitals in Australia within a day. By locating in Adelaide, businesses can manage, train and further grow their national and regional sales and distribution teams. f) Geography, lifestyle and the ideal location At almost one million square kilometres, the state of South Australia is larger than most countries and is four times larger than the United Kingdom. It has a diverse geography, from warm sandy beaches and clear blue oceans to rich agricultural land and stunning outback landscapes. South Australia’s capital, Adelaide, is a vibrant and multicultural metropolis, famed for its festivals and great lifestyle. Fifteen minutes from Adelaide’s CBD you’ll find sun-drenched beaches and some of the world’s best wineries. With an average maximum temperature of 220C, Adelaide has a Mediterranean climate with warm, dry summers and mild winters. It has over 220 days of sunshine a year, delivering a great outdoor lifestyle. Adelaide is building world-class infrastructure in Adelaide BioMed City, and Health Industries South Australia is creating innovative polices that deliver real benefits to business while helping companies take advantage of Adelaide’s fast-growing life sciences ecosystem. Marco Baccanti, Chief Executive, Health Industries South Australia Summer 2016 Volume 8 Issue 2

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Drug Discovery, Development & Delivery

Regulatory Focus on Nanomedicines in the US and Europe The present article aims to produce an overview of nanotechnology and its drug delivery system, as well as the regulatory approach for the approval of nanomedicines in the regulated markets like the United States and Europe. The use of nanoscale technologies to design novel drug delivery systems and devices is a rapidly developing area that promises breakthrough advances in therapeutics and diagnostics. Nanomedicine is an area of nanotechnology, and the goal of nanomedicine is to provide the most effective treatment without side-effects. It is likely to have a wide impact on medical devices and medicinal products, with the potential for the development of new therapies, such as smaller implantable devices or improved dosing and targeting of medicines. Legislation governing the nanomedicines is limited around the world, particularly in the United States and Europe. These organisation strategies for nanotechnology assert that nanotechnology has the potential to enhance quality of life and industrial competitiveness, and therefore lobbies aggressively for minimal legislation on nanotechnology. K e y w o r d s : N a n o t e c h n o l o g y, Nanomedicine, Legislation, Strategies Introduction A drug delivery system (DDS) can be defined as the system that achieves the administration of a therapeutic agent to the patient and improves the drug’s efficacy and safety by controlling the concentration, rate, time, and place of release of drugs in the body. The primary purpose of drug delivery systems is to deliver the drug efficiently and precisely to a targeted site in an appropriate period of time, while maintaining a high concentration of the drug in the diseased site and as low a concentration as possible in the healthy tissue. When coming to the nanotechnologybased delivery systems, they can also protect drugs from degradation. These properties can help reduce the number of doses required, make treatment a better experience, and reduce treatment expenses. Nanotechnology definitely promises to serve as the drug delivery carrier of choice for the more challenging 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

conventional drugs used for the treatment and management of chronic diseases such as cancer, asthma, hypertension, HIV and diabetes. Nanotechnology (sometimes shortened to "nanotech") is the manipulation of matter on an atomic and molecular scale. A more generalised description of nanotechnology was subsequently established by the National Nanotechnology Initiative, which defines nanotechnology as the manipulation of matter with at least one dimension sized from 1 to 100 nanometres.

Fig: Different surface unmodified nanomedicines. (A) Polymeric nanoparticles; (B) solid lipid nanoparticles; (C) polymeric micelles; (D) dendrimers; (E) liposomes; and (F) magnetic nanoparticles. Nanotechnology-based Drug Delivery Systems: 1. Nanoparticulate drug delivery system • Liposomes • Microemulsions • Nanoparticles • Nanomedical Devices • Polymers • Micelles • Nanocapsules

2. Natural polymers in nano drug delivery • • • • •

Polysaccharide Starch Chitosan Proteins Gelatin

1. Nanoparticulate drug delivery system Nanoparticles used as drug delivery vehicles are generally < 100 nm in at least one dimension, and consist of different biodegradable materials such as natural or synthetic polymers, lipids, or metals. Nanoparticles are taken up by cells more efficiently than larger micromolecules and therefore, could be used as effective transport and delivery systems. For therapeutic applications, drugs can either be integrated in the matrix of the particle or attached to the particle surface. A drug targeting system should be able to control the fate of a drug entering the biological environment. Nanosystems with different compositions and biological properties have been extensively investigated for drug and gene delivery applications. 2. Natural Polymers in Nano Drug Delivery Natural biopolymers such as starch, chitosan and gelatin have found use in industries as diverse as food, textiles, cosmetics, plastics, adhesives, paper, and pharmaceuticals. The food industry uses these polymers as a thickening agent in snacks, meat products and fruit juices. They are also used in the manufacture of disposable items like fast food utensils and containers. From a pharmaceutical standpoint, these polymers have been extensively used in solid oral dosage forms, where they have been used as binders, diluents, disintegrant and matrixing agents. In recent times, nanotechnology has started to make significant advances in biomedical applications, including newer drug delivery techniques. There has therefore been considerable research into developing biocompatible, biodegradable submicron devices as drug delivery systems using natural polymers; this is because they occur widely in nature, and are generally Summer 2016 Volume 8 Issue 2

Drug Discovery, Development & Delivery biocompatible, biodegradable, safe and non-immunogenic. There are reports of these polymers being made into colloidal particles that act as carriers for both large and small drug molecules, conferring on the drug molecules properties which enhance delivery actively or passively, thereby tuning them for use as controlled, ocular, transdermal or intranasal delivery systems. In more advanced areas of drug delivery, these polymers have also been tested for gene therapy and tissue engineering. Regulations of Nanomedicines USFDA: FDA has recognised that “because development of nanotechnology-based drugs is still in its infancy, there are no established standards for the study or regulatory evaluation of these products.” As a step forward, FDA is developing a comprehensive database of products containing nanomaterials that were the subject of drug applications to CDER. It should be pointed out that because of the significant amount of preapproval studies required by the FDA, developing nanomedicines such as RNAnanoparticle complexes is the most costly and most long-term endeavour in the nanomedicine context. 1. A product will be regulated by FDA as a drug if it is recognised in an official Pharmacopoeia; is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; or is intended to affect the structure or any function of the body of man or other animals (and is not food). 2. Nanotechnology may challenge the drug device distinction because it can be difficult to distinguish between chemical and physical modes of action at the nanoscale. 3. More knowledge needed about biological interactions and detection and measurement. 4. Agency-wide regulatory/science coordination for nanoscale materials needed. 5. Current testing approaches to assess safety, effectiveness and quality of products with nanoscale materials should be evaluated. 6. Promote/participate in development of characterisation methods and standards for nanoscale materials. 7. Development of models for behaviour of nanoscale particles in

vitro and in vivo. 8. Physio-chemical properties of nanoparticles can impact on biodistribution: • Size • Surface charge • Stability • Density • Crystallinity • Surface characteristics • Solubility 9. Bioavailability of encapsulated and free drug may need to be assessed separately.

process pose the fewest concerns for FDA assurance of the safety of nanotechnology-based drugs. On request, the FDA may require applicants to supply information about a drug’s particle size as part of its review of the product’s safety early in the IND process. However, since particle size is not expressly required to be disclosed by the applicant, either the applicant must voluntarily disclose that the product is nanotechnology-based or the FDA is likely not to become aware

Table 1: List of nanomedicine products approved in the US S.No Platforms







Trade name


Date approved


Fungal infections



Fungal infections



Fungal infections






Lymphomatous meningitis









Vasomotor symptoms














Megace es

Anorexia, Cachexia in AIDS 2005 patients





Metastatic breast cancer






Helioblock sx sunscreen cream



Somatuline depot Acromegaly



i. NDA • The product-specific approvals under the full Section 505(b) (1) NDA

the product utilises nanotechnology until later in the process. In 2010, CDER asked its reviewers in the INTERNATIONAL PHARMACEUTICAL INDUSTRY 25

Drug Discovery, Development & Delivery Office of Pharmaceutical Sciences (OPS) to document nanotechnologyrelated information received in drug application submissions. However, this procedural update only requires OPS reviewers to gather nanotechnology-related information that is reported on a drug application and to search internal reporting databases for particular nanotechnology-related terms; it does not create any new reporting or disclosure requirements for those who submit the drug application. ii. ANDA • For drugs that contain the same or similar active ingredients as previously approved drugs, premarket approval may proceed via a Section 505(b) (2) application or an ANDA. • The FFDCA does not differentiate between active ingredients on the basis of particle size, so a nanotechnology-based active ingredient might be considered the same as a traditional drug, thereby shortening the time necessary for approval and, consequently, getting the product to market faster. • To date, there have been no generic nanotechnology-based drugs approved under the ANDA pathway. • In other words, because a nanotechnology-based drug will likely exhibit different pharmacokinetic properties than a traditional drug, it may not perform in exactly the same manner. Nanotechnology may also be used to produce inactive ingredients, which could influence absorption or toxicity of the product. EMEA: There is a wide range of Community legislation related to issues relevant for nanotechnology and nanomaterials, currently in existence or being elaborated. These issues primarily have to do with risk assessment. Examples of legislation relevant for nanomedicine are the following: (a) Medicinal products marketed in the European Union are covered by comprehensive EU legislation. Medicinal products are defined in the EU legislation as follows: (a) Medicinal product: Any substance or combination of substances presented for 26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

treating or preventing disease in human beings. Any substance or combination of substances which may be administered to human beings with a view to making a medical diagnosis or to restoring, correcting or modifying physiological functions in human beings is likewise considered a medicinal product. All medicinal products marketed in the European Union must obtain an EU product authorisation. Directive 726/2004 lays down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishes a European Medicines Evaluation Agency (EMEA). EMEA’s task, according to its mission statement, is “to contribute to the protection and promotion of public and animal health by mobilising scientific resources from throughout the EU to provide high quality evaluation of medicinal products, to advise on research and development programmes and to provide useful and clear information to users and health care professionals developing efficient and transparent procedures, to allow timely access by users to innovative medicines through a single European marketing authorisation, and in particular through a pharmacovigilance network and the establishment of safe limits for residues in food producing animals.” The European regulatory system for medicinal products offers two routes for authorising medicinal products: A “centralised procedure” with applications made directly to EMEA, leading – if approval is obtained – to the grant of a European marketing authorisation by the Commission. Use of this procedure is compulsory for products derived from biotechnology, and optional for other innovative medicinal products. A “mutual recognition” procedure, which is applicable to the majority of conventional medicinal products. Applications are made to the member states selected by the applicant and the procedure operates by mutual recognition of national marketing organisations. Purely national authorisations are still available for medicinal products to be marketed in one member state. Both procedures are based on a wide range of requirements laid down in implementing rules and – de facto binding – guidance documents. National clinical trials preceding an EU authorisation must observe the rules laid down in the

Declaration of Helsinki, which means, among other things, that they must be assessed by an ethical review committee. Seen in an international context, this EU regulatory system is unique in providing a network between all national regulatory bodies, coordinated by EMEA. (b) Medical devices are also covered by EU regulation, but the Directive on medical devices does not make placing on the market subject to a prior marketing authorisation issued by public authorities. A medical device is defined as “any instrument, apparatus, appliance, software, material or other article, whether used alone or in combination, together with any accessories, including the software necessary for its proper application intended by the manufacturer to be used for medical purposes for human beings for the purpose of diagnosis, prevention, monitoring, treatment or alleviation of disease, investigation, replacement or modification of the anatomy or of a physiological process, control of conception, and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means.” The Directive does not apply to human blood, blood products, blood cells of human origin, human tissue engineered products, etc. However, depending on risks involved, devices can only be placed on the market if they have been subject to a conformity assessment procedure involving a third party, a so-called notified body, designated by a member state. The Directive deals primarily with risk management. Manufacturers are obliged to carry out an assessment of the risks and to adopt a risk management strategy. This means that they have to adopt measures to eliminate risks, or to reduce risks as far as possible, take the necessary protection measures in relation to risks that cannot be eliminated and, as a last resort, inform users of the residual risks due to any shortcomings of the protection measures adopted and advise any other protective measure regarding risks that cannot be eliminated. The Directive on medical devices includes a risk-benefit analysis.

Summer 2016 Volume 8 Issue 2

Drug Discovery, Development & Delivery Table 2: List of nanomedicine products marketed in Europe S.No 1.

Medicinal Product Abraxane (paclitaxel)

Nanotechnology Purpose Solvent-free colloidal suspension of albumin bound nanoparticles to increase water solubility.


Caelyx (doxorubicin)

Pegylated liposome to increase blood circulation (long acting).


Emend (aprepitant)







bioavailability. 4.

Mepact (mifamurtide)







macrophages. 5.

Myocet (doxorubicin)

Liposome encapsulation to reduce cardiac toxicity and to increase tumour tissue distribution.


Rapamune (sirolimus)

Colloidal nanodispersion stabilised with poloxamer to reduce particle size for increased stability and bioavailability.

Conclusion articles/16/ Conclusion: The healthcare revolution brought 3. http://www.nanopharmaceuticals. about by nanomedicine could dwarf all brought org/FDA.html Sabbella - M. The healthcare revolution about by nanomedicine could dwarf all other trends in Vidhya the other trends in the history of medical 4. Pharm Regulatory history of medical technology. There are currently no proper regulatory guidelines developed technology. There are currently no Article4.pdf Affairs, JSS College of nanomedicines, regarding proper regulatoryspecifically guidelinesfor developed 5. due h t ttop inadequate : / / w w wknowledge .fdalaw b l o g . nanoparticle behaviour. Pharmacy, JSS specifically for As nanomedicines, due n e t / f d a _ l a w _ b l o g _ h y m a n _ University, Mysore. the market for nanomedicines is growing, the development of regulatory guidance assumes to inadequate knowledge regarding phelps/2010/08/fda-seeksvidhya.sabbella@gmail. priority. As Currently, the nanomedicine nanoparticle behaviour. the market i n f omarket r m a t is i opoised n - o n at - saacritical f e t y - astage n d -wherein clear regulatory com for nanomedicines is growing, the in providing effectiveness-of-nanodevices-.html guidance is imperative for clarity and legal certainty to manufacturers of development of regulatory guidance 6. h t t p : / / w w w . n a n o t o x . c o m / Ravi - Assistant nanomedicine. As the properties of nanomedicines often differs, the regulations vary with thatValluru of assumes priority. Currently, the industries/nanomedicines-a-nanoProfessor, Department of the regular pharmaceutical Thus, jurisdictions should continue to broaden legislation nanomedicine market is poised at a products. medical-devices.html Pharmaceutics, JSS critical stage wherein cleartheregulatory h t t p : / / w w w.Since p h a regulatory r m a i n f o .agencies n e t / around the world College of Pharmacy, monitoring development7. of nanotechnology. are guidance is imperative in providing reviews/nanomedical-devicesJSS University, Mysore. for clarity and legal certainty to overview ravivalluru@rediffmail. 9 manufacturers of nanomedicine. As 8. h t t p : / / w w w. com the properties of nanomedicines often ar ticle/exploring-world-nanodiffers, the regulations vary with that of medical-devices T. M. Pramod Kumar the regular pharmaceutical products. 9. h t t p : / / e c . e u r o p a . e u / b e p a / Professor & Head of Thus, jurisdictions should continue to european-groupethics/docs/ Department of broaden legislation monitoring the publications/opinion _21_nano_ Pharmaceutics, JSS development of nanotechnology. Since en.pdf College of Pharmacy, regulatory agencies around the world are 10. University, Mysore. simultaneously struggling with regulatory 10-papers/5B2.pdf issues of nanomedicines, there may be 11. http://www.nanopharmaceuticals. benefits from attempting to harmonise org/Liposomes.html K. Sreekanth Reddy - M. national regulations. The agency should 12. h t t p : / / c d n . i n t e c h o p e n . c o m / Pharm Regulatory begin to prepare now for the coming pdfs/32559/InTech-Nanoparticles_ Affairs, JSS College of revolution in nanomedicine. preparation_using _microemulsion_ Pharmacy, JSS systems.pdf University, Mysore. References 13. sreekanthkaja@ymail. 1. articles/n/nanoparticle.htm com miller.pdf 2. h t t p : / / w w w . n a n o . o r g . u k /


Drug Discovery, Development & Delivery

Innovations in the PASS Concept Opening the Door to Real-world Data The role of data collected during postmarketing surveillance has recently been widely recognised as being of great value in terms of providing real-world evidence, as long as the credibility, quality and transparency of data is maintained. In parallel with the dynamic increase of requirements and challenges concerning post-authorisation safety studies (PASS) planning, conduct and assessment, the European Medicines Agency (EMA) offers flexibility and firm scientific assistance to marketing authorisation holders (MAHs). EMA strongly supports the idea of proactive pharmacovigilance planning at early stages of medicinal product development in order to obtain integrated and comprehensive information on a medicine in a real-life setting during its entire life-cycle. Over the last few years, the European Union (EU) pharmaceutical legislation implemented a number of tools and provisions supporting accelerated centralised marketing authorisation processes. The current flexible regulatory approach to early approval options allows the time and cost of the preapproval research to be decreased, and helps to bring products earlier to the market. The aim of the article is to review the present regulatory and scientific approach to PAS studies, and to signal the direction of expected future changes arising from the fact that post-authorisation research is critically important in the context of efficient authorisation procedures and timely access to innovative and safe medicines. Conceptual and Regulatory Framework The European pharmacovigilance legislation and scientific recommendations have evolved substantially over the last few years, aiming to better protect public health by reducing the number of adverse drug reactions, establishing clear roles and responsibilities, improving safety communication, simplifying safety reporting procedures and also increasing transparency. The EU pharmacovigilance legal framework and the Good Pharmacovigilance Practice (GVP) guidelines, which came into force in 2012, apply to all medicinal products authorised in Europe, regardless of the 28 INTERNATIONAL PHARMACEUTICAL INDUSTRY

type of authorisation procedure, whether centralised or via the national route. These changes have affected all areas of safety management in order to unify and streamline safety data monitoring, collection, reporting and risk-benefit assessment, and to increase the quality and scientific value of data. Based on the EU pharmacovigilance legislation, the marketing authorisation holder is obliged to design and maintain a safety management system which is adequate for the monitoring, collection and assessment of detailed, accurate and legible information on adverse events, whether reported by healthcare professionals or patients1.

In August 2015 the GVP Module VIII (post-authorisation safety studies) draft revision no. 2 was adopted by EMA and released for public consultation. The publication of the GVP Module VIII (Rev2) is expected in Q2 2016. Publication of final scientific guidance on post-authorisation efficacy studies is expected in Q3-Q4 20164. Evolving Regulatory Burden The role of data collected during postmarketing surveillance has recently been widely recognised as being of great value in terms of providing real-world evidence, as long as the credibility, quality and transparency of data is maintained.

If any potential, significant risks or safety concerns are detected during the marketing authorisation procedure or the post-authorisation phases (during the renewal procedure or PSUR assessment), a post-authorisation safety study may be imposed by the EMA or the national competent authority. A PASS may also be required as an obligation for products marketed under exceptional circumstances. For centrally authorised medicinal products, the Pharmacovigilance Risk Assessment Committee (PRAC) of EMA is responsible for identifying the need for additional post-authorisation product research. A PASS may also be initiated and financed by the MAH voluntarily, in order to collect additional safety data or to evaluate the effectiveness of risk-minimisation activities2.

The EMA, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP), the International Society for Pharmacoepidemiology (ISPE) and other relevant regulatory and/or society networks released a number of scientific guidelines and best practices to ensure the constant development of PASS.

According to Directive 2001/83/EC, the post-authorisation safety study is any study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures3.

• •

GVP’s Module VIII concerning PAS studies constitutes the crucial, fundamental - and at present, still evolving - guideline for this type of research, with its main focus on non-interventional PASS.

The following list of exemplary recommendations should be adequately applied by MAHs, depending on the type of post-authorisation research (Phase IV clinical trials / non-interventional studies, imposed / conducted voluntarily): •

• • •

Guidelines on Good Pharmacovigilance Practices (EMA) Good Clinical Practice (ICH) E2A-E2F Pharmacovigilance guidelines (ICH) Guide on methodological standards in pharmacoepidemiology (ENCePP) Good Pharmacoepidemiology Practices (ISPE) Guidelines for the format and content of the protocol and the final study report of non-interventional post-authorization safety studies (EMA)

The increasing regulatory burden may lead to significant levels of uncertainty Summer 2016 Volume 8 Issue 2

Drug Discovery, Development & Delivery regarding the choice of guidelines and recommendations to be followed for a particular type of research. Additionally, for some types of studies (like, for instance, PASS conducted voluntarily), EMA recommendations are broader than applicable legal requirements. The GVP Module VIII has a clearly visible, strong tendency towards harmonisation of requirements on studies imposed, as well as studies conducted voluntarily. Both research types should follow the highest level of quality and scientific standards. The main aim of such standardisation of requirements is to increase the public availability of data and reinforce the usefulness of data. It may be found extremely beneficial in the process of

In July 2015, the Scientific Advice Working Party and PRAC of EMA launched a 12-month pilot aiming to support MAHs with scientific advice for PASS. The scientific advice is voluntary, and is available for both nationally and centrally authorised products, applicable for imposed and non-imposed PASS, with a main focus on protocols for nonimposed PASS. The main objective of the pilot which has been initiated is to provide expert advice, recommendations on questionable, inconvenient approaches, and confirmations for innovative methodologies, especially when available guidelines do not provide a sufficient level of detail. It is expected that

Studies imposed as an obligation

Studies conducted voluntarily

Mandatory format of the study protocol and report


GVP recommendation

Study protocol and report -submission to NCA/EMA



QPPV involvement in the review and sign-off of study protocols



Registration of study in EU PAS Register


GVP recommendation

Quality system


GVP recommendation

which MAHs may have on postauthorisation procedures, including PASS. The currently available version is dated 18 April 2016: “European Medicines Agency post-authorisation procedural advice for users of the centralised procedure” (EMEA-H-19984/03 Rev. 60) PASS - Integral Part of Drug Development During the pre-approval phases of the development, medicinal products are investigated carefully and in depth, according to the national and EU legislation, good clinical practice, and other relevant scientific guidelines, to deliver clear, convincing and consistent evidence of appropriate safety, efficacy profiles and a favourable risk-benefit ratio. Nevertheless, in order to obtain satisfactory clinical research data confirming the study hypothesis and facilitating the marketing approval procedure, it is essential to explicitly define the trial timeframes and population type, and limit the variability of subjects’ response.

Clinical trials conducted in a prespecified patient population, enrolled based on strict inclusion/exclusion Pharmacovigilance system required required criteria, as well as treated and observed ENCePP code of conduct recommended recommended within limited timeframes, will never satisfy the growing need for real-world Scientific Advice optional strongly recommended data. Only long-term observation in a post-approval, real-life setting may Table 1. Main legal obligations and GVP recommendations for PASS imposed as an provide the cumulative, unbiased, realobligation and PASS conducted voluntarily by MAH world evidences to ensure that the actual benefits of therapy outweigh the risk. reducing the duplicated time and efforts such a procedure will contribute to the spent on safety data collection by an improvement of study design, quality of At a time of rapid and continuous individual company. data and further integration of advice on increase in the range of innovative Further strengthening of safety, quality, and efficacy, pre- and post- biologicals, biosimilar products and pharmacovigilance capability and authorisation. EMA strongly supports the related biological medicinal products on transparency is planned over the idea of proactive pharmacovigilance the European market, PAS studies are coming years by EMA. It has become planning in the early stages of medicinal becoming an integral part of the medicinal obvious that the standard solutions product development, in order to obtain product development and assessment. cannot be applied to all products, due consistent, comprehensive and valuable Complexity of biologic molecules, as to rapid advances in science, with new information during the lifespan of a well as complicated manufacturing and upcoming technologies leading to medicine6. processes extremely sensitive to changes, generation of innovative products. New determine the final product’s quality, methods of data collection, monitoring Early dialogue with the agency is safety and efficacy. Despite advances and assessment are to be laid down substantial, especially for products in biotechnology and analytical to ensure safety, efficacy and quality with innovative development strategies. sciences, the fundamental complexity throughout the lifecycles of different types Scientific discussion initiated well in of biopharmaceuticals still remains a of medicinal products5. advance of the marketing approval challenge from a pharmacovigilance procedure may be translated into an perspective. Use of existing registries, or EMA Scientific Support expedited authorisation process, in establishment of new registries collecting In parallel with the dynamic increase of spite of the fact that the scientific advice observational data for new biologicals, requirements and challenges concerning procedure is not legally binding. should be applied to evaluate any specific PASS planning, conduct and assessment, areas of concern7. EMA provides MAHs with openness, EMA regularly updates the guidance flexibility and firm scientific assistance. document containing a list of questions Only diligent monitoring of


Drug Discovery, Development & Delivery

Clinical trial data

Real-life evidences

(applicable for certain categories of medicinal products):

Limited number of homogenous patients (enrolled according to strict inclusion/exclusion criteria, similar general health status and disease stage)

Numerous heterogenous population (availability of data from elderly and/or pediatric population, different types of concomitant diseases)

Pre-defined list of concomitant therapies

Wide range of concomitant therapies available for patients (drug interactions, unexpected side effects)

Limited time-frames for data collection

Long-term observation

Defined indication and dosage regimen

Prescribed in an usual labelled manner as well as off label use

Expected response within pre-defined margin

High level of variability in response

Careful data verification, strict statistical regime

Dealing with missing data and statistical analysis challenges

Table 2. Comparison of standard assumptions and nature of data collected during pre- and post-approval research. biopharmaceuticals in a real-life setting enables the observation of the long-term safety and immunogenicity, interactions between different products, or effects of switching between similar biological therapies. Under normal circumstances, such observations cannot be reliably performed and assessed preauthorisation. In December 2015, GVP Module PII (Biological Medicinal Products) draft was adopted by the EMA and released for public consultation. Publication of the final GVP Module PII is expected in Q2 2016. Lists of medicinal products under additional monitoring have been published by EMA since 2013. The lists contain medicines authorised in the EU which are being monitored particularly closely by regulatory authorities. Over the last three years, the quantity of products under additional monitoring has risen from 100 to almost 300. About 25% of listed medicines are under PAS investigations. Noticeable also is a considerable increase in the number of substances authorised under exceptional circumstances. For a significant number of biopharmaceuticals, the post-authorisation surveillance is the fundamental condition for marketing approval8. The information available in the public register of all pharmacoepidemiological and pharmacovigilance studies (referred to as the EU PAS Register) reflects recent changes in the role of PASS in medicines development. The number of postauthorisation safety studies registered in the EU PAS Register increases significantly 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

every year. In 2014, the number of registered studies changed from 203 to 440 between January and December. In 2015, the number of studies had risen from 440 to 690 (56% increase) between January and December9. Number of new studies registered by ENCePP Centres 120








40 20

9 2011





Graph 1. The voluntary registration of studies by ENCePP partners and pharmaceutical industry continues to rise substantially (Source: EMA/847196/2015 ENCePP activity report 2015; 8 March 2016) PASS – Condition for Accelerated Approval The European regulatory approach to marketing authorisation procedure has become flexible and responsive to patients’ demands. To enable early and wide use of promising new medicines, it was essential to introduce accessible approval, licensing and reimbursement pathways together with scrutinous, in-depth risk-benefit monitoring and assessment during the entire lifecycle of medicines. The European pharmaceutical legislation implemented a number of tools and provisions supporting accelerated centralised approval processes

accelerated assessment procedure (reducing timeframes for marketing approval application from a maximum of 210 days to 150 days) conditional marketing authorisation (ensuring approval based on less complete data on the condition that post-authorisation research is going to be conducted) adaptive pathways (a scientific concept that supports staggered approval from an initial restricted patient population and collection of real-life data to supplement clinical trial data) PRIME scheme (supporting development of medicinal products of major public health interest through early and enhanced scientific and regulatory dialogue)

An accelerated approval concept may be feasible only if MAHs engage in early dialogue with the EMA. Prospective, early planning of risk management, including post-authorisation research, is critically important in view of efficient authorisation procedures. Successful and early bringing of the products to the EU market is achievable only for medicines characterised by a well-designed, smart development strategy including comprehensive data collection during post-authorisation research10. In February 2016, the EMA adopted the following revised guidelines on the procedure for accelerated assessment and on the conditional marketing authorisation for medicinal products: •

Guideline on the scientific application and the practical arrangements necessary to implement the procedure for accelerated assessment pursuant to Article 14(9) of Regulation (EC) No 726/2004 (EMA/CHMP/671361/2015 Rev. 1) Guideline on the scientific application and the practical arrangements necessary to implement Commission Regulation (EC) No 507/2006 on the conditional marketing authorisation for medicinal products for human use falling within the scope of Regulation (EC) No 726/2004 (EMA/CHMP/509951/2006, Rev.1 25 February 2016)

Summer 2016 Volume 8 Issue 2

Drug Discovery, Development & Delivery PASS – For Mutual Benefit In view of the rising costs of new medicines creation and the growing need for society to access innovative, advanced therapeutic options at an earlier stage, there is a common, clear understanding amongst regulatory authorities, reimbursement bodies and MAHs that safe and timely public access to novel medicines is a priority. The current flexible regulatory approach to accelerated approval allows time and cost of the pre-approval research to be decreased, and to bring the products earlier to market. Average costs of post-approval research, especially non-interventional trials, are considerably lower than expenses related to clinical development. In such a scenario, marketing approval holders gain the opportunity for further, continuous development of the products in a post-approval setting. The possibility to shorten the duration and limit the scope of pre-approval research may be much more accessible for MAHs, if the PASS design is assessed during early stages of product development, as an integral part of the product research programme, and not at the time of marketing approval application preparation. Monitoring of products throughout their lifespan has never been more critical. Ensuring timely access to new beneficial and safe medicines for patients is one of the main objectives of the EU Medicines Agencies Network Strategy for the next 5 years5.

In light of accelerated approval options and the recognised great value of real-world evidence, PASS studies constitute an outstanding opportunity for those MAHs who can use available resources and translate the obligation into continuous successful development of a medicinal product. Nevertheless, complete, mutual benefits would be impossible to achieve without strengthened collaboration and early dialogue between the manufacturers, relevant regulatory authorities, medical practitioners and patients. References: 1. Guideline on good pharmacovigilance practices (GVP), Module VI – Management and reporting of adverse reactions to medicinal products, EMA/873138/2011 Rev 1, 8 September 2014; 2. Guideline on good pharmacovigilance practices (GVP), Module VIII – Post-authorisation safety studies, EMA/813938/2011, 19 April 2013; 3. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001; 4. “What’s new in Pharmacovigilance, QPPV Update”, European Medicines Agency, Issue 1, April 2016; 5. EU Medicines Agencies Network Strategy to 2020, EMA/ MB/151414/2015, 17 December 2015; 6. European Medicines Agency postauthorisation procedural advice for users of the centralised procedure, EMEA-H-19984/03 Rev. 60, 18

Decreased cost and time of clinical development

New indications

Accelerated approval

Lower price of therapy

Further development

Early access

Real-life data collection

Accelated acces to treatment

Graph 2. Flexible regulatory approach to accelerated approval allows time and cost of the pre-approval research to be decreased and to bring the medicinal products earlier to the market.

April 2016; 7. Guideline on good pharmacovigilance practices (GVP), Product- or PopulationSpecific Considerations II: Biological medicinal products, EMA/168402/2014 DRAFT for public consultation, 8 December 2015; 8. List of medicinal products under additional monitoring, EMA/245297/2013 Rev.33, 27 April 2016; 9. ENCePP Activity Report 2015, EMA/847196/2015, 8 march 2016; 10. Development support and regulatory tools for early access to medicines, EMA/531801/2015, 1 March 2016.

Magdalena Matusiak leads the Pharmacovigilance Team at KCR, Contract Research Organisation. She specialises in strategic planning, protocol development and delivery of pharmacovigilance services during clinical trials and post-approval research. She is also involved in medical writing and scientific consultations with regard to safety management processes and documentation. Ms Matusiak has extensive knowledge of clinical trial regulations with major focus on drug safety and effective assessment of the risk-benefit balance. Email:


Drug Discovery, Development & Delivery

Pre-fillable Syringes for the Biotechnological Requirements of the Present and Future Abstract Pre-fillable syringes are both pharmaceutical primary packaging and drug delivery devices. End users, drug administration agencies and the pharmaceutical industry are imposing increasingly stringent quality requirements on pre-fillable syringes in both these functions. Optimised production and inspection processes ensure that the syringes can meet these requirements. Although siliconisation is crucial as lubricant to the proper function of the plunger in the syringe body, it has to be reduced to the minimum in syringes used for innovative biotech drugs. A longterm study investigated the factors that affect break loose and gliding forces in syringes during the injection process. The findings make a valuable contribution to establishing certainty that syringes in auto-injectors, which are often stored for lengthy periods of time, will still reliably administer the required dosage. 1. Pre-fillable Syringes Pre-fillable syringes are still one of the strongest growth segments in the global primary packaging materials market. In 2015, approximately 3 billion prefillable syringes were sold worldwide. Pre-fillable syringes must fulfill the most varied requirements, both as the lowest interaction primary packaging material possible, and on the other hand as a secure delivery system ("drug delivery device"). Special requirements for purity are presented by innovative medications originating from biotechnological research. The classical application areas for medications in pre-fillable syringes (heparin as a thrombosis prophylaxis and vaccines) have today been supplemented by many additional illnesses that can be treated with the help of pre-filled syringes. Ophthalmological applications, the treatment of arthritis, growth hormones, various forms of cancer or applications for neurological conditions â&#x20AC;&#x201C; every therapy requires adjustments and further developments that initially seem minor, but have very different syringe designs as a consequence when considered in detail (Fig. 1).


expiration of the drug shelf-life.

Figure 1 Pre-filled Syringe as Primary Packaging Material The number of biotechnologically manufactured medications is increasing constantly. Many of these are filled and stored in syringes for the benefit of the user (pre-filled syringes). However, under certain circumstances proteins can react to components of the syringe that are not part of a classic vial. In addition to the packaging material glass (pharmaceutical glass, type I glass in accordance with Ph. Eur.), syringes contain the following "components": silicone oil as a lubricant for the plunger stopper, traces of tungsten from the production process of the glass syringes, stainless steel of the cannulas, as well as the glue used to fix the cannulas. As with the vial, these new sources for leachables and extractables (L&E) are supplemented by the elastomerbased sealing components. In the case of the syringe, one differentiates between halobutyl-based rubber types for plunger stoppers and synthetic isopreneor blends for sealing caps (tip caps and, in the case of needle syringes, so-called needle shields, Fig. 2). Other components such as the plunger rod and, e.g., the backstop, are not primary packaging materials, as they have no contact with the productâ&#x20AC;&#x2122;s primary packaging. The pre-filled syringe primarily protects the medication against oxidation and microbial contamination1. It should interact with the solution or contaminate this with L&E and particles to the least extent possible. This is especially important for the primary packaging of protein-based medications and for ophthalmological applications. In the context of stability studies, pharmaceutical companies are obliged to examine the possible interactions between packaging materials and medication. The drug stability must thereby be ensured until the

Actual Syringe Function End users such as doctors, nursing staff and increasingly patients themselves ("home use") expect and wish that injections can be administered as seldom as possible, meaning at long intervals, as simply as possible and with a minimum of pain. The syringe thus needs to be adapted not only to the medication, but also to the users. This means that prefillable syringes are increasingly being integrated into auto-injectors for use at home. Failure-free function, even with highly viscous solutions or low dosages, must thus also be ensured. Protection from needle stick injuries is another aspect that is increasing in importance. In the USA, "needle safety systems" have already been federally regulated to manufacturers since 1999 in the form of the "Needle Stick Safety and Prevention Act". Needle injuries ultimately represent a potential source of infections with life-threatening diseases like hepatitis or HIV for nursing staff. Auto-injectors also offer these properties, but are not normally used in hospitals or by specialist personnel. Most needle safety systems work by a spring-driven mechanism that shields the needle after the injection has been carried out. Packaging material

Figure 2 development departments thus face a variety of challenges in coordinating automatic injectors, needle protection, syringe and medication with one another. In the biotech sector, the 1 ml long needle syringe is the most frequently used format for subcutaneous injections. The current trend toward larger dosage volumes also brings with it an increasing demand for 2.25 ml needle syringes. In ophthalmology, primarily Luer lock types are used, as special cannulas are needed. More Safety with Backstops In addition to the needle, the finger Summer 2016 Volume 8 Issue 2

Chapter Title

Bringing together the best of

When it’s


compound, every step matters. API



Summer 2016 Volume 8 Issue 2

PC1-16-0005-210x297mm-Apr., 2016 © 2016 Pfizer Inc. All rights reserved. Pfizer CentreOne is a Trademark of Pfizer Inc.

Drug Discovery, Development & Delivery flange is also an element of the syringe of relevance for safety. The exertion of force during an injection increases depending upon the viscosity of the solution. A backstop on the finger flange enlarges the contact area and in this way improves the ergonomics (Fig. 3).

New challenges arise due to the assembly of glass syringes into plastic devices, like in auto-injectors or needle safety systems. Here the important thing is to avoid potential glass breakage with an adapted design of the syringe body and/ or of the plastic device. Camera Technology in Glass-forming Using high-resolution camera technology, the glass syringes in production today can be checked 100 % for so-called cosmetic defects (like air lines, inclusions, scratches, cracks, particles) (Figs. 5 and 6).

Figure 3

Figure 7

Figure 6

2. Product Quality and Modern Production Added to this complex situation of the syringe between technical and pharmaceutical requirements are the high standards of pharmaceutical customers with regard to consistent product quality with low reject rates, problem-free processability on the filling lines and a secure, uninterrupted product supply2. The required quality therefore requires continuous further development of production processes.


Cleanrooms and RTF® Production Following the forming of the syringe, the needles are glued in at the so-called "cold end" of production in the cleanroom (socalled staked-in needle syringes). Further steps and packaging then take place in the ready-to-fill (RTF®) process. The RTF process consists of washing, siliconisation and positioning of the tip cap or needle shield with subsequent packaging in the nest and tub (Fig. 7).

Figure 5

The backstop also functions as a locking element. It prevents accidental leaking of product when pulling back the plunger by stopping the plunger before the end of the syringe body (Fig. 4).

Figure 4

the syringes. This is especially decisive for smaller filling volumes. The newest camera technology allows for 360° inspection, which significantly improves the quality control of the manufactured syringes.

The dimensional accuracy of the syringe body from the cone over the shoulder and the syringe body to the finger flange is also controlled. Several cameras are used on a production line to record and differentiate the individual defects. The technology is so sophisticated in high resolution that individual defect types can be differentiated. This makes it possible to define and check customer-specific product properties. Depending upon the application, narrower dimensional requirements are important, e.g., for use in auto-injectors, while Japanese customers attach extremely great importance to minimising cosmetic defects. The exact shoulder and cone shape in combination with precise positioning of the graduation supported by the camera technology also enables unprecedented precision when emptying

Following ethylene oxide (EO) sterilisation, the product is "ready-tofill", meaning that the syringes can be filled at the pharmaceutical or biotech company directly without additional process steps. Syringe processing, of course, takes place in appropriately classified cleanrooms. Like modern glass-forming lines, modern assembly lines also avoid defect-prone glass-toglass or glass-to-metal contact; optimised washing and siliconisation processes ensure the observance of increasingly strict regulatory requirements. After being put into pouches, the syringes are transported into a cleanroom ISO class 8 for end packaging in polypropylene (PP) boxes and final EO gas sterilisation. 3. Application Examples from Ophthalmology Another therapeutic area in which prefillable syringes have made drug delivery more user-friendly and decreased risk is ophthalmology. The syringes are primarily used here for cataract operations in the anterior eye area and for the treatment of wet macular degeneration inside the eye. In the case of cataract operations, the injection of viscous hyaluronic acid prevents the collapse of the anterior Summer 2016 Volume 8 Issue 2

Drug Discovery, Development & Delivery chamber and simplifies the insertion of artificial intraocular lenses. In the case of macular diseases, monoclonal antibodies (mAbs) injected into the vitreous body can inhibit the adverse growth of blood vessels and in this way maintain the sight of the patient. Both therapies are very different, although the eye is treated in both cases. The hyaluronic acids used for cataract operations are highly viscous, but are not especially sensitive to potential chemical interactions. RTF syringes can be equipped with backstops for enlarging the finger contact area for the injection. Luer lock syringes enabling free choice of needles are commonly used (Fig. 8a). Conversely, the monoclonal antibodies (mAbs) used for the therapy of retina removal are biotechnologically manufactured. In ophthalmology they are injected with fine needles repeatedly

thus very important, as this can be seen by the optometrist during the operation and be recognised as contamination ("droplets"). The droplets may also accumulate in the vitreous humour and possibly cause "seeing spots" with extended therapy. This phenomenon is harmless but bothersome. The use of heat-cured siliconised syringes is therefore recommended for critical application areas like ophthalmology, or for several silicone oil-sensitive3, biotechnologically manufactured formulations. These syringes, also known as baked-on RTF syringes, are not spray siliconised with pure silicone oil, but are instead sprayed with a silicone oil-water emulsion, which is baked onto the glass matrix surface using a dedicated oven at several hundred degrees [°C]. In the process, solid bonds between the glass matrix and the polydimethysiloxane chains are formed, which results in a permanent, hydrophobic anti-friction coating. The number of free droplets later found in the filled syringes thereby decreases by about 90 % in comparison to conventional spray siliconisation (Fig. 9).

Figure 8a

Particles/1 ml (pooled data)

200 180 160 140 120 100 80 60 40 20 0 Spray DC 360, 0.8 mg Baked-on, DC 365 emul.







Figure 9 Baked-on siliconised syringes are thus also highly suitable as packaging materials for solutions sensitive to silicone oil4. First concepts of a completely silicone oil-free glass syringe exist but are not commercialised in glass syringes yet. Figure 8b at intervals of several weeks directly into the interior of the eye (Fig. 8b). In these cases low dosage volume requires highly precise syringe dimensions and scaling. Both treatment areas are subject to strict requirements with regard to the allowed particle load. 4. Baked-on Siliconisation for Special Cases The reduction of free silicone oil (subvisible particles) in the drug solution is 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

5. What is Tungsten Doing in the Syringe? Apart from silicone oil, additional substances can interact with the active ingredient or formulation components. For example, a tungsten pin is used to create the syringe bore (Fig. 10). When traces of tungsten or tungsten oxides remain in the bore area, proteinbased medications can react sensitively in rare cases. For example, protein aggregates were found under particular circumstances in pre-filled syringes that can be traced back to tungsten

contamination5. By washing the syringe immediately following the forming of the cone and by using alternative forming pin materials, tungsten residue can already be reduced to an extent specified by the customer during production of the glass syringes, or even entirely avoided. Staked-in needle syringe bodies are generally less burdened with tungsten residue, as the UV-hardened glue seals the sensitive syringe area in addition to the even comparatively small bore diameter. There is no officially prescribed limit value for tungsten yet, but many syringe manufacturers have specified their own internal tungsten limits. F = 8 Q µ L / π R4 *A F = Frictionless travel force

L = Needle length

Q = Volumetric flow rate

R = Needle inner diameter

µ = Fluid viscosity

A = Cross section area of syringe plunger

Figure 10

6. Alternatives to Glass Syringes Although glass remains widely used as primary packaging for parenterals, cyclical olefins are increasingly asserting themselves as an alternative packaging material for pre-fillable syringes. Cyclical olefins (cyclo olefin polymer: COP, cyclo olefin copolymer: COC) are as clear as glass, but considerably less prone to breakage. The L&E profile of the material is very favourable. Containers can be produced extremely precisely on fullyautomated lines by injection moulding. There are no potential tungsten or glue contaminants. There is no release of metal ions or an increase in the pH value of the solution due to hydrolysed sodium, a phenomenon especially known from glass vials. COP plastic syringes are exceptionally well-suited for the packaging of biotechnological, cytotoxic and/or viscous medications (Fig. 11).

Figure 11

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Drug Discovery, Development & Delivery

7. Syringe Functionality In order for a syringe to function optimally, the interplay of syringe body and plunger must be coordinated. Criteria here are the so-called break loose force that needs to be overcome upon commencement of emptying the syringe, and the gliding force exercised via the plunger rod during the injection itself. Important are simple and safe operation, complete emptying and precise dosage. Typical for the activation of a syringe are two phases with differing force progressions (Fig. 12).

Figure 12 Siliconisation of syringe bodies and plungers Pre-fillable glass syringes are either siliconised inside with pure silicone oil as described or subjected to bakedon siliconisation. Both procedures result in differing gliding properties of the plunger stopper, as the quantity, distribution and type of the silicone oil have a great influence here. In the case of spray siliconisation, the quantity and the distribution profile of the oil in the syringe can also be varied6. The system is completed by plunger stoppers from various manufacturers, which in turn consist of various rubber formulations (bromobutyl or chlorobutyl rubber), have different respective dimensions, are for the most part also siliconised (differing quantities and processes) or have been treated with a special coating of fluoropolymers. Setting the plunger The syringe diameter and the way in which the plunger stopper is brought into the syringe influence the behaviour when emptying a syringe. The manufacturers of filling machinery offer two plunger stopper placement techniques here: The plunger can be placed in the filled syringe by means of a vented tube. To this purpose the rubber stopper must be briefly compressed in a tube and

positioned at the correct position in the syringe. When the tube is pulled out, a rod fixes the plunger at the desired position. This procedure results in slight mechanical stress on the plunger. The alternative vacuum placement method generates a vacuum within the interior of the syringe and hence pulls the plunger stopper inside the barrel until it is just above the surface of the liquid. The plunger thus moves a distance along the interior surface of the glass. The choice of either method has a varying influence on the final break loose and gliding behaviour. Influences of storage An important aspect for pre-filled syringes is of course their long-term performance. The pre-filled syringe has to remain fully functional even after several years of storage. Storage can influence the performance of the syringe system and is, among other factors, dependent upon the filling material and the temperature. Various time points as well as different plunger stoppers show varying results here. Other aspects Manufacturers of pre-fillable syringes provide an intermediate product for pharmaceutical companies and are thus not responsible for the final functional properties of the filled syringe. The break loose and gliding forces of empty syringes are therefore collected as a base measurement. However, their significance with regard to the subsequent behaviour of the filled syringes is limited. Product viscosity, needle length, interior diameter of the needle and diameter of the plunger stopper also have a significant influence here (Fig. 13).

F = 8 Q µ L / π R4 *A F = Frictionless travel force

L = Needle length

Q = Volumetric flow rate

R = Needle inner diameter

µ = Fluid viscosity

A = Cross section area of syringe plunger

Figure 13 With the help of special thin-wall cannulas, highly viscous liquids can also be injected using larger interior diameters. These relationships are expressed with the Hagen-Poiseuille formula and are recorded under the keyword "syringeability"7.

8. Gliding Force Study The understanding of the syringe as an injection system is of great importance for manufacturers and users of syringes. A long-term study from 2011 to 2015 therefore examined how parameters named above influence the break loose and gliding forces, and what the decisive criteria for simple and problem-free usage are. The syringes were tested empty or filled with water for injection (WFI) and equipped with various plunger stoppers. In the process, only needle syringes with the most frequently used cannulas with 25 G, 5/8" and 27 G, 1/2" diameters or lengths were used. The syringes were subsequently emptied on a force measurement device at various points in time and the corresponding force curves were noted. The measurement data from approximately 20,000 syringes collected over the course of the study enable an optimised selection of suitable syringe components. Study parameters: Syringe shape: 1 ml short, 25 G needle, 5/8" 1 ml long, 27 G needle, 1/2" Siliconisation process: RTF spray siliconisation with pure silicone oil (0.8 mg per syringe) RTF baked-on siliconisation with silicone emulsion Filling material: Empty Water for injection Plunger assembly: Vacuum stoppering Vent tube stoppering Plunger: Manufacturer Shape Material Coating Siliconisation Storage period: 0, 3, 6, 12, 24, 36 months at room temperature Accelerated aging 3, 6 months at increased room temperature and air humidity (40 °C, 75 % rH). Results of Gliding Force Study Most syringes function throughout the entire testing period, but some demonstrate peculiar features and are therefore not suited for all applications. A properly functioning system is shown in Fig.14. INTERNATIONAL PHARMACEUTICAL INDUSTRY 37

Drug Discovery, Development & Delivery

The choice of the right syringe is as important for a successful therapy as the medication itself. Only reliable syringe systems lead to acceptance and trust with medical specialists and to increased compliance among patients.

Figure 14 Several force-deflection graphs of sub-optimal systems are described as examples in the following: - Extremely high breakaway forces and a strong drop of the breakaway to the gliding force can cause considerable problems for the syringe user when the syringe suddenly empties rapidly after initial high pressure. Here it is conceivable that the syringe content might be lost or that the patient might suffer pain during the injection (Fig. 15a).

Figure 15c if the required force increases when pressing out (Fig. 15c). - Even an excessive increase of the forces in the course of the storage period is critical, as this has a negative effect on reliability for the user. Syringes with high variability would not function with autoinjectors. Summary The results of the study contribute to providing a clearer picture of the influence factors of decisive importance for syringe function. A series of hypotheses could be confirmed, and others were revised. When designing the study it could be confirmed that the accelerated storage of syringes at an increased ambient temperature and air humidity is a reliable instrument for measuring the effects of storage in an accelerated process. •

Figure 15a - The parallel samples should demonstrate the lowest possible fluctuations with reference to one another. Figure 15b

• • Figure 15b shows an unfavourable example. - Also unsuitable are combinations of syringe and plunger stopper with which the gliding force rapidly increases between the beginning and the end of the injection. It may be possible that the complete dosage will not be administered 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The advantage of baked-on as opposed to spray siliconisation brings a considerable reduction of the free silicone oil in the solution, whereas the gliding forces are slightly higher than with spray siliconisation. The assumption that the break loose forces for syringes with spray siliconisation increase more during storage than for syringes with baked-on siliconisation could not be generally confirmed for all plungers. The influence of the storage duration on break loose and gliding forces is generally rather moderate. In contrast, the plunger stopper is of decisive importance. Here the selection of its shape, the material, the coating and the siliconisation have a considerable influence on the ultimate functional capability of the syringe. The matter of whether the plunger stopper was assembled using vacuum or vent tube stoppering only had significant effects for some plunger stopper types.

9. Outlook There will most likely never be an all-purpose solution for pre-fillable syringes. Thanks to the available range of syringe sizes, types and materials, of graduations, plunger stopper shapes and rubber formulations, as well as siliconisation processes and needle types, there is instead a comprehensive kit available, from which specific solutions can be compiled or modified for the respective application area. For subcutaneous delivery, a highly viscous biotechnological medication in an autoinjector involves other requirements of the syringe than does an aqueous solution that is administered once annually in the form of a vaccination. With manual administering of injections, medical specialists or patients can react unconsciously to fluctuating force requirements. The case is different for the use of pre-fillable syringes in autoinjectors, which play an increasingly important role in the treatment of chronic illnesses. In this case, the available forces are defined by the spring force. The siliconisation of the syringe must therefore be set in such a way that complete emptying of the syringe is reliably ensured with these forces, even after longer storage. An interior diameter of the needle used that is adapted to the viscosity is also important for the period of administering (around 10 s is usually desirable). It is thereby expected of the syringe manufacturer to understand the needs of his customers and work closely together with the pharmaceutical customer during product development. Increasingly individualised medicine, the increasing importance of innovative medications and the increasingly frequent usage of automatic injectors will in future further increase the trend toward highly developed, pre-fillable syringes. References 1. Germershaus O. Primärpackmittel – Freund und Feind der Arzneiform; PharmazeutischeZeitung. 10/2014. 2. Behrenswerth A, Luther MO, Hinsch B. Entstehung, Klassifizierung und Vermeidungvon Rissen in Fertigspritzen. Pharm Ind. Summer 2016 Volume 8 Issue 2

Drug Discovery, Development & Delivery 2014;76(4):626–32. 3. Jones LS, Kaufmann A, Middaugh CR. Silicone Oil Induced Aggregation of Proteins.J Pharm Sci. 2005 Apr;94(4):918– 27. 4. Badkar A, Wolf A, Bohack L, Kolhe P. Development of Biotechnology Products in Pre-filled Syringes: Technical Considerations and Approaches. AAPS PharmSci-Tech. 2011 Jun;12(2):564–72. 5. Bee JS, Nelson SA, Freund E, Carpenter JF, Randolph TW. Precipitation of a monoclonal antibody by soluble tungsten. J Pharm Sci. 2009 Sep;98(9):3290–301. 6. Petersen C, Zeiss B. Syringe Siliconization Trends, Methods and Analysis Procedures.International Pharmaceutical Industry. 7(2):78–84. 7. Adler M. Challenges in the Development of Pre-filled Syringes for Biologics from a Formulation Scientist’s Point of View. American Pharmaceutical Review. 2/2012.

Claudia Petersen, Gerresheimer Medical Systems, Global Director Business Development Claudia Petersen studied from 1990 to 1996 bioprocess engineering at the Technical University of Berlin. Since December 2007 Claudia Petersen is working in various functions for Gerresheimer AG. Her current position is Global Director Business Development for the Medical System Division of Gerresheimer. Claudia Petersen is a member of pharmaceutical organizations like PDA and APV. Email: Bernd Zeiss, Gerresheimer Medical Systems, Manager Technical Support, Buende Bernd Zeiss studied Biology, Microbiology and Chemistry at the University of Göttingen, Germany. Today he is a member of the Gerresheimer Buende business development team. He works in the Gerresheimer Centre of Excellence for prefillable syringes as Manager Technical Support. His main areas of work are customer support, investigating possible interactions between syringe components and drug substance and the evaluation of innovations like COP syringes in comparison to glass. Email:

Product News Sartorius Stedim Biotech Launches Innovative ambr® 250 Modular Bioreactor System New expandable benchtop workstation with unique single-use bioreactor design offers a simple approach to process development for fermentation and cell culture. Sartorius Stedim Biotech (SSB) has introduced the ambr® 250 modular, an innovative benchtop mini bioreactor system for parallel fermentation or cell culture. This system combines a unique single-use

bioreactor vessel and expandable system design to offer bioprocess scientists access to advanced benchtop bioreactor technology for process development. The new ambr® 250 modular system consists of a workstation with 2, 4, 6 or 8 single-use bioreactors, with a working volume range of 100 to 250 mL. These mini bioreactors, based on the same stirred tank bioreactors in the well-established ambr® 250 high throughput system, contain impellers suitable for fermentation or cell culture and show excellent scale-up to larger bioreactors. They are also fully integrated with liquid reservoirs and syringe pumps, allowing rapid experimental setup and turnaround, thus significantly increasing lab efficiency.

The system brings simplicity to the lab bench. By following three easy steps, a bioreactor and all the required accessories can be connected in just a couple of minutes. Once installed, the bioreactor has all the required process New ambr® 250 modular bioreactor system for process development services for parameter

control, including pH, DO, temperature or agitation. Additionally, feeds can now be delivered with high accuracy from the reagent reservoirs via the syringe pumps into the bioreactor. One control unit is capable of controlling up to eight bioreactor stations independently via an easy-to-use touchscreen user interface. Mwai Ngibuini, Product Manager at SSB, states: “Our new ambr® 250 modular provides an excellent single-use platform, which enables rapid process development and optimisation for scale-up to larger bioreactors such as BIOSTAT® pilot and manufacturing scale bioreactors. Utilising this single-use workflow, will allow bioprocess scientists to improve productivity in their scalable bioprocess development and reduce development time lines, ensuring production of industrial enzymes, biologics and vaccines is more cost-efficient.”

Contact: Sartorius Stedim Biotech / TAP, Royston Phone: +44.1763.227200 INTERNATIONAL PHARMACEUTICAL INDUSTRY 39

Clinical Research Three ‘Ps’ for Implementing an Effective eCOA Strategy: People, Processes, and Plan Summary Clinical scientists have proven that collection of clinical outcome assessment (COA) data with an electronic device improves patient compliance and delivers higher quality and more reliable data. The value of electronic clinical outcome assessment (eCOA) data for clinical trial claims, post-marketing safety studies and patient registries has become increasingly recognised by various stakeholders, including regulatory authorities and health economics outcomes research (HEOR) experts. For example, regulatory authorities expect data from patients to be quality-ensured with electronic timestamps, attributions, and a full audit trail. HEOR experts expect to leverage studies with eCOA endpoints in time and quality, and analyse in real time across different clinical trial phases and late phase studies. And data managers expect to detect errors or data inconsistencies sooner, at time of capture, with automated data checks and rapid query response. These trends are driving many biotechnology and pharmaceutical companies to rapidly replace paper COA with electronic COA. As a result, biotechnology and pharmaceutical companies are modifying internal processes so eCOA data can be integrated and leveraged within all phases of eClinical activities. Adopting an eCOA strategy and subsequently implementing it requires an effective collaboration between clinical trial teams, eCOA providers and COA experts familiar with transitions from paper-based COA data collection. Here we review how to implement an eCOA strategy, and detail the people, process and plans required for successful eCOA strategy implementation. Personnel Recommended to Implement an eCOA Strategy It is recommended that an experienced eCOA team be in place, rather than looking to a single individual to carry out this effort. It is not realistic to expect one person to have the expertise to handle all aspects of an eCOA implementation. Furthermore, teams, rather than 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

individuals, tend to be updated frequently on new instruments, devices and medical instruments, creating greater value. The eCOA team may be centralised within an organisation. A centralised eCOA team could either be mandated to be used for all eCOA trials, or serve in an advisory capacity, consulting to clinical trial teams. Another option is for the organisation to have eCOA experts reside within clinical science, data management or clinical operations. Commonalities among Centralised Internal eCOA Teams When an eCOA Team must be used for all studies that collect eCOA, there must also be a centralised, back-office team to support eCOA data. This eCOA team model is likely to recommend that the clinical trial team have three to five people with various backgrounds from PRO and eCOA studies, outsourcing, and marketing (pricing) functions; and augmented with variable scientists and medical professionals from the specific therapeutic area. These medical professionals may advise the larger clinical trial team that, e.g., pain studies generally include a daily PRO diary, whereas cardiovascular studies are not as accustomed to PRO data. Regulatory personnel would not be required to be on the team, but would be part of a regular review cycle to ensure compliance. It is recommended that a mandated eCOA Team be committed to providing a high-level of eCOA service and remain fully informed of all eCOA advancements. The eCOA Team can help the larger clinical trial teams save time and costs by providing a list of pre-selected devices for which formal prerequisites will already have been established (e.g. contracts), which can then be supported with a level of service similar to what is provided for electronic data capturing (EDC) processing. It is worth noting that despite internal mandates that all COA data be collected electronically, smaller studies may still rely on paper COAs due to economic realities or logistical difficulties in making the switch.

eCOA Consulting Team When an eCOA Team is required to consult on all trials that collect eCOA, its intent is likely to inform and educate. This consulting option is generally used within organisations with little operational expertise or recorded lessons learned from many trials. While such fractured intelligence is a lost asset, the eCOA consulting team can advise and educate all groups on all eCOA matters. The Process of Implementing an eCOA Strategy Mission, objectives and strategies define clinical trial programmes. The mission of clinical trials is to develop therapies to improve health for people around the world; trial objectives are to successfully collect data to support a programme while reducing risk, within a defined time period. Strategies to achieve these objectives differ widely, contributing to each organisation’s distinction. The culture of each respective biotechnology and pharmaceutical organisation will likely dictate whether the strategy drives the programme, or vice versa. The order will not ensure success. Instead, the eCOA strategy will determine the strength and accomplishments of the programme. An eCOA strategy will describe how programme objectives will be achieved with outcomes such as • •

Efficacy and/or safety of the drug; and/or Regulatory submissions, especially if research is being conducted under an approved FDA investigational new drug (IND) or investigational device exemption (IDE).

The strategy will determine eCOA device requirements; the process will select the eCOA modality before choosing the eCOA provider. Select the eCOA Device First, then the Provider When eCOA device recommendation and procurement are determined as the initial process steps, the clinical trial team will likely make these decisions either by mandate or recommendation from an internal eCOA Team. One effective way Summer 2016 Volume 8 Issue 2

Clinical Research to recommend devices is to establish an internal web page hosted by the eCOA team, which lists devices pre-selected and supported with service-level agreements, along with vendor information. This type of resource enables the trial manager to collaborate with the eCOA team to select the device based on key factors such as the number of eDiary questions, frequency of data collection, and the type of required data to be collected, e.g. objective measures from a peak expiratory flow (PEF) meter. The combination of required services and device helps identify those vendors to be considered. Details Vetted Within a Vendor Selection Process Fundamentally, the eCOA provider must provide audited evidence of adherence to all appropriate regulations, including – but not limited to – adherence to US 21 Code of Federal Regulations (CFR) Part 11 and the EU Data Protection Directive.

Further, the eCOA provider must fulfill every need of the clinical team members, sites, and participants. This means a wide range of services must be reviewed and vetted, including ease of use by the sites and patients, device purchasing or lease options, and whether the vendor provides a full service help desk. In addition, the clinical trial team will need to evaluate the vendor’s commitment level, transparency, and capability for data integration. And there must be discussion on data formatting, with the knowledge that most vendors can provide trial data in any standardised format. The more important issue may not be data formatting, but the way in which eCOA data will fit with the rest of the clinical trial data. How will the eCOA variables match other trial data? Table 1 presents the range of considerations to be made when selecting an eCOA vendor.

Table 2 presents a checklist for eCOA device selection. Developing a Strategy for eCOA Implementation Each strategy should consider target patient population locations, disease restraints and technology availability. If the patient population is expected to be unable to answer questions, a caregiver/observer (ObsRO) modality may be appropriate. Compliance evidence should be referenced in order to understand if that patient population prefers telephone, smartphone or webbased technologies. Further, each strategy must account for the proliferation and adoption of consumer technologies in the study countries. If eCOA devices are to be provisioned, for example, the strategy should confirm the availability of local devices and/or local customs consent.


Clinical Research device selections are influenced by the instrument(s). COA and eCOA Instruments (Diaries and Instruments) While most biotechnology and pharmaceutical outsourcing groups manage instrument authorisations, the instruments and diaries used for a trial are dictated by the protocol and protocol scientists. If using paper COA, sponsors may have paper case report form (CRF) groups to coordinate instrument and diary translations and establish a COA CRF form for paper studies. If using an electronic version of an instrument or diary (eDiary), sponsors should, according to the FDA PRO guidance, provide evidence to confirm the new instrument’s adequacy. It is common among the large biopharmaceutical and pharmaceutical organisations to have a database of instrument and diary copyright holders, including contacts, so that materials can be re-used and recycled. In addition to internal resources, there are several databases with information on COA instruments, eCOA migrations and descriptions of endpoints used to support specific indication claims. Alphabetically, these include • • For optimal patient completion compliance, the eCOA devices selected should be simple, FDA-compliant, and integrate easily with other required medical devices. All devices must be validated to store and transfer data privately and safely, within a tamperproof eCOA data collection system. All integrations with additional medical devices must be validated for accuracy and safety. Each strategy should define data management standards and governance, including specifications for user site testing. This is defined as testing that takes place outside of the eCOA provider’s controlled environment. Each strategy should also include electronic versions of all patient-facing communications. This includes evidence of how each instrument will be seen on 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

each screen, for the patient. The FDA PRO guidance states that ‘If an electronic version of the instrument will be used, the protocol can include screen shots or other similar instrument representations. Screen shots are required for approval by the IRB and/or or ethics committee. It is also useful that the clinical trial team view screen shots live, with a demo device or via simulation.’ Instruments Required for an eCOA Strategy When ePRO was in early adoption, clinical trials assigned specific devices to the end user. Patients used a handheld device or telephone to collect daily diary entries, and clinicians used a laptop or tablet. Today, a single eCOA device or browser may be used to collect data from a patient remotely and also from a patient visiting a clinic. Rather than being defined by the end user, eCOA

• • • • •

CenterWatch Clinical Trials – http:// ClinicalTrials.Gov – https:// COMET Clinical Trials Consortium about-us/ FDA Clinical Outcome Assessment Compendium tcMdDP Physiopedia - PROQOLID - http://www.proqolid. org/ PROMIS® -

Licensing Electronic Instruments The process for licensing and translating electronic instruments may be handled by the trial sponsor, eCOA provider, CRO or translation provider. Each instrument must be ‘fit for context of use’ as required by FDA, and licensed for use by the copyright owner or agent. Further, each instrument must be validated for electronic implementation. Finally, each instrument must undergo translation and localisation Summer 2016 Volume 8 Issue 2

Clinical Research Conclusions Experts from biotechnology and pharmaceutical organisations that have implemented eCOA agree that success has five prerequisites:

Mixing and/or Switching eCOA Collection Modalities Some protocols or clinical trial teams elect to collect data with COA or eCOA, using more than one modality. For example, diaries may seem practical for rural areas with electronic devices for more developed regions. Phones may be used to screen patients. Mixing modalities carries additional data integration and regulatory risk. The FDA PRO Guidance states, ‘We intend to review the comparability of data obtained when using multiple data collection methods or administration modes within a single clinical trial to determine whether the treatment effect varies by method or mode.’ Mixed modalities have been reviewed by ISPOR. The 2014 Report of the ISPOR PRO Mixed Modes Good Research Practices Task Force entitled ‘PRO Data Collection in Clinical Trials Using Mixed Modes’ states, “we also strongly discourage the mixing of paper and electronic field-based instruments and suggest that mixing of electronic modes be considered for clinical trials and only after equivalence has been established been established.” Providing a paper PRO backup was reviewed by the C-Path PRO/ ePRO Consortium in 2015. While not recommended, several suggestions are listed if it is necessary to provide an equivalent version of the measure to study monitors, help desk, or all participating sites prior to study start. Some teams want to update the eCOA device with newer consumables as they become available. It is recommended that new PRO instruments must undergo a cognitive debriefing to verify the

equivalence of the measurement. Switching eCOA devices also entails risk, since different (or newer) devices may be untested. Also, new consumer devices characteristically have relatively short shelf lives. Rater Training Requirements and Recommendations Rater training is used within clinical trials to improve the consistency of subjective data collected from patients, caregivers/ observers, and clinicians/interviewers. It is regarded as critical for many complex ClinRO and ObsRO assessments; and expanded to include patient rater training on device. Data stability is critical for data analyses. To that end, standardised instruments are translated and localised to ensure that questions are psychometrically equivalent. Variability is introduced when interviewers or caregivers are required to interpret symptoms and behaviours and record patient cognitive, physical and/or mental scores on various instruments. Raters can be influenced by bias, technique, and scale recording; rater variance has been cited as contributing to low reliability and failed trials. Rater training has been proven to reduce rater errors and standardise scale administration. It is recommended by global regulators, and endorsed by ISPOR. Rater training is becoming more available electronically, and on device, enabling eCOA Teams to efficiently select and train raters; certify and/or remediate raters; and ensure that only certified raters gain access to patient instruments. In addition to standardising responses, rater gating consolidates administration and mitigates risk.

1. eCOA strategy development and implementation should be led by a team rather than a single individual, and team members should not only be experienced in eCOA but also committed to replacing paper-based methods. 2. The eCOA team should be centralised, and must stay current on eCOA innovations. 3. The eCOA team should be fixed and include three to five people of varying backgrounds: eCOA studies, clinical study team lead and outsourcing. 4. Organisations should build and strengthen the scientific knowledge and medical viewpoint of eCOA data collection and various eCOA data collection device modalities. 5. If there is no company-wide mandate to replace paper COA with eCOA, the decision to use eCOA should be made by either the clinical trial team or the therapeutic area group. The process an organisation uses to implement eCOA must be simple and effective, with COA competence already in place, before an eCOA strategy is implemented. eCOA should be the default mode for clinical trial outcome data collection. Teams need to justify why they are considering paper mode, not the other way around.

Dr Daniel Eek, PRO Director, AstraZeneca R&D Gothenburg Christine Hall, Director, eCOA Product and Clinical Science Marketing Sonja Hooper, Associate Director Clinical Technology Services (PRO/ ePRO), Johnson & Johnson Dr Frans Wald, Head Global Clinical Trial Support, Boehringer Ingelheim Pharma GmbH & Co. KG Martin Wurm, Head of eClinical Trial Services, Global Clinical Trial Support, Boehringer Ingelheim Pharma GmbH & Co. KG INTERNATIONAL PHARMACEUTICAL INDUSTRY 43

Labs & Logistics Maintaining Cold Chain Integrity for Pharmaceutical Products Almost 30 per cent of scrapped sales at pharmaceutical companies can be attributed to logistics issues. As most medical and biological products require a temperature-controlled environment at all stages of manufacturing and distribution, the control of storage and transportation temperatures is vital in maintaining the quality and effectiveness of medicines and is critical for its manufacturers and for public health and patient safety.1 Protecting Biopharmaceutical Shipments – Good Distribution Practice In order to maintain the safety, integrity and efficacy of their high-value products and reduce supply chain risks, pharmaceutical manufacturers count on refrigerated fleet operators and shippers to follow the European Union (EU) Commission Guidelines on Good Distribution Practice (GDP) of Medicinal Products for Human Use.2 By some estimates, as many as 70 per cent of products require some type of controlled environment, including those that need to be maintained at a consistent “room temperature”. For most medical and biological products, the GDP guidelines require a temperaturecontrolled environment for all stages of manufacturing, shipping and storage. There are four stages of qualification outlined in the guidelines and they include: • Design qualification (DQ) – where the compliance of the design with good manufacturing practice (GMP) should be demonstrated and documented • Installation qualification (IQ) – which should be performed on equipment, facilities, utilities, or systems and include, but not be limited to: • Verification of the correct installation of components, instrumentation, equipment, pipework and services against the engineering drawings and specifications; 
 • Verification of the correct installation against pre-defined criteria; 

• •

Collection and collation of supplier operating and working instructions and maintenance requirements; 
 Calibration of instrumentation; 
 Verification of the materials of construction. 

• Operations qualification (OQ) – should include, but is not limited to, the following: • Tests that have been developed from the knowledge of processes, systems and equipment to ensure the system is operating as designed; 
 • Tests to confirm upper and lower operating limits, and /or “worst case” conditions. 
 • Performance qualification (PQ) – should include, but is not limited to, the following: • Tests, using production materials, qualified substitutes or simulated product proven to have equivalent behaviour under normal operating conditions with worst-case batch sizes. The frequency of sampling used to confirm process control should be justified; 
 • Tests should cover the operating range of the intended process, unless documented evidence from the development phases confirming the operational ranges is available.3 These guidelines should be consulted in order to ensure appropriate procedures are followed and measures taken to maintain product quality throughout the cold chain and limit risks during transport. Qualification Process Each refrigerated transport unit used for the transportation of pharmaceutical products needs to go through a qualification process. The qualification process mentioned above, from Annex 15 of the GMP, can also be applicable for the GDP while qualifying temperaturecontrolled equipment for the transport of pharmaceutical products. Qualification consists of a temperature validation

process that maps the temperature performance of the unit operating in the temperature ranges listed below. Temperature sensors are placed in a number of locations throughout the box to identify if there are any hot or cold spots that could affect the transportation of the pharmaceutical products. It is recommended to conduct the validation at an accredited laboratory such as the Ingersoll Rand Engineering and Technology Center (IRETC) in Prague, Czech Republic. Once the tests are completed, it is essential to complete the process of qualification by preparing adequate documentation that ensures that the four stages of qualification (DQ, IQ, OQ, and PQ) have been completed correctly. At this time, a certificate can be provided to prove that the equipment is qualified for pharmaceutical operation. This extends beyond the transport vehicles used to take bulk pharmaceutical (such as active pharmaceutical ingredients – APIs) and medical components to the manufacturing facility, and finished products from the manufacturing facility to distributors/wholesalers. It must also ensure compliant delivery to hospitals and pharmacies, as well as supermarkets that sell medicines. Temperature Regimes Industry statistics indicate that 25 per cent of vaccines reach their destination in a degraded state because of incorrect shipping, and almost 20 per cent of temperature-sensitive health-care products are damaged during transport due to a broken cold chain. Moreover, approximately 0.5 per cent of transported goods are damaged during transport through non-compliance to temperature guidelines.4 When it comes to transporting pharmaceutical products, there are typically three temperature regimes to ensure temperatures are maintained within required parameters: •

Under 20⁰C: Typically products transported for clinical trials should be kept frozen at all times. The Summer 2016 Volume 8 Issue 2


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cooling compartment should not be allowed to rise any higher than -20⁰C. The recommended storage handling temperature regime for medicinal shipments such as blood and plasma is -30⁰C. Other products within this temperature regime may be carried at -25⁰C. +2⁰C to +8⁰C: Medicinal products carried in this temperature range, such as vaccines and antibodies, should be maintained between +2⁰C and +8⁰C and not deviate outside of this range. +15°C to +25°C: Products carried in this specified temperature regime such as active pharmaceutical ingredients (APIs) or small molecules, should be maintained between +15⁰C and +25⁰C and not deviate outside of this range.

Continuous Temperature Monitoring Common non-compliance issues include failure to: monitor and/or record storage temperatures; temperaturemap warehouses to find hot and cold spots; calibrate temperature monitoring devices; or take appropriate action when temperature excursions are noted.5 No wonder leading operators are equipping their fleets with integrated asset management systems that protect shipments by establishing critical controls at all points in the supply chain. For example, the TracKing asset management solution by Thermo King, a global leader in transport refrigeration and a business unit of Ingersoll Rand, uses a web-based telematics system embedded in the refrigeration unit control system to monitor temperatures, door openings and fuel levels; change set points and other control parameters; change operating modes; and respond to alarms using any computer, tablet or smartphone connected to an operators’ existing secure network. Considerations Before or During Transport of Pharmaceutical Products Preserving cold chain integrity and maintaining product quality is an increasing challenge for pharmaceutical companies and their partners in handling and transporting pharmaceutical products globally. As temperature-controlled shipments grow in volume and regulatory requirements change, pharmaceutical and biotech manufacturers will need the support of their transportation industry partners 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to ensure compliance with regulatory requirements and the safety and integrity of their high-value shipments. Other important factors to consider before or during transport of pharmaceutical products are: •

• •

Load space configuration when the trailer body design is carried out, such as whether to include dividing doors, air shoots, or return air bulkhead design. The load space should be kept clean at all times and only cleaning agents that will not affect the cargo should be used. To conform to temperature monitoring and recording obligations, the units are required to have on-board temperature recording and monitoring as well as printed delivery point tickets to prove the temperature integrity of the load space. Because the products have to stay within a particular range, both temperature and air management must be controlled within this range, with no deviation allowed or any excursions limited to manufacturer specifications. Drivers are required to be trained to show that they can operate the unit within the GDP requirements. Regular maintenance and service records should be kept for inspection if required by the pharmaceutical companies. A calibration check should be completed at least once per year; individual pharmaceutical companies may request more checks. A three-point calibration of the sensors is important to ensure that when the unit is operating, it can maintain the load space temperature at the set points as listed above. To prevent risk of contamination to sensitive shipments in the compartment, cleaning standards in line with GDP guidelines should be enforced under the guidance of certified service personnel.

SIDEBAR: Ingersoll Rand Engineering and Technology Center (IRETC) The Ingersoll Rand Engineering and Technology Center (IRETC) situated in Prague is dedicated to research and development activities within the mechanical and industrial engineering

sector. IRETC is an ISO 9001: 2000; ISO 14001 and ISO 18000 certified institute and is authorised for ATP qualification. IRETC also offers engineering expertise to Thermo King and third-party companies. Specifically for pharmaceutical transport, IRETC offers qualification services. At IRETC, a range of functional and performance tests can be conducted in a controlled environment to certify that the refrigeration equipment used for pharmaceutical transportation can perform to required specifications. This includes: • • • •

Thermal mapping of trailers and trucks from -32°C to +60°C Vibration tests to replicate overthe-road conditions for loads up to 10,000 kg Calorimeter tests of unit cooling and heating capacities at simulated extreme ambient conditions Thermography to visualise temperature spread within loaded vehicles

On completion of the qualification process, the unit can be certified for pharmaceutical operation. References 1. Based on estimates from World Health Organization (WHO), Parenteral Drug Association (PDA) and other industry associations 2. distribution_practice/index_en.htm Source: EudraLex, Volume 4, EU Guidelines for
 Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Brussels, 30 March 2015 Source: World Health Organization (WHO), Parenteral Drug Association (PDA) and other industry estimates 
 3. Source: Recent review of regulatory inspection findings for UK wholesale distributors 4. Agreement on the International Carriage of Perishable Foodstuffs and on the Special Equipment to be Used for such Carriage (ATP) 5. Source: Recent review of regulatory inspection findings for UK wholesale distributors 6. Agreement on the International Carriage of Perishable Foodstuffs and on the Special Equipment to be Used for such Carriage (ATP)

Essangui Mbaitjongue is Business Development Manager for Thermo King, a manufacturer of transport temperature-control solutions for a variety of mobile applications and a brand of Ingersoll Rand. She holds a master degree in international economics from La Sorbonne and an MBA degree from Manchester University. She is responsible for developing solutions and services that will meet the needs of Thermo King customers in the transport of pharmaceutical products. She has more than eight years’ experience in marketing and business development. Email:

Summer 2016 Volume 8 Issue 2


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Labs & Logistics Understanding How New Data Integrity Regulations Apply to Your GDP Temperature-controlled Pharmaceuticals The 2015 UK Data Integrity Guidance states raw data must be “legible and accessible, retained in the format in which it was originally generated, throughout the data lifecycle”. From a business perspective, we know that raw data generated in the supply chain is valuable to understanding its performance – if handled correctly. But how? It’s more efficient to ensure raw data is connected to the original data record, which can be done using a relational database. If you’re manually processing flat files, it can be resource-intensive to review numerous spreadsheets, for example, and more subject to error when archiving and storing paper records or flat files. That is just one example of how there are different ways to set up your temperature monitoring programme. Each way may offer unique business benefits and options for data integrity. Data loggers, types of files, raw data, and a database – all work hand in hand to create a cohesive process-driven system. As you establish your monitoring programme, consider how to achieve both compliance and your business needs … by making the right choices.

laboratory chromatographic data systems. Regulatory authorities are now asking where the data has originated from, what type of electronic proof certifies authenticity, such as e-signatures, and whether those systems have been properly validated for their intended purposes. The new data integrity guide covers all areas, machines and equipment that generate data in manufacturing and supply chain functions for pharma.

Regulatory Landscape There are three recent major regulatory and industry standard update documents published concerning data integrity: FDA April 2016; WHO September 2015 and MHRA March 2015.

Definitions and Interpretations for the Cold Chain It’s likely you’ve seen a news headline that describes fraudulent activity regarding data integrity of pharmaceutical labs or production. But in fact, “95% of data integrity issues are actually unintentional and arise out of poor data management”, as stated by Bob McDowall, Director, R.D. McDowall Limited, in a recent webinar.

Not only has the FDA published Data Integrity and Compliance with CGMP this year, they also announced they will begin more inspections related to 21 CFR Part 11. Without a plan in place to handle electronic records in every GMP department in a pharmaceutical company and their partners, those companies risk receiving warning letters, or worse, 483s from the FDA for non-compliance. The FDA has stated this is not just a problem in developing countries such as India, but an industry-wide concern, noting issues around quality control inspections, equipment qualification, and training in all GMP environments. The 2015 UK MHRA guidance was published following ongoing concerns of fabricated/manipulated data in 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

But let’s not forget the internationally recognised Pharmaceutical Inspection Cooperation Scheme (PIC/S) Guidance on Good Practices for Computerized Systems in Regulated GxP Environments. It echoes similar requirements in the US and UK, across the lifecycle of a drug from GLP, GCP, GMP to GDP. Also, GAMP 5 has been instrumental in developing GDP-compliant data management systems for the cold chain industry, such as temperature monitoring systems; stating “Patient safety is affected by the integrity of critical records, data, and decisions, as well as those aspects affecting physical attributes of the product.”

How can you ensure your temperaturecontrolled data management activities are compliant with new regulatory requirements for data integrity? Raw data – must be legible and accessible, retained in the format in which it was originally generated, throughout the data lifecycle. Paper is acceptable. However the MHRA guidance states “In the case of basic electronic equipment which does not store electronic data, or provides only a printed data output, the printout constitutes the raw data”. Archive – MHRA says “Archive records should be locked such that they cannot

be altered or deleted without detection and audit trail.” In cold chain, you need to make sure your temperature and shipment records are files that cannot be changed after generation from the device. Whether you print the file for record-keeping or upload to a database, the original record needs to be kept intact, ideally with the raw data integral to the original files. If your data logger generates a PDF report, you should understand that the suitability of a PDF file for archival preservation depends on options chosen when the PDF is created. These options include whether to use encryption, and whether to preserve additional information from the original document beyond what is needed to print. ISO 19005-1 underlines the importance of PDF/A, a specialized PDF file format for regulated industries. It was created to address the growing need to electronically archive documents to preserve over extended periods of time, to ensure they could be retrieved and rendered with a consistent and predictable result in the future. This is important for complex supply chains if you have multiple destination sites, including remote geographies that can change over time. You don’t want destination sites to have to install software updates to ensure they can open a PDF file generated from a data logger. Instead, by using a data logger that generates a universal PDF format, like PDF/A, it doesn’t matter what version of Adobe they have or what version was used to create the file. Think of Microsoft Word updates over the years; if someone sends you a .docx created in ‘new’ Word, how can you read it if you have ‘old’ Word? You have to re-save it as .doc (old format) or install a .docx reader on top of old Word, but losing functionality. With PDF/A, no matter how many updates your operating system runs, you can still read those files and they will retain functionality and compliant archiving for long-term storage. Electronic audit trail required by 2017 – GMP audit trails are metadata that are a record of GMP-critical information, Summer 2016 Volume 8 Issue 2

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Labs & Logistics which permit the reconstruction of GMP activities. As already described, it is cumbersome to have paper records of your shipment data. However, for some organisations who haven’t convinced management yet to upgrade, it’s their only option. The MHRA guidance says this is acceptable, if the paper audit trail can also demonstrate changes to the data. However, they will expect companies by the end of 2017 to have an integrated electronic system or validated audit software. Computerized system user access – Regulators are asking: who has access to your data? Can you prove who amended a record or created a supplementary report? In setting up a temperature monitoring for your cold chain, who has access to add data to your central repository or database? Hundreds of people at various destination sites, such as hospitals, clinics or depots, or is the database access limited to a certain number of admins or product owners? How does that data get into the central document system; manually entered by hand, or securely emailed in? Relational Database vs. Flat Files The new MHRA guidance explains relational databases are inherently more secure, as the data is held in a large format which preserves the relationship between data and metadata. This is more resilient to attempts to selectively delete, amend or recreate data, compared to a flat file system. Beyond compliance, relational databases offer greater business advantages. Compiling spreadsheets and running formulas can take a lot of time. Paper files, however compliant they may be, are cumbersome to use for processing excursion reports. When all data is housed in a central system, running regular reports and analysis of your shipping performance is a no-hassle activity, and in turn creates business value in the form of greater efficiencies and cost savings to your logistics and quality operations. Building In Data Integrity As the number of products and shipments grow for many pharmaceutical manufacturers, they are looking for better ways to manage extensive shipment and temperature data. Most often this means transitioning to a streamlined, comprehensive data monitoring 50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

system. Having a central repository for temperature data covers several regulatory requirements at once. A validated database ensures the records are original, there is a permanent archive in place and in some systems, keeps the raw data intact with the original record. Because these central repositories are custom, requiring configuration and supplier involvement, following GAMP 5 guidance ensures a system is validated for its intended purposes. GAMP 5 explains “Procedures for specification, configuration, verification, and operations of the system should be agreed between the regulated company and the supplier and be documented in the appropriate plan. Procedures adopted may be those of the regulated company or from the supplier QMS”. Therefore, if you’re considering adopting a new data monitoring system for your temperature-controlled supply chain, the GAMP 5 Good Practice Guide explains that the supplier’s quality management system (QMS) should: 1. Provide a documented set of procedures and standards 2. Ensure activities are performed by suitably competent and trained staff 3. Provide evidence of compliance with the documented procedures and standards 4. Enable and promote continuous improvement If compared to the 2015 MHRA guidance, the UK definitions focus on components of the system recommended to be built in to ensure data integrity. These include: access to clocks for timed events; user access rights which prevent data amendments; access to raw data for staff performing data-checking activities. It later states, “…system design should always provide for the retention of full audit trails to show all changes to the data while retaining previous and original data. It should be possible to associate all changes to data with the persons making those changes, and changes should be time stamped and a reason given. Users should not have the ability to amend or switch off the audit trail”. Regulatory Inspectorate’s Advice In May 2015, ELPRO and Envirotainer hosted a Leading Minds Seminar in New Brunswick, NJ. Ian Holloway from the MHRA presented how the new data

integrity rules affect temperature-control professionals. He stated “Increasing demands for traceability and cold-chain integrity are making data systems more complex and configurable with increased risks of inadequate data integrity. Companies should consider a risk assessment of data associated without the supply chain considering raw data for both cold-chain and logistics aspects.” He presented a series of questions to challenge pharmaceutical manufacturers to ask themselves: • • • • •

• •

Is your raw data retained and secured against unauthorised changes? Do you have adequate metadata – data-about-data? Would you detect unapproved changes? Do system users have appropriate access controls and defined user rights? Is your data attributable, legible, contemporaneous, original, accurate, complete, consistent and enduring? What risks do you have from cloud storage/services? Are any spreadsheets fully validated and secured?

Concerning Data Quality and Sources: Lessons Learned During the seminar, Holloway provided actual inspection examples of how temperature data was questioned in a number of pharmaceutical supply chains (companies’ names kept anonymous). Case example 1. A temperaturecontrolled medicinal shipment was being transported in India using a temperaturecontrolled vehicle, then sub-contracted to a self-employed haulier. The refrigeration unit was switched off to reduce fuel costs. The problem was first detected on arrival in the UK. Learning Point: Transport arranged by head office commercial team (higher rank and importance than local staff at the production site). How good is your knowledge of the local cultural aspects of your partners? Case example 2. After a shipment reached the UK, the data loggers were sent back to the origin site in a thirdworld country for reading. This resulted in questionable data, making it difficult to decide when the data logger had Summer 2016 Volume 8 Issue 2

Labs & Logistics Table 1.1 Technology



Low cost, go/no-go decision

USB data loggers

Compliant or not? Questions to ask vendors.

To be compliant, you need an original record. So if you’re using an indicator, does it offer more than a visual reading? Can you print out a record, or upload to a database? In those two cases, you would be compliant. USB data loggers MHRA requires data record to be proven original by produce electronic “preserving the integrity (accuracy, completeness, records, but how can content and meaning) of the record through the you prove they retain data’s full lifecycle”. integrity? If you use USB data loggers that have been validated according to USP 1079 or EU GMP Annex 15 to ensure prevention of manipulation, and can produce a validation report, you will be compliant in preserving the integrity. For example, one system on the market produces a PDF/A that, by GAMP 5 design, cannot be manipulated. Some data monitoring systems also use measures such as a unique check sum identification that is original to each logger and its PDF; proving its source and originality. Ask: How does the monitoring system prove that files are original and unaltered? Is there a system of checks and balances that is easy for the user to understand and follow?

Database or hosted document management system

How can you ensure your database vendor has a solution that fits your regulated activities?

Ask: How does the system ensure that each data logger file is uploaded with the correct metadata? Ask: What performance checks does the system have to ensure each file is unique, and that no duplicates are present? Ask: Does the hosted document management system conduct automatic integrity checks, or will it accept any document? Ask: Under what guideline is the system developed, and how is 21 CFR Part 11 compliance ensured? Ask: How are files and metadata stored?

been stopped with reference to receipt of product in the UK. Slow timelines mean that it was too late to carry out a meaningful investigation. Learning Point: Prompt local reading is much more reliable and can mean that evidence is still obtainable to facilitate investigations if there are suspected deviations. Case example 3. An airfreight shipment from India to the UK consisted of 11 pallets, but only two data loggers had been used to monitor transit temperatures. This is not adequate to ensure that none of the nine unmonitored pallets had not been exposed to unacceptable temperatures in a different hold of the aircraft. Ref EU GMP Guide: 1.4(xvi). Learning Point: No documentation was available to indicate which two of the

11 pallets have been monitored. 2015 MHRA regulatory expectation is now one data logger per pallet; not per shipment. This was the same company at both ends of the route – systems and communication should have been better! Summary Without a doubt, there are a lot of regulatory requirements and industry standards around the world for ensuring your data maintains integrity; especially concerning if you’re responsible for international supply chains. Many of the principles are the same, as outlined in this paper. However, most quality and logistics professionals are not also trained in IT. That’s why it’s critical to work with experienced data partners when considering a data monitoring system for your temperature-controlled products. Choose a data monitoring partner whose system can help you

comply with regulations and ensure integrity of your valuable data - the state of being whole, entire, undiminished, or in perfect condition. Keep posted for the next Leading Minds Seminar at References 1. MHRA GMP Data Integrity Definitions and Guidance for Industry; Revision 1.1 and Final Release, March 2015 2. FDA Data Integrity and Compliance with CGMP, draft guidance, April 2016 3. United States Pharmacopeia Chapter <1079> Good Storage and Distribution Practices for Drug Products; Packaging, Storage & Distribution Expert Committee, Pharmacopeial Forum Volume No. 30(6) Page 2118 4. USP Chapter <1083> Good Distribution Practices, PF 38(2) [Mar.–Apr. 2012], Packaging, Storage & Distribution Expert Committee 5. FDA 21 CFR Part 11, Electronic Records; Electronic Signatures; Pharmaceutical CGMPs, August 2003 6. Holloway, Ian; “GDPs in Today’s Pharmaceutical Supply Chain”, Leading Minds Seminar, May 5 2015, New Brunswick NJ, 7. Foster, Mary G. PharmD; “Practical Approaches: Logistics & Storage - General Chapter <1083> Good Distribution Practice”, Leading Minds Seminar, May 5 2015, New Brunswick NJ, 8.; About FDA, “FDA to Conduct Inspections Focusing on 21 CFR (Part 11)”, June 13, 2013,www. officeofmedicalproductsandtobacco/cder/ ucm204012.htm 9. WHO Guidance on Good Data and Record Management Practices; Draft for comment September 2015 10. GAMP 5: A Risk-Based Approach to Compliant GxP Computerized Systems; International Society for Pharmaceutical Engineering (ISPE), Updated February 2008. 11. ISO 19005-1: Document management – Electronic document file format for longterm preservation – Part 1: Use of PDF 1.4 (PDF/A-1), October 1, 2005.

Courtney Becker-James, Strategic Marketing Director at ELPRO, has been working in the temperature-control pharmaceutical industry since 2004. Her roles have varied from creating industry-leading events and content, to business development and marketing. Collaborating with pharmaceutical manufacturers and industry advisory boards allows her to bring best practice papers and information to industry practitioners. INTERNATIONAL PHARMACEUTICAL INDUSTRY 51

Labs & Logistics

Standardisation is Vital for the Future of the NHS Standardisation can make a difference in healthcare. And while standardisation might not make headlines very often, what happens when it’s missing – especially in the NHS – often does. The pressure on the NHS to deliver more for less increases in line with the stories we hear about mistakes made in the operating rooms, mis-medication and the hours wasted looking for recalled devices, medicines or equipment. We hear time and time again that this level of inefficiency can put patient safety at risk and increase pressure on healthcare professionals, and that the NHS wastes billions of pounds on these preventable errors. In 2014, the Department of Health published its eProcurement Strategy, setting out a number of measures to tackle this. This strategy included a mandate that introduces GS1 standards as a requirement, not just for all Trusts in England but also for their suppliers. What the standards give, in practice, is a globally unique identification number for every product, person and place within the NHS, and their introduction by the Department of Health reflects a move more generally towards standardisation throughout the healthcare industry. As well as the eProcurement Strategy, we’ve also seen the introduction of the Falsified Medicines Directive that requires the serialisation of every pack of prescribed drugs using GS1 standards. When it comes to serialisation and the need to be able to track and trace in the NHS, we’re seeing that those getting ahead of the game are reaping significant rewards. The power of implementing GS1 standards is in the interoperability it brings, meaning inventory systems can talk to purchase-to-pay solutions, and Trusts can know exactly what they have and where. The technology is available for this to happen, and the mandates included in the eProcurement Strategy and Falsified Medicines Directive will make sure it does. The Department of Health’s strategy is just one of an increasing number of 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

documents that references the importance of barcodes to the future of healthcare – the Carter Review, the National Information Board’s Personalised Health and Care 2020 Framework, and recent legislation around falsified medicines all point to the significance of standards in global healthcare. A recent McKinsey study highlighted just how important they are: •

Implementing global standards across the entire healthcare supply chain could save 22,00043,000 lives and avert 0.7 million to 1.4 million patient disabilities Rolling out standards-based systems globally could prevent tens of billions of dollars’ worth of counterfeit drugs from entering the legitimate supply chain Healthcare cost could be reduced by $40 billion-$100 billion globally from the implementation of global standards

The impact of GS1 standards is farreaching, both in the benefits they bring but also in the collaboration needed between manufacturers, distributors and the Trusts to make it happen. At GS1 UK, we’ve been working across industries since the first barcode was scanned over 40 years ago. Our standards now play their part around the world and around the clock – there are over 5 billion successful scans of a GS1 barcode every single day. GS1 standards offer the healthcare industry the same benefits that are embedded in every stage of the retail supply chain – improving operations and inventory management, and saving time and money. As we apply these standards in healthcare, we’re also saving the Trusts time and money and, most importantly, we’re increasing patient safety. Proving this great value is key if we’re going to engage all key stakeholders inside and outside of Trusts in making this difference. The announcement of the six demonstrator sites of excellence by the Department of Health in January this year showed its commitment to

making it happen. Each site is receiving a share of £12m funding with the aim of demonstrating the benefits, as well as challenges, they encounter from implementing GS1 standards. Getting Engagement on All Levels All six demonstrator sites were represented at our recent GS1 UK Healthcare Conference, and over 350 people from Trusts and their suppliers joined us. On our main stage we had chief executives, directors of nursing, finance and surgery, as well as senior leaders in the Department of Health and the General Medical Council. Pat Mills, Commercial Director of the Department of Health, led the call to action for the adoption of GS1 standards beyond the demonstrator sites. He underlined that: “the whole GS1 rollout is the world we need to get our health service into. It’s the world where we can actually track and trace all the way through, be it medicines, products, patients; the world where we’ll have detailed information on patients, outcomes, correlations; the world where we actually know everything we’ve bought and where it sits in the supply chain and in inventory, and we can actually manage our inventory properly – we don’t have to keep throwing things away because they’re out of date.” The potential that GS1 standards have for medicines, products and patients was the main theme throughout the conference, and with this, the importance of getting clinical engagement if a real difference is going to be made. As Lord Prior, Parliamentary Under Secretary of State for NHS Productivity, and our headline speaker, pointed out: “The benefits that GS1 brings procurement are obvious… The benefits that GS1 brings to patient safety are also obvious… (and) the real impact we’ll have from GS1 is around clinical productivity.” Proving these benefits to clinicians will be a fundamental role of the demonstrator sites, and the potential improvements for patient safety are top of that list. As Nick Thomas, Deputy Chief Executive of Summer 2016 Volume 8 Issue 2

Analytical Support for R&D, Clinical Development and Licensed Manufacture GLP, GCP and GMP compliant MHRA and FDA inspected


Labs & Logistics The real power comes when you link people, products and places. We’re working with the Department of Health to drive the implementation of three primary applications across Trusts:

Plymouth Hospitals NHS Trust, which is one of the chosen sites, outlined: “Patient safety is absolutely at the top of the list of the reasons we’re committed to GS1 as an organisation – whether we’re talking about product recall, or e-prescribing, or the ability to put in place safe controls and processes within theatres. Improving the patient experience is, too – if we can get the right thing to the right people at the right time, every time, then obviously that’s going to have a significant benefit for the patients we look after.” A Safer and More Efficient NHS – GS1 Standards in Practice What does this actually mean in practice for the Trusts and suppliers implementing these standards? As part of the eProcurement strategy, GS1 standards provide the foundation for three core enablers that improve patient safety, deliver stronger regulatory compliance and drive efficiencies: 1. Every person: identifying patients and care-givers with a wristband, which includes a GS1 barcode, enables accurate and consistent information to be captured and stored – a major driver for patient safety 2. Every product: easily accessing accurate and transparent product information for medical supplies, assets, equipment and pharmaceuticals enables precise ordering, improved product availability and lower transaction costs 3. Every place: identifying every physical and operational location within the healthcare system enables information to be collected and stored where each event occurs 54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

1. Purchaseto-pay: enabling Trusts to manage their procurement processes more efficiently while providing improved product availability 2. Inventory management: ensuring Trusts keep fewer products in stock and reduce wastage, yet ensuring products are readily available where and when they’re needed 3. Patient safety recall: making it easier to identify and remove all recalled products across the Trusts or even with the patient once they have been discharged These applications have been introduced alongside an increasing drive for serialisation and the need to be able to track and trace in the NHS. As well as being part of the Department of Health’s eProcurement Strategy, GS1 standards play a key role in the Falsified Medicines Directive, adopted by the European Parliament in 2011 and set for panEuropean implementation by February 2019. The legislation requires the serialisation of every pack of prescribed drugs with a 2D barcode matrix with an expiry date and lot number, as well as the expiry date and lot number in human readable form. The measures mean every pack can be verified and decommissioned. If anything needs recalling, it can be identified down to the individual packet. It’s a big change for pharmacies and for manufacturers, but it’s a change that needs to happen. Why Standardisation Really Matters The benefits of standardisation work across the board, for Trusts and their suppliers. Compliance with GS1 standards will mean that suppliers will have a single depository of their data for the NHS, as well as fewer invoice queries and order disputes, and reduced transaction and wastage costs. The Department of Health

and wider legislation has introduced GS1 standards because they allow Trusts to achieve complete traceability throughout the supply chain and true interoperability between people and systems. They provide a global language that enables collaboration not only within Trusts, but between them and their suppliers. Through the use of standards, the healthcare industry is better equipped to deal with the current challenges – it knows that adopting GS1 standards is the right thing to do to provide a common foundation in order to further improve confidence in care delivery. Standards mean that products can be checked and verified at all stages of the supply chain, they mean that Trusts know what they have in stock at any given time and that clinical staff time is freed up to provide proper care for patients. Standardisation is already making an impact on the healthcare supply chain – since April 2014, Derby Teaching Hospitals NHS Foundation Trust have saved around £25k per month through the use of GS1 standards in general surgery, imaging and cath labs, and the Carter Report estimates that “the introduction of GS1 standards will allow every NHS hospital in England to save on average up to £3 million each year while improving patient care.” With the government committed to rolling out the system across all Trusts in England by 2020/21 – we’re only seeing the beginning of how vital GS1 standards are proving to be. For more information please visit

Glen Hodgson, Head of Healthcare at GS1 UK, is charged with supporting the NHS and the healthcare industry to deliver a more robust approach to patient safety and greater efficiency. He is a highly accomplished senior executive, with over 15 years of national and international experience, and has served at board level in many operational and commercial roles in the pharmaceutical/healthcare arena. Email:

Summer 2016 Volume 8 Issue 2


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The Future is Bright for BYOD but is it Always the Best Approach? Technology is well and truly embedded within the lives of people of all ages, geographic locations and economic backgrounds, ultimately driven by the increasing sophistication and associated reduction in cost of using emerging technology for all kinds of applications. In line with this, the ownership and use of smartphones has become extensive – in fact, it is estimated that by the end of 2016, the number of smartphone users worldwide will exceed two billion.1 With increasingly tech-savvy consumers, the pharmaceutical industry has reached a point when it can finally begin to consider utilising the low-friction, rich, real-time data that can be captured using patients' own devices. The bring-your-own-device (BYOD) model – in which patients use their own devices (smartphones, tablets etc) to complete patient-reported diary assessments during a clinical trial – is a hot topic across the sector, with many companies keen to explore the approach, which promises to bring an array of benefits to clinical trials. However, far from a one-size-fits-all model, sponsors and CROs must weigh the benefits of the methodology against the needs of their unique protocol to ensure successful implementation. Here, CRF Health’s Director of Health Outcomes, Paul O’Donohoe, tells IPI readers why certain barriers mean the model might not always be the most appropriate methodology, and highlights the factors that should be considered when approaching a BYOD design for electronic clinical outcome assessments (eCOA). Current Reasoning Traditionally, sponsors and CROs have captured patient data during clinical trials via provisioned devices. However, thanks to the increase in availability of technology and society’s expectation for it to be utilised to aid communication and interaction on a daily basis, the last couple of years has seen a notable rise in the number of sponsors and CROs looking to adopt the BYOD approach within their studies. It is worth noting at this point that although the widespread usage of smartphones makes them the ideal platform for data collection, 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

BYOD, in theory, also allows clinical trial participants to use other devices such as tablets, laptops and desktop PCs to access and respond to study-related patientreported outcome (PRO) assessments. Much anticipated by the industry, the move towards BYOD promises many advantages and represents an evolution in the way field-based electronic patientreported outcome (ePRO) assessments are implemented in clinical trials. For sponsors and CROs, a BYOD approach suggests obvious benefits in terms of reducing the time and cost associated with the traditional method of supplying patients with a dedicated handheld device. Sponsors can not only save time, but crucial funds as well, by potentially removing the need to source and provision costly devices to the entire study population. What is more, through a BYOD approach, sponsors and CROs can significantly reduce the burden on study sites by eliminating the need to store devices, as well as receive deliveries and return devices. For patients, using their own device means they may be more easily able to fit the trial into their everyday schedule and reduce the perceived burden of having to carry around an additional device for the duration of the study. Furthermore, it also retains optimal familiarity, improves accessibility and usability, and makes it simpler for them to meet study obligations. These factors combined should help to improve the patient’s overall study experience, which in turn, should boost compliance and increase quality of data captured. While research is ongoing as to how compliant patients will be when using their own devices, crucially, there is still no concrete evidence to demonstrate this. Interestingly, provisioned eCOA studies already typically see compliance levels of higher than 90%, so even if BYOD is proven to increase this, there is not actually much room for improvement. To aid understanding and gather evidence of its benefits, the industry now needs to focus on conducting solid research which will support the widespread adoption of

BYOD approaches in clinical trials. What the Regulators Say When it comes to the official viewpoint, there is currently no formal guidance from the regulatory bodies on implementing a BYOD approach, although they have informally indicated they are open to the concept and recognise the benefits it might bring to patients participating in a clinical trial. As a result, sponsors and CROs have not surprisingly been hesitant when it comes to adopting this methodology, because they have no guarantee that the data they capture as evidence will be accepted as part of their submission. It goes without saying that as with any regulatory submission, sponsors should ensure that data consistency, quality, integrity, attribution and proof of the chain of custody are all transparent. It is also advisable for sponsors and CROs to consider the current guidance from the FDA and EMA.2,3 Although this mainly concerns the development, administration and interpretation of PRO instruments, it does include some fundamental principles that must be considered when implementing a BYOD trial design, particularly regarding consistency of administration. The ePRO Consortium also offers further support on best practice approaches.4 Neither of these is by any means comprehensive for BYOD trials, and it is clear that more guidance is needed if the industry is to embrace this new approach for key endpoints in Phase II and III trials. What BYOD Adopters Need to Think About There is no doubt that there is a promising outlook for BYOD clinical trials, however, there are still a number of challenges which remain very real issues for sponsors and CROs looking to adopt this approach. Firstly, organisations must ensure that every trial is accessible to as many patients as possible. There are a number of ways sponsors and CROs can do this, from making sure that the app utilised within their study is designed to work across the most widely used operating Summer 2016 Volume 8 Issue 2


Sponsors and CROs should also be clear on how reimbursement will be managed from the outset, as there are cost implications associated with data transmission when subjects are using an app-based solution on their own device. Organisations could potentially come up against issues with participants who, quite rightly, may not want to be responsible for additional charges using their own contract, due to reimbursement rates or timelines. This is not a problem in trials where patients are provided with a dedicated device, as the sponsor will meet the costs.

systems (Android, iOS etc) or web browsers (Internet Explorer, Chrome), through to guaranteeing study enrolment is not biased by technology ownership, age, or socio-economic status. Despite smartphone penetration increasing, it is still unlikely that there will ever be total saturation of appropriate devices in any target sample of reasonable size, and any bias driven by smartphone ownership would be seriously frowned upon by regulators. Sponsors and CROs could consider implementing a hybrid approach to combat this, where those patients who don’t own smartphones are provided with a provisioned device to enter their data and patients who do own smartphones can enter data via an app on their own device. While this approach would eliminate risks of biasing samples, it could in turn impact on the potential cost savings of adopting a BYOD methodology. The issue of equivalence and comparability of data captured across the wide range of devices potentially involved in a BYOD trial is another important consideration for sponsors and CROs. A participant using a desktop PC, for example, may be limited as to when they can submit data, whereas a patient using a smartphone can make entries at any time. Although not a major issue, regulators have also raised concerns over how patients interact with these different modalities, which have varying screen sizes, and whether this will impact on data integrity.

Finally, by opting for a BYOD approach, sponsors and CROs will have to accept that they will automatically lose some element of control, and so patient engagement throughout the duration of a BYOD study is key. From muting their phones, meaning audible alarms would not be heard, to turning notifications off, patients have the potential to significantly impact on compliance. In extreme cases, they could even delete the trial app, causing the loss of any unsubmitted data. Current Viewpoint It is clear that despite its recent rise in popularity, there are still a number of issues which need to be addressed before BYOD can be used as a viable alternative to traditional eCOA data collection methods for key outcomes in Phase II or III clinical trials. While the industry is currently developing ways to address these challenges, at present, the design of hybrid BYOD studies offers a perfect starting point and offers an appropriate solution for sponsors and CROs taking their first steps into the approach. There is no doubt that BYOD has the ability to transform clinical research and improve patient experiences in the future. However, while a BYOD approach provides an unrivalled option for certain types of trials, it is certainly not a onesize-fits-all model. Flexible solutions will always be needed to offer a different approach for sponsors and CROs who must consider the benefits of the BYOD methodology against the unique needs of each of their trials. For further information on CRF Health's solutions, please visit References 1. h t t p : / / w w w. e m a r k e t e r. c o m /



4. 5.


Article/2-Billion-ConsumersWo r l d w i d e - S m a r t p h o n e s by-2016/1011694 European Medicines Agency. Reflection Paper on the Regulatory Guidance for the Use of Health Related Quality of Life (HRQL) Measures in the Evaluation of Medicinal Products. London: European Medicines Agency, 2005. US Food and Drug Administration Guidance for Industry Electronic Source Data in Clinical Investigations. Food and Drug Administration, 2013. Equivalence of Electronic and Paperand-Pencil Administration of PatientReported Outcome Measures: A Meta-Analytic Review. Chad J. Gwaltney, PhD,1,5 Alan L. Shields, PhD,2,5 Saul Shiffman, PhD 3,4,5 Muehlhausen, W., Doll, H., Quadri, N., Fordham, B., O’Donohoe, P., Dogar, N. & Wild, D. Equivalence of electronic and paper administration of patient-reported outcome measures: a systematic review and meta-analysis of studies conducted between 2007 and 2013. Health and Quality of Life Outcomes, 2015, 13:167.

Paul O’Donohoe is Director of Health Outcomes at CRF Health and is based in the organisation's London office. He is responsible for developing CRF Health's internal health outcomes expertise and supporting clients across the range of scientific issues that can arise during the course of a clinical trial. He is passionate about developing the field of eCOA through research and active involvement in industry consortia. Previously Paul worked as a research psychologist at a child and adolescent mental health clinic based in Dublin, Ireland. He moved into the health consulting field with United BioSource Corporation where he worked across the health outcomes, health economics and health data capture groups. He has an MSc in Cognitive and Clinical Neuroscience. Email: INTERNATIONAL PHARMACEUTICAL INDUSTRY 57


Data-driven Drug Pricing: Technology Solutions that could Change the Paradigm New drug pipelines are dwindling and the cost of failure is high. The estimated cost of taking a single drug to market is $350 million1 and with regulatory agencies demanding more, larger and longer studies due to the increased desire for niche therapies, this figure is only going to increase further. If data can be accessed quicker, decision-making will be faster and futile drug development will be stopped before it gets to the most expensive later stages. This allows pharmaceutical companies to focus on their more successful drug candidates. The healthcare and life sciences industry worldwide is currently going through significant change. Large pharma is in the process of buying pipeline through acquisition. Here in the UK, both Pfizer and AstraZeneca have now had to consolidate resources, resulting in site closures. The industry is under pressure to find ways to work more efficiently in order to maximise investment in any new drug product. Developments such as riskbased monitoring (RBM) and the need for centralised clinical data are on the verges of drastically improving the efficiency of clinical trials. The apparent reluctance of some to embrace this transformation is reflective of the conservative nature of the industry. Brave individuals are needed to take the leap forward before the rest of the industry follows, creating an improved, more efficient process. At the heart of this change is the requirement for enhanced data accuracy, a compliant audit trial and a speed-up of clinical decision-making. As well as improving the industry’s efficiency, healthcare expenditure is also a major concern with prices for branded drugs having outpaced inflation every year since 2006.2 The NHS drugs bill is considerably more than £10 billion a year3 and there are urgent calls for a value-based drug pricing policy. Drug development however is among the most expensive developmental processes, or possibly the most expensive, and with drug pricing being driven down, this will drastically impact on pharma and biotech profitability. Current failure rates at Phase III are too high to risk a decrease 58 INTERNATIONAL PHARMACEUTICAL INDUSTRY

in profitability during successful trials, not to mention the huge risk that healthcare providers will refuse to finance the treatment due to lack of evidence of costeffectiveness. Drug Pricing Recent events, such as Martin Shkreli’s decision to increase the price of Daraprim (an old anti-infective) from $13.50 a pill to $750 a pill, have sparked a debate about drug pricing policies and the freedom which manufacturers have over drug pricing. “Unlike western nations, drug makers in the US face no limits on the prices they can charge – and those prices have steadily increased over time. The prices of medications rose 9.4% between 2006 and 2013, compared to a general inflation rate of 1.5%, according to the AARP. Spending on prescription drugs rose by 12.2% in 2014, while overall health care spending grew by 5%, according to the federal government.”4 Unlike in the US, prices of prescription drugs in the UK are currently set through discussions between manufacturers and the government. Prices for branded (onpatent) and generic (copies of off-patent brand) drugs are set differently. Though generics tend to be cheap, branded drugs are more expensive, and their prices are not necessarily based on their clinical value.5 Value-based pricing (as described in5) would see drugs priced upon clinical evidence of their therapeutic benefits. Manufacturers would set an initial price for their drug before the clinical evidence is measured against competing drugs (including generics). From this, a costeffective price can be set. The cost of a drug based upon clinical evidence, however, needs to take into account many factors such as side-effects (reduced price for side-effects?) and premiums for treating rare diseases. Further questions surrounding value-based pricing include “what is the cost of an additional year of life?” and “are genetic variations taken into consideration for a drug’s effectiveness?” These demands have hindered progression towards a valuebased approach.

Bridging the gap towards value-based pricing is proving to be challenging, however, a current progression in precision medicine sees pharma paying into a drugs fund such as the cancer drugs fund, and the money paid in would be used to test patients with the new medicine. Patients who respond successfully to the drug would then be required to pay a value-based price for continued treatment. This would reduce healthcare expenditure for treatments that have varied responses in the population, as well as providing faster access to innovative medicines for those in need of it. A value-based pricing approach is the most impartial and logical pricing policy, however, greater pressure must be placed upon manufacturers in order to prevent drug prices soaring and an exponential increase in healthcare expenditure. The following technological solutions have a huge potential to influence the efficiency of drug development and reduce healthcare expenditure, allowing for a true value-based pricing policy to be determined. Centralised Clinical Data Centralised storage of clinical data will alleviate the challenge of locating files when a number of different vendors have been used throughout multiple trials, as well as providing the knowledge that it is being held in a trusted and compliant environment. Denmark currently has a central storage facility in which data can be stored for the sponsor. This however is a unique occurrence, as in Germany, for example, no official body will store the data on behalf of a sponsor. But this begs the question, why does data storage need to be a regulator’s responsibility? As the potential for continuous streams of clinical data becomes a reality, networks and systems need to be capable of handling vast amounts of data. Greater quantities are required from clinical trials in order to satisfy regulatory bodies, but understanding the procedures from data collection and transmission, to storage within an organisation, will be key to ensure data security, data Summer 2016 Volume 8 Issue 2

Technology integrity, data quality and privacy. As big data is becoming part of everyday research, it appears that cloud services are best prepared for the vast quantities of recorded data. However, it has to be questioned how much of the continuous stream of data will be analysed compared to how much data is received? One aspect of centralised data that could utilise the power of cloud services is long-term data storage (LTDS). Similarly to hosting data during a trial, a trusted third party (T3P) would maintain the data in a secure and compliant manner, providing access to the data on request and following a traceable procedure. The archived data can be held for as long as expected by the regulators and then be retrieved when required. Some questions still remain regarding LTDS, such as “what if the relationship between sponsor and T3P breaks down?” or “what if the T3P goes out of business or is acquired?” It is clear, however, that centralised data has huge potential for the future of clinical data stewardship. eSource Data It is estimated that the number of smartphone users will reach 2.29 billion worldwide in 20176 and as the power to track and analyse data via a mobile device increases, it seems logical to apply this technology to a clinical setting. It is well known that the smartphone of 2012 had more computer power than that available to Apollo 11, however it is not computer power that is restricting mobile applications in a clinical setting, but the appropriate legislation and security of the data recorded. According to a post on the Federal Register by Associate Commissioner for Policy Leslie Kux, the FDA is soliciting comments “from a broad group of stakeholders on the scope and direction of the use of technologies and innovative methods in the conduct of clinical investigations”. “Clinical investigations that ensure the protection of the rights, safety, and welfare of trial participants and that yield reliable data are critical to the FDA’s mission to ensure that medical products are safe and effective,” Kux writes. “Creative uses of technology in conducting clinical investigations have emerged over the previous decade and include advances that have the potential to improve recruitment, participation, and retention of trial participants.”

Through the application of mobile technology, clinical trials could become more patient-centric with study descriptions, visit schedules, medication reminders and visit notifications all available on a user’s phone/tablet. There are, however, questions concerning what constitutes electronic source data. In a meeting at the EMA it was announced that electronic source data is defined as “source data captured initially into a permanent electronic record used for the reconstruction and evaluation of a clinical study. NOTE: “permanent” in the context of these definitions implies that any changes made to the electronic data are recorded via an audit trail.” Backup procedures for eSource data has been a topic of concern both to prevent data loss and in the event that the device fails or is lost. “The eSource in the files of the site should be protected from tampering or loss” it was announced. “This is often accomplished by making backup records that can be used to restore an operational instance of all the data for a study in the event of a local failure or corruption. The procedures for making the backup need to be validated to prove that the copies are complete, authentic and that the restoration operates as intended.” In the instance that a device fails or is lost, “the system providers must provide auditable proof that such controls in support of site responsibilities are adequate and trustworthy. The idea that a paper or PDF copy of eSource records being made physically at site prior to or in conjunction with the transmission of the originally captured source data is impractical, unworkable and unnecessary.” It was recommended that replacement devices should be available, or possibly a web backup. eSource data has a vast potential to improve the way data are collected during clinical trials. In an era where mobile and tablet capabilities appear to have no boundaries, it seems logical to apply these modern-day essentials to a clinical setting. Paper source data generation can therefore no longer be viewed as the “gold standard” of data capture.7 Digital Recruitment of Patients Data sits at the core of all evidencebased decision-making and thus the success of any drug. The clinical trial

process has been described as “the best mechanism to provide legitimate evidence that medical progress has been made”8, however, many studies find that recruitment is the toughest challenge faced when conducting a clinical trial. Newer methods of recruitment, known as digital recruitment (eRecruitment), aim to ease this process by utilising the expansive network that is the internet. Using the traditional methods of recruiting patients for clinical trials is a hugely time-consuming process, not to mention challenging and expensive. These methods utilise mass marketing through the mediums of print, radio and TV. According to the Tufts Centre for the study of drug development, nearly 100% of studies conducted outside of North America use these standard approaches. Even in North America, all but about 14% of studies continue to rely on these traditional approaches. Despite digital recruitment still being in its early phases of development, those who have used it have seen very promising results. Companies are meeting recruitment numbers in record time, meaning huge savings in cost and time for their trial. The original timelines for Phase II-IV studies usually end up doubling in order to meet desired enrolment levels.9 "Many companies automatically assume that there are regulations prohibiting the electronic recruitment of patients. In reality, there are no such restrictions. Regulatory guidelines on soliciting trial participants are media agnostic. When clients realise this, their excitement is palpable. Suddenly their hands are untied and they can seek trial subjects where they 'live' - in other words, online." - Ramita Tandon, Senior Vice President and General Manager, iCTRS. Facebook advertising is a great way to expose your company to millions of people in seconds, as some Australian researchers found out in 2010. A Facebook advert ran from May to September 2010 and invited females aged 16-25 from Victoria, Australia to participate in a health study. 551 women clicked on the ad, at which point they were taken to the study's website where they could submit their contact details, and 426 subsequently agreed to complete a health-related survey. Of those that agreed to take part, 278 completed the survey.



The internet has become an essential part of everyday life to millions of people and with stats such as 701,389 Facebook logins and 2.4 million Google searches every 60 seconds, these only reiterate that fact10. While companies will still have to experiment with what is the best route to the patients, it is clear that digital recruitment could play a huge role in the efficiency of future clinical trials. Risk-based Monitoring On-site monitoring can account for up to one-third of a trialâ&#x20AC;&#x2122;s overall cost11 and so a more cost-effective approach to monitoring is much needed. RBM is defined as targeting your monitoring activities to deliver the greatest benefit to the study. Through key risk indicators (KRIs), centralised monitoring can determine where potential issues in the data are occurring and implement the appropriate actions to mitigate the risk, both in the current instance and to prevent future occurrences. There is a sense that SDV is still very much the focus, even with RBM, and that not enough consideration is given to how the data are created, e.g. IMP handling, or how images are taken and stored. It appears to be taking time for the teams to adjust from accuracy to quality and removing the checklist mentality. No single approach to monitoring will work for all trials, hence the risk based monitoring plan needs to be adapted to the associated risk for that particular study design. Application of risk should be targeted not just at patient safety but 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

also at data integrity. When questions do arise, we should always look at root cause analysis and demonstrate corrective and preventative actions. The Futureâ&#x20AC;Ś With healthcare expenditure rising year upon year and greater demands for improved clinical evidence, it is crucial that the pharmaceutical industry streamlines drug development and adopts a value-based pricing policy. The industry can no longer remain reluctant to embrace new technology in an era where it is driving innovation. Greater regulatory clarity is needed to adopt new technologies, ensuring data integrity and process compliance. The current mindset of focusing on data accuracy, not quality, is one that will fade over time, with the future of drug development being one of centralised data and on-demand access from cloud-based solutions which are almost infinitely scalable. References 1. matthewherper/2013/08/11/howthe-staggering-cost-of-inventingnew-drugs-is-shaping-the-future-ofmedicine/#21a524806bfc, visited on 12 Apr 2016. 2. h t t p : / / w w w. p w c . c o m / u s / e n / health-industries/top-healthindustry-issues/drug-pricing.html visited on 12 Apr 2016. 3. w w w. p a r l i a m e n t . u k / b r i e f i n g papers/POST-PN-487.pdf visited on 13 Apr 2016. 4.

research-and-analysis/blogs/ stateline/2016/03/07/highdrug-prices-prompt-demands-fortransparency visited on 21 Apr 2016. 5. h t t p : / / w w w. p a r l i a m e n t . u k / documents/post/postpn_364_ Drug_Pricing.pdf visited on 21 Apr 2016. 6. h t t p : / / w w w . s t a t i s t a . c o m / statistics/330695/number-ofsmar tphone-users-worldwide/ visited on 15 Apr 2016. 7. content/be-bruga/scdm/ Publications/~/media/be%20 bruga/scdm/documents/ eSource%20White%20Paper%20 06122014%20FINAL.ashx visited on 20 Apr 2016. 8. h t t p : / / w w w . h e a l i o . c o m / hematology-oncology/practicemanagement/news/print/hemonctoday/%7B8865f086-ae714bd2-bcf6-9b34472036da%7D/ experts-discuss-the-current-state-ofcancer-clinical-trials visited on 15 Apr 2016. 9. h t t p : / / c s d d . t u f t s . e d u / f i l e s / uploads/jan-feb_2013_ir_ summary.pdf visited on 21 Apr 2016. 10. h t t p : / / w w w. e x c e l a c o m . c o m / resources/blog/2016-update-whathappens-in-one-internet-minute visited on 21 Apr 2016. 11. h t t p : / / w w w . risking-it-all-introducing-risk-basedmonitoring-cancer-research-uk visited on 20 Apr 2016.

Elliott Frodsham, Business Development and Operations Assistant, is a current Newcastle University pharmacology student on an industrial placement year at Datatrial. Elliottâ&#x20AC;&#x2122;s year has given him an invaluable experience into business development and operations, as well as an instrumental insight into the life sciences industry. He is currently working as a study delivery associate, as well as writing a monthly blog surrounding current hot topics in the industry. Many thanks to Emma Banks (CEO) for her guidance with this article. Email: Summer 2016 Volume 8 Issue 2


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Safe, Fast and Compliant: The Raman Advantage for Pharmaceutical Manufacturing The contamination or incorrect measurement of raw materials used in the manufacture of pharmaceutical and healthcare products poses a significant risk to patient safety. As a result, regulatory requirements for raw material identification and QA/QC manufacturing processes have become increasingly stringent and manufacturers are faced with the challenges of meeting these requirements while simultaneously trying to improve productivity, reduce costs and deliver innovative products to market. In addition, manufacturers are also under pressure to achieve 100% inspection rates and lean manufacturing. The availability of fast and accurate technologies capable of identifying a wide range of raw materials is therefore essential to ensuring product safety and authenticity. In recent years, handheld Raman has become an increasingly popular technique used in the pharmaceutical manufacturing process for raw material identification (RMID). The global laboratory and handheld Raman instruments market is expected to grow at a CAGR of 9.74% over the next four years, demonstrating the popularity of the technique. But what are the reasons behind Raman’s ascent as a method of choice for rapid and reliable raw material identification? Raman Spectroscopy and the Power of 1064nm: An overview Raman spectroscopy is an accepted technique by the United States Pharmacopeia (USP) and the European Pharmacopeia (EP) for RMID, and is widely used as part of the pharmaceutical manufacturing process to ensure the safety and efficacy of pharmaceutical products. In Raman spectroscopy, a laser is focused at a sample and the light scattered by the sample is measured. Specific shifts in a portion of the scattered light correspond to the energy of a material’s molecular vibrations. These shifted or inelastically-scattered photons create the peaks in a Raman spectrum. A Raman spectrum is essentially a signature fingerprint of a compound or chemical and is used to positively identify the material. The specificity of Raman and its 62 INTERNATIONAL PHARMACEUTICAL INDUSTRY

relative ease of use, including the advent of small and portable instrumentation, have made Raman spectroscopy effective in applications where chemical identification is required. Fluorescence interference is one of the most common frustrations for users of handheld Raman instruments utilising a shorter wavelength such as 532nm or 785nm, especially when attempting to analyse materials such as cell culture media, xantum gum and gelatin or materials in coloured containers. The intensity of fluorescence depends on the material; however, fewer materials fluoresce at longer excitation wavelengths, meaning that longer excitation wavelengths, such as 1064nm, can analyse a wider array of materials. Handheld Raman instrumentation has traditionally utilised shorter excitation wavelengths due to the relative complexity of developing smaller parts for longer wavelengths. However, recent technological advances have made it possible for handheld Raman spectrometers utilising a longer wavelength 1064nm source to be successfully developed for use in pharmaceutical applications. With the introduction of handheld Raman analysers with 1064nm excitation lasers, manufacturers are now able to analyse a wider range of materials than ever before. Handheld Raman analysers using 1064nm excitation lasers, such as Progeny™ from Rigaku Analytical Devices, enable users to measure coloured solids and liquids, which helps to increase inspection rates and improve confidence in results. The power of 1064nm lasers and elimination of fluorescence interference also mean that substances can be measured through containers and packaging materials such as polymer bags, glass bottles, flasks and vials. The ability to screen materials using non-contact, non-destructive analysis through containers dramatically reduces the risk of cross-contamination and avoids delays on the warehouse floor. Optimising the Pharmaceutical Manufacturing Process Handheld Raman can be implemented

at multiple stages of the pharmaceutical manufacturing process, starting with RMID. Traditional processes for RMID include quality control (QC) lab analysis, a costly and time-consuming step especially when productivity must be optimised with fewer resources – and all without compromising quality. By implementing an identification method at the point-of-need with a tool that can be used by any employee, companies benefit from a process that is much more efficient and cost-effective. Handheld Raman is designed to fit seamlessly into any work environment for RMID processes. By providing the ability to analyse and identify materials against a variety of criteria at the point of need, handheld Raman eradicates the delay in waiting for results from external laboratories, improves cycle time and optimises material movement. Ultimately, pharmaceutical manufacturers are able to easily meet the requirements for 100% inspection of incoming materials with handheld Raman, and a comparison between the traditional RMID and handheld Raman RMID workflow is outlined in Figure 1. Utilising a handheld Raman device enables users to make quick decisions with easy PASS/FAIL results, helping to achieve leaner manufacturing processes without comprising on the quality of the material. Handheld Raman can also be used to distinguish different concentrations of active pharmaceutical ingredients (APIs) in drug product (DP) doses and placebos with little or no sample preparation. Following primary analysis of DP and API release testing using a technique such as HPLC, 1064nm handheld Raman is an ideal supporting secondary identification method. Handheld Raman can also be applied to in-process control testing during post-packaging operations, final release testing and receipt ID testing of finished goods. This eliminates the need to send samples to an analytical laboratory and provides significant savings. As well as portability, 1064nm handheld Raman has advantages compared to traditional ATR-FTIR and compendial wet chemical techniques. This includes reduced sample preparation, minimal instrument clean up Summer 2016 Volume 8 Issue 2

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Manufacturing package verification testing of DP without transferring the DPs to an analytical laboratory. Handheld Raman not only offers efficiency and fast data collection for final release of post-packaged DP, but also allows for an extra layer of quality to be incorporated into the post-packaging and post-package release testing, all while reducing material transfer steps and analyst exposure to high potency APIs and DPs. Counterfeit Detection Another popular application for handheld Raman is the identification of counterfeit pharmaceuticals and other healthcare products. The circulation of counterfeits is a global problem and includes not only products containing potentially harmful substances, but also products that contain no, or diluted amounts of, active pharmaceutical ingredients.

Figure 1: Comparison of the traditional and 1064nm Raman RMID process. and the removal of exposure risks of high potency APIs, because of Raman’s ability to measure through containers – such as plastic bags, thin plastic, clear glass and amber glass bottles. In one study, several different DP formulations of API at different loading levels using a 1064nm, handheld Raman analyser to verify whether a qualitative analysis approach, such as correlation, would suffice in the discrimination between similar products with different

API concentration. Three sets of DP tablets and capsules with API/excipient blends with API loading – in the range of 4-28% – and corresponding matching placebos were analysed. The results demonstrated that the handheld Raman analyser could easily distinguish different API loadings and placebos for two of the three drug products from clinical trials investigated. For appropriate DP formulations, the use of this portable and rapid technique could be applied to in-process control checks of packaging lines and subsequent post-

Figure 2: 785nm excitation and 1064nm excitation Raman spectra from a green capsule of over-the-counter headache relief medication. 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Raman spectroscopy is highly specific to chemical composition and so is well suited for distinguishing authentic vs. counterfeit products. A common challenge of traditional handheld Raman instruments using 785nm excitation is fluorescence interference. The higher excitation wavelength of the handheld Rigaku Progeny 1064nm analyser minimises this signal blocking fluorescence. To demonstrate this advantage, a green gel cap of an over-the-counter headache relief medication was measured with a handheld Raman analyser using 785nm and Progeny, using 1064nm excitation. As seen in Figure 2, the 785nm excitation shows a broad curve which is from fluorescence and obscures any materialspecific Raman peaks. However, the 1064nm excitation of Progeny clearly shows specific Raman peaks that can be used to identify an authentic material. Figures 3a and 3b, respectively, show Raman spectra of authentic and counterfeit Cialis tablets and authentic and counterfeit commercial pain relief powders. All of these spectra were collected with a 1064nm handheld Raman analyser using measurement times of less than 30 seconds. In both cases, the analyser easily distinguished the counterfeit from the authentic, as the Raman spectra are clearly different from each other. The authentic commercial pain relief medication is a mixture of three APIs: acetaminophen (paracetamol), aspirin and caffeine. When the Raman peaks of the authentic and counterfeit are carefully

Summer 2016 Volume 8 Issue 2


Figure 3a (left): 1064nm Raman spectrum of authentic and counterfeit Cialis tablet cores. Figure 3b (right): 1064 nm Raman spectra of authentic, and counterfeit commercial pain relief powders and pure caffeine. compared to each other, and then against the spectrum of pure caffeine, it appears that at least the amount of caffeine in the counterfeit powder is much less than in the authentic. It is also therefore likely the ratio of the acetaminophen and aspirin is different as well. A lack of caffeine in the counterfeit can reduce the efficacy of the medication. For an over-the-counter pain relief medication, reduced efficacy may be of most concern for the manufacturer, but for many other types of life-saving medication, a counterfeit without the correct API can have disastrous consequences. These results demonstrate how handheld Raman enables the on-the-spot verification of the chemical composition of commercial products resulting in rapid identification of counterfeits and immediate removal from the supply chain. They also clearly show the advantage of using a 1064nm excitation handheld Raman vs. a 785nm handheld Raman in order to reduce fluorescence and achieve better identification of some products. Confidently Compliant In addition to achieving good manufacturing practices and complying with 21 CFR Part 11, pharmaceutical manufacturers using handheld Raman now have new standards specific to the calibration of Raman spectroscopy systems to consider. Effective 1st April 2016, revisions to the General Chapter on Raman Spectroscopy in the European Pharmacopoeia Commission have been introduced that set acceptable tolerances for Raman wavelength shifts and associated tolerances. The reference standards used to verify the wavenumber

scale have now been changed, and indene and naphthalene have been replaced by polystyrene and paracetamol. Despite this, cyclohexane will remain. These substances have been chosen as they are ‘easy to work with’ and it means that reagents, liquid, powder and polymer materials are now all covered by the regulations. Pharmaceutical manufacturers using handheld Raman will need to ensure they are compliant with these new standards, and the introduction of these new regulations demonstrates recognition of the growing importance of handheld Raman for pharmaceutical manufacturing. Conclusion The implementation of handheld Raman into pharmaceutical manufacturing process supports the safe and costeffective development of pharmaceutical products, overcoming the limitations of existing technologies and processes for RMID. One manufacturer and distributor of health and personal care products implemented 1064nm handheld Raman into their RMID process and reduced their cost per analysis by 90%, and testing time from 30 days to just hours. Beyond pharmaceutical manufacturing, 1064nm handheld Raman analyser is also being used in applications including biopharmaceuticals, nutraceuticals, and cosmetics to broaden the range of materials that can be analysed quickly and accurately while complying with industry regulations.

Dr. Suzanne Schreyer is a Senior Applications Scientist with Rigaku Analytical Devices. She received her PhD from the University of Waterloo (Ontario, Canada) in Analytical Chemistry (Chemometrics) in addition to degrees in Engineering (B.Sc.) and Chemistry (B.Sc. and M.Sc.). Dr. Schreyer has 15 plus years’ experience with optical spectroscopies including Raman, Fourier Transform Infrared, Fluorescence, and Near InfraRed. She has also spent several years working as a chemometrician for the pharmaceutical industry and has taught university courses on drug discovery and design. Email: INTERNATIONAL PHARMACEUTICAL INDUSTRY 65

Manufacturing MES Adoption in Pharmaceutical Manufacturing – A Changing Landscape Manufacturing execution system (MES) solutions have the potential to improve productivity and simplify compliance within the pharmaceutical manufacturing industry. However, factors such as cost and lack of specialist expertise have proven a barrier to many small and midsized pharmaceutical companies. Siobhan Fleming, business development manager at manufacturing software specialist LZ Lifescience, discusses the role of MES solutions in the pharmaceutical sector, typical barriers to adoption and the increasing use of the technology as it becomes more accessible to a wider part of the industry. An Introduction to MES MES is a form of software that can be used to manage and oversee production activities in real time. The ultimate goal of the technology is to achieve ‘right first time’ production, by eliminating errors and providing the right information, to the right party, at the right time. MES technology has the ability to simplify compliance, lower production costs and increase equipment efficiency. It also increases visibility throughout the manufacturing process, providing a centralised point of information in line with good manufacturing practice (GMP). Traditional paper-based monitoring and reporting are replaced by electronic batch records (eBRs), which can be accessed in real time by all users. Due to the many benefits, MES solutions are increasingly being implemented in pharmaceutical manufacturing plants. In fact, MES technology is being adopted by the Iife sciences industry at a faster rate than any other vertical market1. Typically, such systems are used to schedule manufacturing batches or lots, document shop-floor activities for monitoring and reporting purposes, synchronise manual activities with automated processes and deliver instructions to operators. By integrating with manufacturing control systems (DCS, PLC, SCADA), MES technology has the ability to support quality control (QC), equipment management and deviation 66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

management, as well as assisting with enterprise resource planning (ERP). While automation systems help to control the manufacturing process and ERP systems focus on supply chain management, there is an information and/or time lag between these two layers, often addressed within the manufacturing department using spreadsheets or word documents. MES focuses on plant operations to address this gap, so that materials and information flow smoothly through the plant to produce quality products, while maintaining low levels of inventory. Factors Driving Adoption There are a number of factors that influence the decision of pharmaceutical manufacturers to implement MES technology. For example, changing compliance requirements and regulatory standards are making traceability more difficult to achieve with manual or hybrid systems. Pharmaceutical manufacturers must deliver their products to precise parameters and have access to timely and accurate data throughout manufacturing. Errors have the potential to cause a compliance issue, potential 483 or warning letters wasting time and money and resulting in serious reputational damage. In addition, many organisations are increasing their investment in technology and IT budgets to lower the overall costs of production. Market price pressures from governments and insurers are squeezing margins, creating a need to improve efficiencies and reduce costs during the manufacturing process. By monitoring and overcoming potential quality issues in real time, pharmaceutical manufacturers are able to reduce waste and ensure fast product release in a competitive marketplace. The global expansion of manufacturing facilities and a greater need to replicate information across multiple sites is also driving the adoption of MES solutions. Increasingly, pharmaceutical organisations are

looking to standardise systems and processes globally. In addition, the strong trend in mergers and acquisitions results in a larger network of sites to manage and a requirement for better corporatelevel visibility into site-level operations. This can be facilitated through a cloudor web technology-based MES that provides centralised data for real-time visibility and distribution of information, regardless of location. Overcoming the Barriers to Implementing MES Heavy IT Footprints Despite the recognised benefits, the prohibitive cost of implementing and licensing ‘traditional’ MES has essentially resulted in it being adopted by only the largest manufacturers. Smaller and midsized life science companies have been put off from using MES solutions and have tended to scale their workforce to match production requirements, which means that increased production comes with increased overhead. Web-based technologies remove the need for upfront investment and heavy IT footprints. Such technologies can also be scalable to needs and budget, integrating with existing hardware and IT systems to enable seamless deployment to all users. The pharmaceutical industry has been slower to adopt cloud-based technology due to concerns around security, performance and availability. But with other industries demonstrating the viability of cloud-based approaches, the mind-set has changed and cloudbased solutions are now considered by many organisations as part of their upgrade strategies. The ISPE Good Automated Manufacturing Practice (GAMP) community of practice is now developing guidelines to validate cloudbased solutions; evidence that the next generation of MES solutions will be cloud-based2, 3. Lack of Tailored Solutions The MES platforms traditionally deployed in ‘big pharma’ were designed for general industry rather than with the specific needs of the rest of the pharmaceutical industry Summer 2016 Volume 8 Issue 2

Manufacturing therefore reducing downtime, improving operational efficiencies and reducing manufacturing operation and supply chain risk.

in mind. They were equipped to handle continuous processes, such as those found in the oil & gas and bulk chemicals industries, and were less adaptable to new and changing requirements that pharmaceutical manufacturers face. This is still largely the case; it is estimated that only around 20 of the ~75 MES vendors carry out more than 5 per cent of their business in the pharmaceutical industry4. Gradually, software providers are recognising the importance of tailored solutions to meet the demands of specific and highly regulated industries. In addition, traditional licensing structures are costly and inflexible, making it an ‘all or nothing’ decision. Newer products now offer modular licensing structures which mean that only the deployed functions are paid for, allowing growing organisations to ‘start small’ and increase the scope of the system as their needs and production grow. Some vendors offer a licensing system by concurrent user. As a result, only the users logged onto the system at any given time require a licence, which dramatically reduces the user licence cost. Downtime and Disruption It is a common belief that any major change to operations management, such as the introduction of new technology, must result in significant upheaval and downtime. Traditional MES often requires heavy customisation, along with significant time and cost. In contrast, solutions developed specifically for the life science sector make the implementation process significantly faster as the typical functions required are already built in. Implementation times of only three to six months are very achievable, meaning there is little impact on business productivity. Much of this activity takes place away from the shop floor and causes minimal disruption to production.

The Need for Flexibility On the change management side of running a dynamic manufacturing environment, one of the hardest requirements is to achieve and maintain the same level of flexibility that paper provides. While traditional systems were designed with set processes and requirements in mind, modern solutions with modular and scalable structures allow manufacturers to adapt quickly to changing trends and customer requirements. This is a key consideration. For example, we see a trend towards individualised medicine and the proliferation of companies targeting therapies for patient populations that are becoming smaller and smaller. Manufacturing systems must be flexible enough to accommodate frequent line or product changeovers without adversely affecting compliance. This is prohibitively complex, costly and time-consuming with a traditional MES solution, whereas a configurable solution offers the flexibility to manage these challenges effectively. Demonstrating ROI Return on investment (ROI) is the main consideration when making a change to business operations. It is often thought that ROI can only be achieved in the long term, but the availability of MES options at a lower price point is changing that. Seeing an ROI within a shorter timeframe is particularly important for smaller pharmaceutical companies, which often have less capital to invest. Lower-cost MES is enabling these organisations to access the benefits without disrupting cash-flow. When implementing a flexible and scalable MES solution, ROI is typically feasible within 12 months. It can be achieved by a combination of reducing working capital such as materials and inventory, lowering the direct costs or compliance, increasing reliability and

Staying in the Race Pharmaceutical manufacturers are operating in an increasingly competitive and fast-moving environment. Many factors, such as price pressures, more complex regulatory requirements and globalisation are creating new challenges that can be addressed through the right technology. A number of developments within the MES industry are improving access to the technology and opening up opportunities for small and mid-sized companies to realise the benefits. Those companies that embrace new, more efficient ways of managing operations, including the cloud, are placing themselves at a competitive advantage, with the ability to accelerate their time-to-market and improve efficiencies throughout the manufacturing process. References 1. Strategic Analysis of the Global MES Market, Frost & Sullivan (Sept 2014). 2. Stokes, D. Compliant Cloud Computing – Managing The Risks, Pharmaceutical Engineering (2013). 3. Cloud Computing in a GxP Environment: The promise, the reality and the path to clarity, GAMP Cloud Computing SIG, Pharmaceutical Engineering (2014). 4. Data from CGI Group (2013). Siobhan Fleming is business development manager at LZ Lifescience. With experience in pharmaceutical automation, Siobhan has strong knowledge of the full software lifecycle in the pharmaceutical manufacturing environment. She is passionate about delivering affordable MES options to the life sciences industry and has a background in compliant software solutions, automation system integration, computer system validation (CSV), document management and enterprise resource planning (ERP) software. Email:siobhan.fleming@lzlifescience. com INTERNATIONAL PHARMACEUTICAL INDUSTRY 67

Manufacturing Why is Good Tablet Design So Important and How Can it be Achieved? Detailed design of pharmaceutical and nutraceutical tablets is essential in order to produce robust tablets with bespoke designs. Tablet manufacturers should not overlook tablet design because it is key to the quality of the end product. “With sufficient fore-thought and consideration, most potential tablet making problems can be eliminated at the early stage of design.” -– Steve Osborn. Good tablet design is extremely important; it has an impact upon anti-counterfeiting, tooling strength, tablet coating, durability and functionality. Good tablet design helps to avoid downstream manufacturing problems such as tablet sticking, picking, lamination, capping and premature tooling failures. It is essential to consider these at the beginning of the process, ensuring a problem-free, high-quality, end product, so getting all these factors right is imperative to a ‘good’ tablet and to maximise the efficiency of the tablet manufacturing process. Several elements need to be considered when designing a tablet, including shape and profile, breakability, tablet/tooling performance, branding and finally, anticounterfeiting. Tablet Shape and Profile The first thing to consider is the tablet shape followed by an optimum tablet profile. There are two basic tablet shapes, round and non-round; however, the complexity of non-round shapes can be very varied and require specialised tool manufacturing capability. The shape plays a key role in the final quality of the tablet. Once the base shape has been decided, tablet size must be determined, and consideration should be given to the type of press available for tablet manufacture as this can limit the size of the tablet. Next follows selection of the tablet profile, of which there are many options, including flat-faced, bevellededge, single-radius / double-radius (compound) cup, ball or pill. The type 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

of profile required is influenced by several factors; the granule, embossing requirements, coating process, packaging and the company’s branding. Should a large amount of branding be required, a profile with a larger surface area is preferred, such as a shallow cup or flat bevel. Thought should also be given to the volume of the tablet and if it is to be coated. Successful coating is dependent on tablet profile. Coated tablets, whether they are film or sugar-coated, present challenges for the tablet designer. The complexity of the coating process is vast. Many of the variables are within the manufacturer’s control but expert tablet design can help eliminate some potential problems. Typically, the centre of a tablet, the core, is lower in hardness, so during the coating process core erosion may take place. This is when the tablet comes into contact with the coating pan and other tablets, causing wear to the core. This vulnerability, caused by mechanical stress during coating, can be reduced by avoiding very deep concaves and ensuring a robust design. For film-coated tablets, double-radius profiles are the preferred choice. For shallow tablets with hard, sharp edges, the coating process will damage the exposed edge of the tablet, which can result in chipped edges and sometimes cracks within the coating. Therefore, flat and shallow tablet profiles should be avoided as these will not roll effectively in the coating pan. Doubleradius designs ensure a strong tablet edge and a balanced profile, which will roll in the coating pan. Another benefit of the double-radius design is that it can accommodate most marking and branding requirements (i.e. de-bossing, breakline, logo), because it increases the usable surface area available for this. Poor embossing and branding design on the tablet can lead to bridging (where the coating collects in the detail on the face of the tablet because the coating does not fully follow the contours of the embossing on the tablet core, but bridges

over, leaving a void under the coating) and infilling (when too much coating material has filled the detail, making it indistinct) during film-coating. Possible causes for this can include: 1. Inadequate adhesion of the film coating – the coating supplier should be consulted to improve the adhesion characteristics of the coating. 2. Inappropriate embossing design where the angle may be too acute or too deep (bridging) – The embossing should be re-designed in consultation with the tooling supplier. It can also be due to the stroke or section of the embossing being too wide or too shallow (in-filling). 3. Inappropriate coating procedure, i.e. spray rate, drying time, etc. – the coating supplier should be consulted. Another challenge is twinning; tablets sticking together during coating. This is normally caused by the flat surfaces of the tablets coming into contact and adhering to each other. To avoid this, a slightly curved surface can be applied, which reduces the contact area and eliminates the potential for twinning. Tablet Breakability Good tablet design will enable the tablet to be broken easily and accurately, ensuring that when the tablet is broken, the required tolerance for dosage is achieved. Breaklines that are used to divide a tablet must be both functional and effective. Uneven breaking of a tablet may result in significant fluctuations in the administered dose. The degree of inaccuracy may be associated with breakline design, tablet hardness, and / or formulation. Figure 1 - The tablet on the left shows a D type breakline, a more rounded cross‐ section causing an uneven break. The tablet on the right shows an optimised cross section, where the breakline has a small radius and penetrates deep into the profile of the tablet to effectively achieve an optimum break.

Summer 2016 Volume 8 Issue 2


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Figure 1 Not all breaklines are functional breaklines, for example, short bisects (Fig.2 – B type or H type) which are mainly used for aesthetic purposes and will not break evenly. Combinations of a G type and D type breakline, applied to opposite sides of a tablet with the correct physical dimensions, are considered the best options for successful tablet division.

alignment of the breakline on the upper and lower punch tips is critical and requires the turret to have a lower key facility. Attention should also be paid to breaklines that stand above the punch tip edge. Upper and lower punches must be set correctly for effective tablet ejection and take‐off. If not set correctly, damage can occur to the breakline on the punch tip, resulting in catastrophic failure and damage to the tooling and the tablet press. It can also cause severe chipping of the tablet on ejection. Figure 3 Illustrates a breakline that stands above the edge of the tip.

Figure 3

Figure 2 Tablet Breaklines The following factors should be considered when selecting a breakline: • Accuracy of breakage, which is important for equal dosage • Holding of the tablet and ease of breakage. This relates to tablet size and hardness. • Inclusion of other detail such as a logo and its influence on the breakline. Product identification must be maintained to ensure brand integrity when the tablet is divided. • Robustness of the tablet during compression, coating and packing, because the tablet’s physical qualities are changed by adding a breakline; it may become weaker. The breakline should penetrate into the tablet whilst maintaining an optimised radius and angle. A larger radius usually makes the breakline less effective.

Normally setting is gauged from the overall length of the tool, but adjustment may be required to prevent: tablet chipping during take‐off, decapitated tablets at ejection, or upper and lower punch tips coming into contact with each other. Tooling Performance Tablets are becoming more complex and exotic in both shape and profile for brand identity and marketing. As the tablets become more complex, so does the tooling, which increases the demand for tooling strength, durability and overall performance. This has to be a major consideration when designing a tablet. Figure 4 shows a stress and fatigue analysis of a punch tip using finite element analysis, or FEA. FEA is a software-based numerical technique for calculating the strength and behaviour of engineering structures. It is used to calculate deflection, stress and strain to determine fatigue limits of both material and design.

Figure 4 – FEA analysis of a punch tip. When assessing the results of the FEA analysis, it is important to identify areas of high stress concentration. When reviewing the image and colour banding, the red areas are those with higher stress concentrations. If the fatigue limit is exceeded in these areas during cyclic loading, eventually a breakage will occur. A good design should ensure that the stresses are equally dispersed across the shape, as shown in the image. An expert designer will be able to add appropriate strengthening features to the design such as blended lands and profile changes. They should also ensure that any embossing detail is not in direct proximity to the high-stress areas. Optimising the embossing position on the tablet face can be of benefit to the strength of the design rather than being detrimental. One of the most important features of any tablet design is the blended land. Often, tablet manufacturers elect not to apply a land as it may not be visually acceptable on the finished tablet. Lands that are applied incorrectly, either unevenly or made too large, can present a range of issues, including: flashing or lamination during compression; chipping of the land during take‐off, or build‐up of coating on the edge of the tablet which eventually will chip. The answer is to always include a blended land as, when applied correctly, it will optimise tablet and tooling strength and performance. When applying a blended land it is important that the designer considers all these factors. The size of the land should be appropriate to the design of the tablet.

Where a breakline is functional and present on both sides of the tablet, 70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2016 Volume 8 Issue 2

Manufacturing Figure 5 shows the application of a blended land to a punch tip. The correct method of applying the land is to ensure that the flat area on the tip edge is maintained, whilst blending the intersection between the profile and the flat. This is achieved by applying a radius to the finished punch tip.

Figure 6

Figure 5 – Blended land A correctly selected and applied blended land provides benefits to handling, loading, setting, tooling strength, the visual appearance of the tablet and ultimately, your brand. Tablet Branding When considering the visual appearance of the tablet, it is important to think about the type of font and logos used for branding. Typefaces and designs must take into account practicality of tablet manufacture. Caution is required during the design process when applying branding to your tablet. Failure to consult with an expert tablet design team could result in a product that looks good on paper but is not practical to produce. For tablets with a logo, the design and placement are very important. The tablet designer should always seek to maximise the face area to avoid picking and lack of distinction. However, be aware, as problems may arise if too much of the face area is used, leading to embossing distortion and weakness in the tooling. Figure 6 shows a good example of the importance of spacing on logos. The top example clearly shows the embossing within the safe zone for this particular tablet shape. The bottom example shows embossing that goes beyond the safe zone and on the side view you can see how the embossing protrudes.

Occasionally, when the need to exceed the safe zone is required, the best practice is to ensure the detail is spaced far enough away from the edge of the tip. As a general guide the embossing should sit below the landed edge of the punch tip. If this guide is not followed, then the embossing will be unprotected and prone to damage, causing further downstream problems during the tableting process. If a company decides to have a common theme of identification on their tablets, it is important to take into account how that identification will scale up or down, according to the size of the tablets to be produced. When designing logos, applying identification and other detail, think about the smallest tablet that is likely to be produced, as this reduces the working area available. Where company or product logos are required on the tablet face, the complexity of the logo should be considered. If logos have been designed for advertising, packaging etc., they may need to be adapted and modified to have less detail. This can often be achieved with very little detriment to the final appearance of the tablet. The correct font style is very important to avoid tableting problems such as ‘picking’. Picking is compressed granule that has adhered to the detail on the punch face, resulting in ‘picking out’ of parts from the tablet face. Figure 7

Figure 7 is a classic example of picking. For identification purposes, this product requires heavy embossing contained in a small area. This design creates powder traps, and these areas are prone to picking. In this instance, the centre of the ‘6’ has been completely picked out. Therefore it is important to use techniques to prevent this from occurring. To reduce picking, the best practice should be to design font styles that have large open counters and no sharp corners, which could act as a trap for granule. Selection of the right font style can also help to avoid coating problems, tooling failures and lack of distinction. Fonts with curved sides can be used to increase spacing between the letters. By using curved characters, the potential for granule traps in tightly-spaced embossing can be reduced. It is also essential that the spacing between the embossing is not too small, generating further powder traps. When the font has been chosen it is important to ensure clarity of definition. The profile of the embossing is equally important to reduce picking, and to ensure good tablet coating and tooling strength. The best practice is for the stroke angle to be between 70 and 80 degrees. The stroke depth should be 50% of the width and the stroke break radius blends 30% of the stroke depth (Fig 8).

Figure 8 Another technique used to minimise picking is a reduced counter. The counters, which are sometimes referred to as islands, are very vulnerable to picking and granule can easily get trapped in these areas on the punch tip face. The counter is modified to increase the surface area by reducing stroke depth, which will minimise the tendency for the product to pick. A tapered peninsula (Fig 9) can also be applied. The taper is applied to blend between the surface of the tablet face and the INTERNATIONAL PHARMACEUTICAL INDUSTRY 71

Manufacturing stroke angle. This method softens the profile reducing the risk of powder being trapped in the shaded areas shown in the image. This maintains definition without reducing the overall stroke depth of the embossing and will assist you in keeping a clear brand identity.

Figure 9 ‘Sticking’ is another major issue in the design and manufacture of tablets. Sticking differs from picking in that it is granule adherence to the punch tip face, rather than in and around the embossing. This is not normally associated with design, however when picking occurs on a tablet this in turn can result in sticking on the punch tip face by providing a key to which further granule will adhere.

Figure 10 Figure 10 shows that sticking has occurred to the punch tip on the left. This is because the soft part of the tablet, at the top of the convex, is sticking to the punch tip face. There are several remedies for this: A coating can be applied to the punch tip to prevent sticking. A higher press force could be applied if the design allows. Punch tips could be polished in the MF automated polishing machine. Or, a design related solution would be to change the cup profile to reduce the depth. Anti-Counterfeiting Techniques As counterfeiters become more technologically advanced, basic tablet 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

designs are more easily re‐produced. There are many anti-counterfeiting technologies available to manufacturers. This is usually done by applying features directly to the tablet. The purpose of an anti-counterfeiting feature is usually to enable the authentication of an item, and also to act as a deterrent to anyone considering counterfeiting a product.

References 1. 2. J Marriott & R Nation, Department of Pharmacy Practice, Victorian College of Pharmacy, Monash University, Melbourne. 3. Protecting your Brand with AntiCounterfeiting Solution – John Mack 4. Eurostandard Educational Collection, 2010 – I Holland Ltd

It is estimated that up to 25% of medicines consumed within poor countries are counterfeit or substandard. In the US and other industrialised countries, death and serious illness have already been caused by counterfeit drugs, which hurts pharmaceutical companies’ bottom lines. An estimated 30 billion US dollars’ worth of drugs are counterfeited each year and this is increasing yearly. By using anticounterfeiting measures, this issue is less likely to occur. An expert tablet designer can employ techniques to make this more difficult. These are not always visible to the naked eye, but they ensure that a branded tablet can be identified as an original. Several anti-counterfeiting techniques can be used on each product, to help reduce the risk; for example, altering the thickness of the embossing in places, changing the angle of the lettering, or simply by having the logo on different inclines. Although hard to see with the naked eye, expert tablet designers can see the difference between the original and the counterfeit. Conclusion Good tablet design is imperative, and it is something that should be strongly considered. It is important to consult with an expert tablet designer as early on in the process as possible, who can ensure that tablet designs are not only unique and visually appealing, but are also robust and producible in a rigorous tablet manufacturing environment. By making just a few simple changes to a design it can stop future problems from picking and sticking to counterfeit issues. The importance of design should not be underestimated. Punches and dies are the most critical interface with your end product, the tablet, and together everything should be measured and taken into account before tablet production.

Steve Osborn, Product Design Manager, is I Holland’s leading expert on tablet and tooling design. A key member of the Customer Support Group, he has held the role of Product Design Manager since 2004. He is also responsible for the manufacturing functions of hob make / hobbing and heat treatment. Email: Summer 2016 Volume 8 Issue 2

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Manufacturing Cleaning and Coating: How to Overcome Challenges in Device Design and Manufacturing Cleaning and coating methods can significantly affect the consistency and quality of medical device performance. However, many design engineers and manufacturers are unaware of this fact. It’s important to keep in mind device cleaning and coating considerations at every stage of design and manufacturing for optimal performance once the device is in a doctor’s use. Read on for four of the top challenges and solutions design engineers and manufacturers experience regarding cleaning and coating during medical device production. Weighing Options Cleaning and coating systems help achieve consistently clean products and ensure the best and most consistent performance from a device. A wellengineered process is easy to validate and will reduce costs associated with device sterilisation by removing sources of bioburden from the manufacturing process. During medical device manufacturing, engineers need to decide whether they must clean component parts prior to assembly, clean the final assembled product, or both. Virtually all devices will require cleaning to some extent to improve cosmetics by removing particulate, oil or inorganic contamination that results from the manufacturing process. The challenge is to specify a cleaning process that is suitable for a variety of materials and geometries that may include delicate plastic injection-moulded parts, stainless steel microtubing, or sophisticated mechanical assemblies. Generally, application of a lubricant coating is dictated by the desired performance of the medical device once assembled; not all devices require a coating, or lubrication. A lubricant coating is typically applied so a device will function better with reduced friction. Any device that moves side to side, slides, or rotates may be a candidate for a lubricant coating. In addition, devices such as a syringe needle or cannula for injecting medicine or fluids may be cleaned and then coated with a thin film of medical-grade silicone fluid to reduce friction when the needle pierces the skin. 74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Similarly, mechanical assemblies that consist of multiple component parts, such as a surgical stapler, often need an engineered dry lubricant coating to reduce friction and minimise stacked tolerance issues. After the engineer or manufacturer determines whether or not a device must be cleaned or coated, the exact process is tailored to production volumes. In lowvolume production environments, basic cleaning devices – including aerosols, dry wipes, presaturated wipes with waterbased cleaners, solvents, or solvent- and water-based cleaners – may be specified. For high-volume production, the engineer will typically employ more automated cleaning systems to improve cleaning consistency and reduce costs. Those systems may be either solvent- or waterbased and use machines engineered for the application. Lubricant coatings applied inhouse will most likely be either silicone fluid- or dry polytetrafluoroethylene (PTFE)-based. Typically, sophisticated hydrophilic treatments are applied off the manufacturing premises because they require proprietary materials and application methods to impart surface properties that become lubricious when in contact with body fluids. In general, surfaces must be perfectly clean and dry prior to any coating application. Key factors in choosing a cleaning or coating system include worker safety, equipment costs, cost per part treated, required floor space, reduced bioburden, materials compatibility, and ease of use. Each application will have its own unique requirements, and it is highly recommended that design and manufacturing engineers meet with experienced cleaning and coating providers to discuss specific concerns. In the cleaning process, the largest consideration is typically costeffectiveness (expressed as cost per part cleaned). Other concerns include materials compatibility (e.g., can the fluid be used on plastic parts?), regulatory compliance, ease of use, and safety and environmental concerns.

In the coating and lubrication process, product performance is usually the number one consideration. When the device has been manufactured and is in physicians’ hands, will it perform in the way for which it was designed? Following this matter (as with the cleaning process), manufacturers and engineers are most concerned with materials’ compatibility, cost, regulatory compliance and product cosmetics, as well as safety and environmental issues. 4 Key Challenges The following are top challenges design engineers and manufacturers should consider regarding the cleaning and coating process at every stage of production. 1. Cosmetics. Medical devices must be pristine on both clinical and cosmetic levels, as well as function flawlessly. A doctor, nurse, or patient will not accept anything less than perfection on the cleanliness and cosmetic appearance of a device. They must see a device with surfaces that are smooth and spotlessly clean. Also, a device must be pristineclean to be properly sterilised. The optimal surface is obtained through cleaning and coating processes that quickly eliminate defects such as fingerprints, oils or stray particles that may remain from the manufacturing process. 2. Bioburden. Many factors can cause bioburden in a manufacturing process, but fundamentally, water is a primary growth medium for bacteria. Therefore, removing water from the manufacturing process removes a major source of bioburden issues. Solvents are often preferable to aqueous (waterbased) cleaners or coatings — solvents present an environment that is hostile to bacteria growth, and as a result greatly simplify process control requirements for eliminating bioburden. If bioburden is not properly addressed, it can result in increased difficulty in the validation of subsequent product sterilisation processes. A solventbased cleaning process with sub-micron filtration can run at very high production volumes while significantly reducing Summer 2016 Volume 8 Issue 2

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Manufacturing bioburden issues with a minimal footprint on the cleanroom floor, as well as a minimal capital outlay compared to a water system. Also, when compared to a water-based cleaning system, a solvent cleaning system will significantly reduce utility costs associated with water consumption and treatment, heating water, parts drying, and maintaining proper cleanroom air conditioning. 3. Stacked Tolerances. One common challenge regarding design and assembly is stacked tolerances in mechanical assemblies, which can create noticeable production variances in device actuation forces. This is a particularly common challenge with complex, single-use mechanical assemblies such as staplers and arthroscopic devices. In design and engineering, a dimensional tolerance refers to the permissible limit of variation in a physical dimension. Tolerances are specified by the design engineer to allow for reasonable leeway for imperfections and variability but without compromising performance. However, tolerances often become a challenge for design engineers and manufacturers when they begin to stack up on each other. For example, when a mechanical assembly such as a medical stapler is assembled, the tolerances of each metal stamping, spring, or plastic part may begin to combine in such a way that the assembled device requires excess force to actuate or execute. This issue is most commonly found in highvolume production, when tooling used to manufacture metal stampings, springs, and plastic parts begins to wear. Design engineers and manufacturers address stacked tolerances in several ways. Engineers may choose to design components with tighter tolerances to gain high precision. However, increased precision requires frequent inspection and maintenance of tooling and fixtures throughout the manufacturing process, which drives up finished device costs. An alternative method of dealing with stacked tolerances is to apply a lubricant coating such as PTFE or silicone on the finished assembly to reduce operating friction. Dry lubricants using PTFE particles are a low-cost way for the design engineer and manufacturer to reduce the effects of stacked tolerances. In fact, many single-use medical devices currently on 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the market would not be commercially viable without this coating. Dry lubricants are used on many devices or mechanical assemblies found in the operating room, including catheters, cutting tools, staplers, hypotubes, and other surfaceto-surface complex assemblies found in devices designed for minimally invasive procedures. Dry lubricants reduce the force needed to actuate or execute a device by 25 to 30 per cent and provide a silky, almost effortless actuation for the medical professional performing the procedure. In comparison to an untreated stainless steel surface that has a coefficient of friction of 0.80, a dry PTFE lubricant can produce a remarkably low coefficient of friction of about 0.06 to the same surface. As an added benefit, PTFE lubricants are non-migrating, so they will not degrade product cosmetics by transferring to packaging or work surfaces. 4. Maintaining Calibration. For dry lubricants in particular, maintaining calibration is a top challenge for device manufacturers. Maintaining calibration of lubricant dispersions and fluids is important to the consistency and quality of the coating and thus the consistent performance of the device. The first step in maintaining calibration is controlling the evaporation of carrier fluid. Many PTFE dry lubricants are mixed with a carrier fluid that evaporates very quickly. This is beneficial because it speeds the production process as the carrier dries quickly and leaves a very consistent coating on the device. However, this also means that the fluid can evaporate quickly out of the vessel during the coating process. In some cases, manufacturers will add an inexact amount of carrier fluid to maintain approximate percentage saturation, but this is not precise and can affect the quality of the coating.

will soon be introduced to the market that allows for instant and easy realtime measurement of PTFE content in the carrier. All are relatively simple and low-cost ways to maintain lubricant calibration for coating consistency. Another fluid calibration challenge: the PTFE particles themselves. Many coatings with PTFE micropowders require constant agitation because the particles have low hang time in the liquid carrier. Low hang time means that as the fluid sits in the vessel and parts are dipped, the PTFE particles in the fluid will sink to the bottom of the vessel. Many manufacturers address this issue by constantly agitating the fluid. However, if done improperly, this practice can have inconsistent results and lead to streaky coatings. A key solution to the short hang time of PTFE particles in a carrier fluid is to specify dispersions that use micropowders that are matched to the carrier fluid by a knowledgeable supplier. These lubricants use a premixed and supplier-calibrated formula that maintains the ratio of carrier fluid to PTFE particles to improve hang time and coating quality. In Summary Itâ&#x20AC;&#x2122;s vital for medical device engineers and manufacturers alike to consider the significant role the cleaning and coating process can play in the performance, quality, and consistency of the finished device. There are many challenges to address in the process, but consulting with an expert cleaning or coating provider who can answer questions and concerns in an educated and timely manner is a helpful best practice. Working with a knowledgeable partner has a number of positive results: increased quality and consistency of the process and device performance, as well as flexibility in the design and manufacturing process, resulting in maximum profitability for the device manufacturer.

To control evaporation and keep fluids calibrated for maximum consistency and quality, use of process-specific equipment for the cleaning and coating process is highly recommended. This may include hermetically-sealed equipment, controlled temperature baths, specialised solvent recovery systems, engineered parts-feeding systems such as hoists or conveyers, or engineered application systems such as spray or brush applicators. Also, test equipment Summer 2016 Volume 8 Issue 2

Cleaning with a solvent-based vapour degreasing system is an excellent choice for medical devices, especially in high-volume environments, because they easily clean complex shapes and minimize problems with bioburden. Vapour cleaning systems offer fast cleaning cycles and consistent results in a machine with a small physical footprint.

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In this top-down photo, a vapour degreaser is being loaded with a basket of nozzle assemblies which are difficult to clean using any other method because of their complex shapes and tiny apertures. The first cleaning step is in the boiling solvent (top of photo) and then the parts are rinsed in the second chamber. Notice the cooling coils around the top of the machine which trap the solvent vapours inside the system, reducing cleaning costs and improving environmental performance. Many different grades of PTFE lubricants and carrier fluids could be used on medical devices. But for the best results, companies should ensure their lubricants have a long â&#x20AC;&#x153;hang timeâ&#x20AC;? to ensure the smoothest coating with the fewest quality issues. In this photo, the same lubricant powder with two different carrier fluids show dramatically different hang time behavior.

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

This stainless steel has been treated with a Duraglide coating. Coatings such as these can be used on stampings, plastics, springs or other parts which rotate, pivot or slide against each other. These coatings can almost completely eliminate the problems with stacked tolerances.

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Jay Tourigny is senior vice president at MicroCare Medical. He has been in the industry more than 25 years, and holds a Bachelor of Science degree from Massachusetts College of Liberal Arts. Tourigny holds numerous US patents for cleaning-related products that are used on a daily basis in medical, fibre optic, and precision cleaning applications.


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Packaging Serialisation – The Bigger Picture Preparing for All Requirements with a Scalable Machine and Software Concept Whether potency pills or even life-saving pharmaceuticals such as heparin – the trade in counterfeit medicine is still booming. Accordingly, drug producers and contract packers are shifting their focus to serialisation of pharmaceutical packaging. Time is pressing, as numerous laws and guidelines have already, or will, come into force all over the world in the coming years. Companies concerned are facing the challenge of finding and implementing appropriate technologies, and connecting them with their manufacturing and packaging processes. A scalable machine and software concept undoubtedly is the safest option. The European Union‘s Falsified Medicines Directive 2011/62/EU came into effect in February 2016. It stipulates the usage of coded packaging with unique serial numbers for all prescription drugs. Similar to many other countries, the serialisation feature is a 2D data matrix code. It contains a randomised serial number, the batch number and expiry date, as well as further data, if required. At the same time, the EU demands a second level of security in the form of tamper-evident closures, such as integrity seals or glue, which are recorded in the CEN norm DIN EN 16679:2015-03. They clearly indicate whether a package has been previously opened or tampered with. Toward Complete Connectivity On November 27, 2013, the Drug Quality and Security Act (DQSA) was adopted in the US. In early 2015, the implementation began on batch level. As of 2017, serialisation of primary packaging will be mandatory. The biggest challenge for all parties involved, however, will follow in 2019, when the serial number of each individual pack and outer packaging must be known to pharma wholesalers – either in the form of the National Drug Code (NDC) or the Global Trade Identification Number (GTIN). First, all drug producers must comply with this law. In an interval of one year each, repackers, wholesalers and dispensers will follow. Exactly ten years after commencement of DQSA, that is the end of November 2023, the complete connection and aggregation is supposed to be implemented. Based on the unique 78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

serial number, products can then be electronically traced on all aggregation levels, as well as on a batch and single packaging level along the entire supply chain through to the dispensing point – unambiguously and in real time. In parallel, many other countries are developing and implementing new guidance and laws. In the MENA region (Middle East and Northern Africa), efforts for drug traceability are already underway. Saudi Arabia, for instance, initiated the first phase in March 2015 with obligatory data matrix codes on pharmaceutical packaging. Phase 2 – actual serialisation – will come into force in 2017. While phase 1 only requires a machine to print data matrix codes, phase 2 necessitates producers and packers to have machines for serialisation as well as an IT infrastructure to generate the serial numbers. Moreover, they must be able to send the numbers to their machines, as well as reporting the results to manufacturers’ databases and recording them. Significant Differences Now what are the fundamental differences between the different implementation stages? On the one hand, the EU attributes special importance to tamperevidence. On the other hand, the US wants to implement the first aggregation step at a very early point in time, thus changing the requirements for both local pharma companies and importers. While

serialisation is currently still often seen as a regional responsibility, the different legislations will have a global impact. Many large drug producers operate production facilities in different countries and export their products all over the world. Equipping packaging lines according to only one standard would be very short-sighted. Take a practical example: a large generic producer from the MENA region sells his products in the local market, as well as in Europe and the US. The majority of pharmaceuticals are packaged at the production sites in Jordan and Saudi Arabia. Against this background, all pharmaceutical packaging must conform to different national serialisation standards. Accordingly, flexible solutions which are able to fulfill far more than just one national guideline are highly sought-after. The same applies to contract packers, who must comply with the laws of the respective market, as well as with the requirements of their clients. Adapting Established Processes In general, most producing and packaging companies will not be able to avoid developing and applying a global strategy to consistently assign serial numbers. This requires solutions that are compatible with in-house processes, leading to the adaptation of often highly demanding packaging processes. Furthermore, new processes must be established for both management

Summer 2016 Volume 8 Issue 2

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and storage of serial numbers. The requirements can be subsumed in a single key word: “modular”. A comprehensive serialisation solution should not only be able to mass-serialise the packed product, verify the codes and apply labels or tamper-evident seals to the packaging. The entire process needs to be controlled, and the data retrieved at any time. Only this way do producers – and later on the dispensing points – have an exact overview of all process steps. To this end, Bosch Packaging Technology has developed the CPI software for Track & Trace, which can be easily integrated into existing IT infrastructures. The company can rely on the experience from the automotive sector, where automation and connectivity of machines, processes and IT have been tried and tested for years. Logic and functionalities have been transferred and adapted to the specific pharmaceutical requirements for Track & Trace applications. From Machine to Database How can we imagine a holistic serialisation process in reality? It starts on the application level (level 1). Here, the modular CPS system from Bosch serialises up to 400 folded cartons per minute. The camera system automatically verifies the printed tracking data. Subsequently, a 80 INTERNATIONAL PHARMACEUTICAL INDUSTRY

security seal is applied by the tamperevident labeller. The modules can be operated via a central user interface, and the data can be documented (level 2). To control both operating condition and data at any time, the connection between the physical machine level and the control software must be integrated across many stages of the company’s IT (level 3). From this level onwards, the CPI solution for Track & Trace ensures that the entire production environment or several sites are depicted (level 4). Moreover, an interface is also possible for data transfer, for instance to the SecurPharm database or to the customer (level 5). The Highest Flexibility Back to the example of the generic producer, who has lately equipped numerous packaging lines with CPS modules and CPI software. The company benefits especially from the new data connection between all lines that are situated at different locations and can now be monitored from the headquarters. Thus all relevant data is available in the entire company network, and all results are recorded in the audit trail. The data sets are bundled with the production results according to aggregation specifications, and sent back to the CPI software. From here, they can be transferred to regulatory or producer-

owned databases. Depending on country and guideline, the serial numbers are either allocated centrally or generated by the company. Contract manufacturers in turn receive the numbers from their clients. This requires very high flexibility within the process cycle. The CPI solution from Bosch is equipped for all three cases. Companies can not only manage serialisation from the allocation of the serial number through to the last aggregation step; they can also flexibly connect single components, third-party machines, packaging lines, own or third-party IT systems and entire factories with each other according to the respective guidelines. Hence it really is worthwhile looking at the bigger picture – for manufacturers and contract packers, as well as for mechanical engineering companies with a focus on international customers.

Daniel Sanwald Bosch Packaging Technology Product manager Track & Trace Phone: +49 711 811 57319 E-mail: daniel.sanwald@

Summer 2016 Volume 8 Issue 2

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The Key to Successful Design: Understanding the Patient’s Needs The key to delivering medicine to patients effectively is quite simple; effective design starts with the need to truly understand the patient’s needs. This declaration may seem provocative and overly simplistic. Of course we need to understand the patient’s needs. In the real world, packaging is often complicated, particularly packaging for medicinal products. There are complex and often conflicting factors such as shelf-life and barrier property concerns, childresistance requirements, needs to protect product in the distribution environment, factors for logistical cycle times, complexity from regulatory and labelling requirements, and most certainly cost pressures. Navigating these channels to deliver effective packaging to patients can be challenging. Most packaging is an afterthought to the patient. Poorly executed packaging is a lightning rod for consumer complaints and could ultimately frustrate patients to the point where they discontinue their therapy. Alternatively, truly successful packaging helps foster better health outcomes for patients, the ultimate goal of all professionals in our industry. Asking the Right Questions As a leading contract manufacturing organisation, PCI Pharma Services is fortunate to support many pharmaceutical and biotech clients, with many products and delivery forms destined for over 100 countries around the world. We partner with clients to support clinical/investigational studies as well as commercial medicines, both over-the-counter and ethical prescription medicines, in addition to animal health applications, devices, consumer products, and so many other healthcare forms. The common denominator is the recipient of the therapy. As we engage our pharma clients at the early stages of package design, they can often be taken aback by some of the questions we pose. A common response is “Hmmm, I hadn’t thought to ask that”. Asking probing questions and understanding the end-to-end needs of both the product and the patient foster a thorough review of all critical success factors. Over and above the typical questions, we often ask questions such as “what is the profile of the typical 82 INTERNATIONAL PHARMACEUTICAL INDUSTRY

patient for this medicine?”, “what are they experiencing?”, “who administers the medicine, how and in what setting?”, “what other medications might they be taking?”, “what are the side-effects of this drug and/or in combination with other drugs?”, “is dexterity a concern?”… There are so many factors to explore and ultimately, that guides a healthy and robust discussion early in the design phases. Using Packaging as a Leading Tool With the advent of healthcare reform, much more attention is being paid to gauging the effectiveness of drug therapies. Patient compliance and adherence have long been well documented problems in the healthcare industry. Alarming amounts of financial resources are spent dealing with recurring health issues directly attributable to poor patient compliance to their prescribed medication, often resulting in hospitalisations and avoidable emergency situations. The burden on the healthcare system is increasing, and is not sustainable by all expert opinions. As a result, increasing resources and efforts are being channelled to support patients earlier in their personal health cycle. Pharmaceutical companies, healthcare providers, and insurance providers are targeting resources to support patients

in driving to better health, including adherence to medication in combination with supporting healthier lifestyle choices. Increasing attention is being paid to the role of packaging in supporting patient compliance and adherence. Packaging is a powerful medium, yet it should be recognised that it is not the silver bullet in solving this dilemma. Packaging is an effective tool in driving positive patient behaviours, and is undisputedly the most direct medium for capturing the attention of the patient, by virtue of the fact that it is intimately married to the drug itself. It is simply unavoidable. To that end, packaging is being recognised as having a critical role as part of the broader adherence strategy, complementing activities such as support programmes and resource interventions aimed at keeping patients on therapy and engaged in their journey to improved health. Packaging is being brought to the forefront as companies identify their strategies to drive positive patient behaviours and engage stakeholders throughout the healthcare continuum. As a designer of complianceprompting packaging, it is important to understand the specific needs of the medicine, the disease state, and the

Summer 2016 Volume 8 Issue 2

Packaging patient. Packaging is not one-size-fitsall and it is shortsighted to believe that packaging is an off-the-shelf solution to cure all the patient behaviours that lead to poor adherence. Studies have shown that utilisation of calendarised formats can have substantial effects on raising patient compliance and persistence with medication regimens. Calendarisation is one tool, but not the only methodology, for addressing poor adherence through packaging intervention. Effective package design factors in all the complex issues that lead to poor adherence and provides a comprehensive approach to driving positive results. Poor compliance can be, and often is, driven by a multitude of conscious and unconscious behaviours. The tools incorporated into effective packaging can help educate and systematically address these individual factors, complementing other non-packaging-related interventions to have a synergistic effect. Identifying the Right Solution One of the critical factors in identifying the right package and tools is looking at the patient journey. A company utilising compliance-prompting packaging for both a physician sample and a saleable pharmacy package for ongoing therapy would employ different strategies to address patient concerns and behaviours, based on their stage of the journey. For example, a patient who has progressed through the healthcare lifecycle to the point where they have been diagnosed, and are now being prescribed a medication, has a distinct set of concerns, which may vary considerably depending on the diagnosis and disease state. Fear and motivation are two monumental factors to address at this stage of their healthcare progression. Pharmaceutical companies and healthcare professionals need to recognise the psychological considerations of patients as they buy into fostering better health for themselves. Effective packaging for physician samples should educate about the diagnosis and disease state, support motivation for changing health behaviour and lifestyle changes, address concerns about medication cost, educate about the drug and potential side-effects, and ultimately motivate the patient to pursue ongoing therapy. It is widely reported that in the United States, less than 1/3 of all prescriptions written result in the patient filling that prescription. Clearly, there is tremendous unmet opportunity in improving motivations to

seek better health outcomes. Packaging can play a key role with so many of the facets for success. Common tools can be incorporated to drive patient understanding and behaviours â&#x20AC;&#x201C; items such as patient diaries, enrolment devices, reminder tools, direction for additional resources and other methodologies that engage the patient and help foster the patient-doctor relationship well past the 5-7 days of free therapy provided. Examples of best practices highlight tools to aid doctors and patients in goal-setting and long-term tracking of milestones for improved health. Other tools that are easy to implement help defray cost of medication, such as cash cards, pharmacy discount vouchers or educational materials for healthcare reimbursement that help ease the cost burden of therapy. Conversely, packaging for ongoing therapy should reinforce the momentum of the starter pack and be focused on establishing health habits, engendering patient compliance, and driving persistence to keep patients on therapy while maintaining the ongoing health dialogue with their healthcare provider. This may include calendarisation

of therapy, reminders for driving prescription refills, enrolment in support organisations, or capturing data for associated testing. Packaging need not be cumbersome, but just the opposite; it should be focused so as to be portable and discreet as possible. In the US, the recent study of the WalMart $4 generic programme demonstrated substantial lift in patient compliance and persistence with very basic calendarised format improvements. Subtle changes can have dramatic impacts when packaging is patient-focused and convenient. Measuring Success As we partner with pharmaceutical companies to develop effective packaging, the most glaring aspect that has not progressed is the strategic development of measurement tools to pair with packaging strategies. Whether in response to competitor activity or through homegrown interest in adherence as a market trend, companies have focused increasing time and energy into developing compliance-prompting packaging. Unfortunately, without an established methodology for gauging effectiveness, as well as agreement


Packaging in defining what success looks like, programmes often fall victim to the inability to generate tangible ROI. We preach to clients that packaging investments need to be viewed in the perspective of their overall patient adherence initiative, with established metrics and milestones for evaluating success. With measurements for success, companies can expect substantial ROI through their investment in patient-friendly packaging. Ensuring Patient Safety The industry is addressing the advent of mass product serialisation, adopting a universal methodology for authenticating legitimate drug product in the supply chain. This requirement is one facet of thwarting drug counterfeiting around the world. Emerging markets have taken the lead in implementing regulatory requirements for serialised drug product. The United States and Europe have requirements in 2017 and 2019 respectively that have spurred longawaited mobilisation within the industry. Serialisation and anti-counterfeiting initiatives should be strategic in nature and focused on the benefit to the patient. Strategies should utilise multilayered technologies with overt and covert tools, cycling those tools regularly in a comprehensive approach. Staying ahead of the sophisticated criminal element requires commitment on the part of drug companies, and engagement across the logistical supply channels, to be truly effective. Companies can be overrun by the multitude of technologies available, with wide-ranging costs and complexities, so it is imperative to partner with companies with true expertise and find the appropriate level of engagement. This approach will ensure the focus stays on the patient, driving both value and peace of mind. Perspective – The Right Choices Can Keep You from Overpackaging your Product Paul Smallman Associate Director, Technical Services – PCI Pharma Services UK “So often we engage clients and find that product shelf-life stability has locked them into packaging that may not be optimal for their product. In the short-cycle, pharmaceutical companies are facing for early developmental activity, so often we find they choose a path of convenience for putting product on stability. This may be an off-the84 INTERNATIONAL PHARMACEUTICAL INDUSTRY

shelf bottle and closure combination or defaulting to cold-form / alu-alu blister films, assuming that will be a sure-shot for success. Companies can fall into the fallacy that utilising cold-form materials provides them a foolproof barrier at the time of shelf-life stability. Unfortunately the long-term impact is that they may be using more cumbersome and costly materials than they actually need. In addition to the cost premium of coldform materials, the footprint for the blister layout is typically twice as large as comparable thermoformed barrier films. This has wide-reaching impacts for packaging operations as well as the ultimate portability for patients.

life study to optimise the package format. The further upstream we can address commercial development, the greater the likelihood that we can develop a package that meets all the patient’s needs for safety and effectiveness in driving improved health.”

“The market has really progressed in its ability to analyse drug product in advance of executing shelf-life stability. We partner with clients to guide them to tools and analysis that can help optimise their choices as the onset, saving them substantially over the long term.”

Paul Smallman, with over 20 years’ experience in packaging, technical and engineering in FMCG and Pharmaceutical environments, Paul Smallman is Associate Director, Technical Services at PCI Pharma Services. Managing in excess of 100 product launches a year for various size pharmaceutical companies, his expertise in the design and development of regulatory compliant solutions guarantees innovative solutions for his customers. Paul is also a member of the ISPE Communities of Practice for packaging.

Perspective – Develop Packaging at the Right Time to Keep the Focus on the Patient Victor Gherdan Jr. Manager, Package Design – PCI Pharma Services US “In the resource-intensive activity of bringing drug to market, packaging is often one of the last items to be addressed. So often we see that clients look to pull their packaging strategy together as they start to firm up their NDA filing, often in late Phase II or more commonly in Phase III clinical study. The challenge with this approach is that it substantially limits their ability to focus on patient-centric packaging. We advise clients to take advantage of the opportunity to leverage key learnings and patient feedback from the various phases of clinical development. What are key factors for patient adherence? How did patients respond to packaging utilised in controlled studies? Are these successful factors translatable to commercial? With the proper lead-time we can truly leverage packaging as a tool to generate successful outcomes for patients. This may include focused market study, human factors study, childresistant and senior-friendly testing, or potentially executing new shelf-

Victor Gherdan Jr. is the Packaging Design Manager for PCI Pharma Services based Philadelphia, Pennsylvania. Victor is a graduate of the Rutgers University School of Engineering where he received a BS in Applied Sciences in Engineering with a concentration in Packaging Engineering. Victor began his career with Novartis Consumer Health as a packaging engineer. He then joined Packaging Coordinators Inc as a packaging designer, as well as holding roles as tooling designer and design manager during his extensive career with Cardinal Health, Catalent, and ultimately PCI Pharma Services. He is currently leading the award winning design team focused on drive innovative thinking and a consultative approach to help clients reach their packaging goals and patients achieve better health outcomes.

Summer 2016 Volume 8 Issue 2

Safely Packaged The EU Falsified Medicines Directive will help prevent contaminated medicine and counterfeit drugs from reaching vulnerable patients by implementing stringent safety features.

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Exhibition Previews & Reviews Finished Dosage Formulations Growth A Major Addition to CPhI Worldwide As UBM EMEA launches a new colocated event at CPhI Worldwide, 4-6 October, CPhI shares the findings from the recent round-table debate on the global growth in finished dosage forms. The media/analyst briefing day gathered leading experts Jim Miller (PharmSource), Alan Sheppard (IMS Health) and Paul Fleming (BGMA) and members of the pharmaceutical media (with IPI being one of the carefully-selected global media invited) to discuss finished dosage formulations – everything from big pharma, contract manufacturers, to in/ out-licensing and dossier specialists, end product distributors and generic pharma. Chief amongst the trends reported was the increased need for different segments of the supply chain to work together in the creation of new patented drugs or value-added generics. “Outsourcing for delivery systems is a key trend, as is partnering with more established companies in specific segments. For instance, if you only have a single oncology product, partnering and out-licensing with someone who has a wider dossier is a very good strategy.” Alan Sheppard, Principal, Global Generics and Biosimilars at IMS Health. Licensing and partnerships are integral to growth because they allow market

entry with lower risk, and capitalise on local knowledge to speed up regulatory approvals and pricing processes. The key technological challenge for both generic and patented formulations identified is access to new technologies – spray-drying, micronisation, hot-melt extrusion and nano formulations – which enable the creation of more advanced, bioavailable and patient-friendly combinations. Citing IMS figures, Alan Sheppard reported that, in the last four years, the USA (58%) and Europe (17%) have dominated growth in new speciality medicines – with the largest profit opportunities in smaller patient cohorts and speciality drugs, where there are still unmet patient needs. However, in generic formulations, although the US still represents 28% of growth, the pharmerging markets are really the driving force underlying this upwards trend with 58% of growth. Significantly, and perhaps due to patient concerns in these regions, branded generics in emerging markets, particularly in Asia, are strongly preferred – whereas in the developed economies, in-prescribing is most common. Generic companies and CMOs are now reimagining what is possible – as access to new technologies opens up more opportunities for innovative development. But collaborations are even stretching to excipient technologies, says Jim Miller, president of PharmSource, as they help “facilitate matrix and multiparticulate formulations – allowing increased bioavailability, all of which has put new demands on the performance of excipients.” However, two major possible market challenges are the impending costs of GDUFA ii in the United States – particularly for CMOs with limited generics production. And, for generic companies, a longer-term question will be “how to get a fair reward for incremental formulation developments,” added Paul Fleming, Technical Director of the British Generic Manufacturers Association.


Collectively, there is a trend for governments, both developed and developing, to increase their use of generic drugs. And, with the drugs pipeline dominated by poorly bioavailable compounds, a clear picture emerges that finished dose forms represent a tremendous opportunity for pharma companies, growing revenues at a breath-taking speed – both in emerging and developed markets. In response to this, UBM is organising an event that not only explores the key facts of the market, but also gives exhibitors and visitors the chance to source, analyse and connect with their ideal partners on a successful route to market. Since its introduction at CPhI Worldwide in 2011, the Finished Formulation zone has grown rapidly to become the third-largest segment of the overall event; totalling 11,000 square metres in 2015. Developing this zone into a co-located event is a natural progression for the CPhI brand, which has evolved through its three decades from a small API event into the global meeting place for the entire pharmaceutical supply chain. By giving Finished Dosage Formulation its own voice, its own story, a vital platform emerges for people who haven’t seen CPhI as their essential business event in the past. Cara Turner, Event Manager Pharma at UBM EMEA, commented: “We celebrate the launch of the new FDF event at CPhI Worldwide. This is the first time at a global level, that a networking, content and exhibition platform has been created specifically for finished dosage formulations. “Looking ahead, we forecast this part of CPhI growing extremely quickly and envisage new audiences attending – there are natural synergies with diagnostic providers, licensors, delivery platforms and distributors, not to mention, it opens new avenues for existing audiences by widening the range of partners they can meet in one location.” Summer 2016 Volume 8 Issue 2

Review The New Venue for 2016 was a Big Success and the Anglonordic Life Science Conference is Now Preparing for its Fourteenth Year in a Row. On the 19th of May, the Anglonordic Life Science Conference XIII moved into a new prestigious venue, 8 Northumberland Avenue, based at Trafalgar Square in central London. The new venue was very much appreciated by the delegates and in total, more than 300 decision-makers, representing leading and upcoming R&D companies (both biotech and medtech), international pharmaceuticals and investment firms attended. This year was a record of the number of investors attending; in total, 85 investors representing 70 investment firms attended. New for 2016 was also that the conference expanded from one guest country to include three guest countries. The three guest countries were Spain, Belgium and South Australia. South Australia was also the host of the exclusive reception that took place at the magnificent building, Australia House, the evening before the conference. The guest of honour at the reception was George Freeman, Minister for Life Sciences in the UK. Below are some of the keynote speakers 2016. Christian Jung, Principal, Wellington Partners – Update About The Investment Status In The Medtech Industry Janke Dittmer, Partner, Gilde Healthcare – The Digital Health Investment Landscape Roel Bulthuis, Head of MS Ventures – Latest News on European Funding Laurence Barker, CBO, Dementia Discovery Fund – Introduction to the Dementia Discovery Fund Nick Johnston, Partner, Perella Weinberg Partners – Preparation for Exit in Medical Technology: Maximising Optionality to Increase Success 8 Northumberland Avenue, London’s Most Central Venue. The conference moved for 2016 into one 88 INTERNATIONAL PHARMACEUTICAL INDUSTRY

of the most prestigious venues in London, 8 Northumberland Avenue. The Percy family, the Dukes of Northumberland, built their family seat – Northumberland House – at the beginning of the 17th century. Some considerable size, the entire estate was bought in 1874 by the Metropolitan Board of Works, and Northumberland Avenue was created. In 1887, the Hotel Victoria was built at number 8 – a firstclass hotel that operated right up until the 1940s, when it was requisitioned by the War Office and occupied by the Crown. The doors of 8 Northumberland Avenue remained closed to the public for 70 years. In 2009, a near-derelict building was inherited from the Ministry Of Defence. It took a year of major refurbishment to restore the building to its former grand Victorian style. The multi-million pound restoration was completed on time and on budget. The doors of 8 Northumberland Avenue were once again open to the public in the spring of 2010. The magnificent rooms are one of the grandest Victorian hotel interiors remaining in London, and today they represent the Anglonordic Life Science Conference. The Fourteenth Year in a Row. Entering its fourteenth year, the Anglonordic Life Science Conference continues to grow and the conference will continue to keep its “by-invitation-only

policy”, and to start with a reception the evening before. Next year’s conference will be held on the 4th of May. Byinvitation-only, the select audience is restricted to decision-makers representing drug discovery and medtech companies from the Anglo-Nordic region (plus three guest countries) and international pharmaceutical and investment firms. Service suppliers can only attend as sponsors or exhibitors. The conference consists of five areas that have simultaneous activities. The five areas are: the main conference room 1 with focus on biotech, the main conference room 2 with focus on medtech, the one-to-one meetings area (using the famous Meeting Mojo online booking system), the exhibiting area and the lounge area. The conference will continue with its successful media partnership with PharmaTelevision, which offers the speakers and delegates the possibility to apply for interviews at the conference. Hume Brophy will be the main media partner 2017, and will run the press office. Please see the conference website www. for more information, and to request for an invitation. Contact Information: Mattias Johansson, Director Anglonordic Life Science Conference XIV

Summer 2016 Volume 8 Issue 2

Review Grand Opening of SGD Pharma’s Fifth Plant to Become World Excellence Centre for Type I Moulded Glass After the foundation stone of its French plant was laid at Saint-Quentin-la-Motte, SGD Pharma organised a grand opening at Normandy for its fifth industrial site, dedicated to the pharmaceutical industry. Pharma Publications reviews the event. On one of the most historical coasts of France, the plant represented a fourfold challenge for the company: technological, industrial, financial and human. - Within a very short time SGD Pharma has developed its new design and built a new plant without any outage, additional delay or interruption from the old historical site to the new one. - More than €65M investment in a site designed with specific concern for environmental aspects and the employees’ working conditions, and equipped with the best technologies to manufacture high-quality glass. - The successful transfer of 250 people over a transition period that lasted various months. - The 13-hectare site benefits from stateof-the-art equipment, enabling a daily capacity of 1 million bottles and 20,000 tons per year.

SGD Pharma invited more than 200 industry professionals from around the world to take part in its grandiose opening event, by celebrating its new type I plant. This unique event took place on April 21st and 22nd in the royal town

of Eu, Normandy, France. Invited for various technical seminars, advancing the technology behind glass parenteral packaging, attendees had the chance to have a look at the causes, reduction strategies and regulations that govern the process. They also gained information on glass parenteral packaging and its advanced technology, along with knowledge about the key success factors for quality and productivity in routine production. The grand event was worthy of the name – within the first-class ceremony, attendees made great connections and fruitful collaborations during the festive dinner which was held by the Royal castle of EU, after an enjoyable performance by a violin quartet.






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IMPLEMENT, INTEGRATE & OPTIMISE YOUR SUSTAINABLE SERIALISATION STRATEGY WHY ATTEND PHARMA SERIALISATION & TRACEABILITY 2016:  Post conference site visit: Visit a local pharma organisation in Geneva to provide you with an insight into what their operations look like, what equipment they are using, what their team looks like and to provide first hand insight into serialisation in operation  Maturity roundtable sessions: Take your pick of discussions depending on which stage of implementation you are in and discuss your challenges with peers in the same maturity stage of their project  Wrap up take away session: An interactive session to allow you to map out your goals and strategies going forward and provide a tangible reference source for you going forward into 2017  Specific streams addressing project management challenges, supply chain and the IT and data management issues associated with implementation









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SMi Presents the 5th Annual Conference on…

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Biosimilars Europe Holiday Inn Kensington Forum, London, UK


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The latest updates on regulation, market access strategies and improvement of commercialisation 2016 Featured Speakers: • Dr Virginia Acha, Executive Director – Research, Medical & Innovation, ABPI • Huiguo Hu, General Manager of International Business, Shanghai CP Guojian Pharmaceutical Co. Ltd • Dr Niraj Chhaya, Risk Management, Boehringer Ingelheim GmbH • Atanas Dimitrov, Head of Strategy & Portfolio Management, Merck Group • Dr Alok Sharma, Head, Bio-Analytical Development, Lupin Ltd • Dr Andrea Laslop, Head of Scientific Office, Austrian Agency for Health and Food Safety • Joan O’Callaghan, Research Scientist for Regulatory Science Ireland, Health Products Regulatory Authority, Ireland

TWO INTERACTIVE PRE-CONFERENCE HALF-DAY WORKSHOPS Wednesday 28th September 2016, Holiday Inn Kensington Forum, London, UK Biosimilars: Maximisation of IP regulatory rights 8.30am - 12.30pm Workshop Leaders: Marie Manley, Partner and Head of the Regulatory Department, Bristows LLP and Libby Amos, Associate, Regulatory Department, Bristows LLP How is the payer environment for biosimilars evolving? 1.30pm - 5.30pm Workshop Leader: Dr Ad Rietveld, Director, RJW & partners Ltd Register online or fax your registration to +44 (0) 870 9090 712 or call +44 (0) 870 9090 711 92 INTERNATIONAL PHARMACEUTICAL INDUSTRY Summer 2016 Volume 8 Issue 2 ACADEMIC & GROUP DISCOUNTS AVAILABLE @SMIPHARM #biosmi

Book Review The angle of the book where Male Infertility is highlighted. Male Infertility is a current subject of interest which is responsible for 40 – 45% cases of failure of normal human reproduction. Some of the main causes of Male fertility we have noticed are:

Assisted reproductive technology (ART) is the technology used to achieve pregnancy in procedures such as fertility medication, artificial insemination, in vitro fertilization and surrogacy. It is reproductive technology used primarily for infertility treatments, and is also known as fertility treatment. It mainly belongs to the field of reproductive endocrinology and infertility, and may also include intracytoplasmic sperm injection (ICSI) and cryopreservation. Some forms of ART are also used with regard to fertile couples for genetic reasons (preimplantation genetic diagnosis). ART is also used for couples who are discordant for certain communicable diseases; for example, HIV to reduce the risk of infection when a pregnancy is desired. Clinics in Reproductive Medicine and Assisted Reproductive Technology, by B N Chakravarty is a very timely given the publication of - THE ASSISTED REPRODUCTIVE TECHNOLOGIES (REGULATION) BILL – 2010, MINISTRY OF HEALTH & FAMILY WELFARE, GOVT. OF INDIA, NEW DELHI It is estimated that 15 percent of couples around the world are infertile. This implies that infertility is one of the most highly prevalent medical problems. The magnitude of the infertility problem also has enormous social implications. Besides the fact that every couple has the right to have a child, in India infertility widely carries with it a social stigma. In the Indian social context specially, children are also a kind of old age insurance.

Sperm production problems • Chromosomal or genetic causes • Undescended testes (failure of • the testes to descend at birth) • Infections • Torsion (twisting of the testis in scrotum) • Varicocele (varicose veins of the testes) • Medicines and chemicals • Radiation damage • Unknown cause Blockage of sperm transport • Infections • Prostate-related problems • Absence of vas deferens • Vasectomy Sexual problems (erection and ejaculation problems) • Retrograde and premature ejaculation • Failure of ejaculation • Erectile dysfunction • Infrequent intercourse • Spinal cord injury • Prostate surgery • Damage to nerves • Some medicines Hormonal problems • Pituitary tumours • Congenital lack of LH/FSH (pituitary problem from birth) • Anabolic (androgenic) steroid abuse • Sperm antibodies • Vasectomy • Injury or infection in the epididymis • Unknown cause

that this book was written as a practical demonstration and we believe that this book will be beneficial not only to Indian students, but to the all specialist who are interested in reproductive medicine in Europe and the US. The evidence regarding the outcomes of interventions used in ovulation induction, superovulation, and in vitro fertilization (IVF) for the treatment of infertility. Short-term outcomes included pregnancy, live birth, multiple gestation, and complications. Long-term outcomes included pregnancy and post-pregnancy complications for both mothers and infants. One of the chapters of extreme interest to us was Chapter 13 – Sexual Ambiguity – Intersex Disorders. The clinical situation in which there is existence of both male and female genital organs in the same individual is defined as sexual ambiguity. In this chapter Dr B N Chakravarty & Dr N J Gupta have made clear evaluations of these conditions. It is extremely encouraging to see such a clear emphasis on the conditions, categories and surgical outcomes. We complement Dr B N Chakravarty on a well compiled publication, with practical evidence. We hope that this publication becomes an essential read for all interested in Reproductive Medicine. ISBN: 978-81-239-2645-2 Copyright © Author and Publisher Published by: CBS Publishers & Distributors Pvt Ltd. , 4819/XI Prahlad Street, 24 Ansari Road, Daryaganj, New Delhi 110 002, India.

Dr Chakroborty explains all these factors well in his book, and has shown practical steps to identify each of the conditions, and their management. Dr B N Chakravarty has dedicated 8 Chapters to the subject of male infertility. This is a commendable move on his part, which will enable contemporary practitioners to evaluate their way of thinking. In his preface Dr Chakravarty claims that his book was written for the benefits to students. We strongly agree INTERNATIONAL PHARMACEUTICAL INDUSTRY 93

Chapter Title News EU Clears Bial’s New Parkinson’s Drug Over the next year certain patients with Parkinson's disease could get access to a new treatment option in Europe after regulators green-lighted Bial's Ongentys. The European Commission has approved the drug as adjunctive therapy to preparations of levodopa/DOPA decarboxylase inhibitors in adult patients with the disease and end-of-dose motor fluctuations who cannot be stabilised on those combinations. The decision came after regulatory advisors recommended Ongentys' (opicapone) clearance earlier this year, highlighting its ability to decrease off-time (time when patients are severely restricted by their symptoms) and increase on-time without troublesome dyskinesia. This was evidenced by data from two pivotal Phase III studies, BIPARK-I and BIPARK II, which demonstrated that the drug achieved an absolute reduction in OFF-time of two hours without increasing ON-time with troublesome dyskinesia, while a one-year extension study also showed that this effect was sustained. The European Parkinson's disease Association estimates that 1.2 million people have Parkinson's disease in the European Union. Bial said it plans to start launching its new drug across the region in 2016 and 2017. Source: IPI Staff Reporter Bayer Science & Education Foundation launches new round of funding Applications for the Bayer Science & Education Foundation's international scholarship programs are now being accepted for this year's round. In the academic sector, ambitious students can apply for an Otto Bayer, Carl Duisberg, Jeff Schell, or Kurt Hansen scholarship if they are aiming to undertake a study project abroad or from foreign countries planning a project in Germany. The subjects funded include all fields of study related to life sciences, chemistry or medicine as agricultural engineering, biology, biochemistry, plant-/biotechnology, bio / chemical process engineering, human and veterinary medicine, pharmacy, computational life sciences and teacher training in biology or chemistry. The Bayer Science & Education Foundation's program offers this year again an extra budget of EUR 50,000 for students from African countries who are planning study projects on the scientific topics above in Germany. In addition to the scholarships in the academic sector, the Hermann Strenger scholarships are available to support young people on a non-academic training program looking to gain initial work experience abroad. Applications are invited from committed trainees in commercial, industrial, scientific or medical occupations as well as young professionals in these fields who have completed their training within the past two years. With this program, the Bayer Science & Education Foundation is looking to offer targeted funding to young people in the non-academic sector, enabling them to gain professional experience abroad. The application deadline for all five scholarship programs is July 18, 2016. Application forms are available online at An independent scientific committee will award funding in mid September 2016.

AstraZeneca today announced it has entered into a commercialisation agreement with Aspen Global Incorporated (AGI), part of the Aspen Group, for rights to its global anaesthetics portfolio outside the US. The agreement covers seven established medicines - Diprivan (general anaesthesia), EMLA (topical anaesthetic) and five local anaesthetics (Xylocaine/Xylocard/ Xyloproct, Marcaine, Naropin, Carbocaine and Citanest). Under the terms of the agreement, AGI will acquire the commercialisation rights, outside the US, to AstraZeneca’s portfolio of anaesthetic medicines for an upfront consideration of $520 million. Additionally, AGI will pay AstraZeneca up to $250 million in a Product Sales-related payment, as well as double-digit percentage trademark royalties on Product Sales. AstraZeneca will manufacture and supply the products on a cost plus basis to AGI for an initial period of 10 years. Upon completion, Aspen will assume responsibility for all activities relating to the sale of the portfolio in all relevant markets. AstraZeneca's portfolio of anaesthetics is available in over a hundred countries worldwide, including key markets such as China, Japan, Australia and Brazil. The portfolio continues to generate stable revenue, with global Product Sales in 2015 of $592 million. The US rights to the products were divested to Abraxis, now part of Fresenius Kabi, in 2006. Source: World Pharma News Boehringer Ingelheim and Harvard Scientists Establish a Research Alliance Boehringer Ingelheim today announced it has established a research collaboration with the Harvard Stem Cell Institute's - Harvard Fibrosis Network to discover new ways of treating fibrotic diseases such as idiopathic pulmonary fibrosis (IPF), chronic kidney disease (CKD) and nonalcoholic steatohepatitis (NASH). The Harvard Fibrosis Network unites Harvard investigators in several of the University's schools and at Harvard-affiliated Massachusetts General Hospital and Brigham and Women's Hospital. In collaboration with the Harvard Stem Cell Institute and the Harvard Fibrosis Network, Boehringer Ingelheim is initially sponsoring three projects to explore novel pathways and molecular targets for the treatment of IPF, CKD and NASH. Through the research collaboration, the project teams will also have access to the chemical compound collection and siRNA library at the ICCB-Longwood screening facility and will be supported by Shannan Ho Sui's bioinformatics team at the Harvard Chan Bioinformatics Core at the Harvard Stem Cell Institute's Center for Health Bioinformatics to discover new drivers of fibrosis. Source: World Pharma News

Source: IPI Staff Reporter

Pfizer Sets Painkiller Marketing Code with Chicago's Opioid Police Pfizer and the city of Chicago have hammered out an agreement on painkiller marketing, setting out a code of conduct that ensures the powerful drugs are prescribed to the right patients and used with all their serious risks in mind.

AstraZeneca Enters Commercialisation Agreement with Aspen for Anaesthetic Medicines Portfolio

The marketing agreement--which publicly codifies Pfizer’s internal rules--could potentially be used as a model for other


Summer 2016 Volume 8 Issue 2

ChapterNews Title drugmakers selling the highly addictive opioid drugs. The city of Chicago is set to announce the code on Wednesday. Like many other cities around the country, Chicago has been struggling with an epidemic of painkiller abuse, but unlike most, has taken that battle to the courts. Last year, the city sued a set of painkiller companies--including the maker of OxyContin, Purdue Pharma--over their marketing practices. The city claims that the companies violated its municipal code and Illinois state law by pushing their opioids for chronic pain, despite the fact that the FDA hadn’t approved the drugs for that use. Source: Fierce Pharma Sanofi Enlists for Top Army Hospital’s Fight Against Zika Virus Lending its vaccines expertise to a leading Zika candidate, Sanofi ($SNY) has teamed up with the U.S. Army’s Walter Reed Army Institute of Research to guide an inactivated Zika vaccine candidate through clinical development. Through the partnership, WRAIR will transfer its Zika vaccine technology-dubbed Zika purified inactivated virus (ZPIV)--to Sanofi while the French pharma preps for Phase II testing and formulates an overall development strategy. Simultaneously, the WRAIRpartnered National Institute of Allergy and Infectious Diseases will sponsor a Phase I trial as the vaccine becomes one of the first to reach the human testing stage. Sanofi will continue to develop its own Zika vaccine through in-house technology, hoping to leverage decades of experience in dengue fever, a flavivirus similar to Zika. Sanofi’s Dengvaxia became the first licensed dengue fever vaccine late last year and has so far notched 5 approvals. Source: Fierce Pharma Novartis Enlists Body Painter to Showcase Psoriasis Patient Testimonies Most psoriasis patients feel shunned and embarrassed at times because others don’t understand their medical condition, Novartis ($NVS) recently found. Now, the company is sporting a campaign to help change that--and it’s teamed up with a body painter to do it. The Swiss drugmaker has brought on artist Natalie Fletcher-herself a psoriasis sufferer--to showcase patients’ stories. In a new video, Fletcher paints beach scenes and broken hearts to explain the “nightmares they struggle with and the hopes they have of clear skin”--all while using skin as a canvas. “I hope that people get a little bit of awareness about what psoriasis is and what people who have it deal with,” Fletcher says in the video. “Not only do they suffer physically, but they suffer emotionally from it. Oftentimes people become depressed or really lonely, and I think it’s nice to get that message out there of ‘it’s not contagious and it’s not their fault’ and just bring some kindness.”

sooner than they expected. After three doses, the effects of the shot--dubbed Mosquirix-are next to nothing after 7 years, scientists say--and what’s more, the decline happens fastest in children living in areas with above-average malaria rates. The results--published in the New England Journal of Medicine-throw into question whether the jab can actually play a meaningful part in the fight against malaria, researchers said. While in the first year, Mosquirix cut the risk of contracting malaria by 35.9%, after 7 years, that difference was only 4.4%. And after 5 years, among children exposed to higherthan-average malaria rates, the vaccinated group saw 10 more cases than did the control group. The results don’t come as a complete surprise. Just last year, Phase III data showed a significant drop-off in protection after four years: Among children who received a booster fourth dose of the vaccine, the number of malaria episodes at four years slid by 36%, but without the booster dose, the edge against the disease all but disappeared. Source: Fierce Pharma Malaria Findings Hold ‘Great Promise' in VAX R&D In a study that could provide a needed boost for malaria vaccine research, a team in Australia has blocked P. falciparum parasites from infecting human red blood cells by targeting three proteins found to be necessary for infection. Led by professor Alan Cowman, the group at Walter and Eliza Hall Institute targeted and deleted the proteins Rh5, Ripr and CyRPA and in turn blocked malarial infection. According to the researchers, the proteins form a complex that is “essential in the sequential molecular events leading to parasite invasion.” Published in Cell Host & Microbe, the new findings “hold great promise for understanding the function of these proteins and their development as vaccines,” Cowman said in a statement. While in early stages, the work could provide a new direction for vaccine researchers in the field and comes as GlaxoSmithKline seeks to roll out its first-gen malaria vaccine Mosquirix. Seen as far from perfect, GSK’s jab offers 39% efficacy that fades over time. Last week a study found that the vaccine’s effectiveness fades to nearly 0% in children after 7 years, information that could shape future immunization strategies. Source: Fierce Pharma

Source: Fierce Pharma New Waning Efficacy Data Puts GSK Malaria Shot's Future in Question Researchers already knew that the protection offered by GlaxoSmithKline’s malaria vaccine--the world’s first--wanes over time. But new data shows it may dwindle to nearly nothing


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Summer 2016 Volume 8 Issue 2


EXTRACT TECHNOLOGY STANDARD PRODUCT LINE now includes a unidirectional flow positive pressure isolator

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IPI - Summer 2016  
IPI - Summer 2016