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Volume 9 Issue 2

Peer Reviewed

International Pharmaceutical Industry

Supporting the industry through communication

THE North of England

An Internationally Recognised Health and Life Science Ecosystem

CpG Oligonucleotide Therapeutics A History Lesson for CRISPR?

Technology Assisted Cohort Optimization of Early Phase Multi-Centre Patient Studies

Innovations for Prefillable Syringes

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Contents 06 Editor’s Letter REGULATORY & MARKETPLACE 08 Change Management International Pharmaceutical Industry

Supporting the industry through communication

EDITOR: Orsolya Balogh orsolya@pharmapubs.com

The life sciences industry is currently facing unprecedented turmoil. Peter Muller of Schlafender Hase outlines five trends pharma companies will need to weather in 2017, and the considerations needed for smooth adaptation. The life sciences industry is in a state of flux for a whole series of reasons, which can largely be traced back to shifting market dynamics and growing regulatory rigour.

BOOK MANAGER: Anthony Stewart anthony@ipimedia.com

12 Safety and Regulatory Solutions to Address the Needs of Small and Medium Biopharmaceutical Companies

BUSINESS DEVELOPMENT: Clive Baigent clive@ipimedia.com

Small and medium-sized enterprises (SMEs) are often faced with the challenge of having limited resources which can impact their ability to seamlessly move products through the pipeline from clinical development to launch and post-marketing activities. This is further exacerbated by the growing complexity of regulatory requirements and significant pressure companies face to get their products to market as quickly as possible – balancing these two requirements can be virtually impossible. In this white paper, Dr Chitra Lele, Chief Scientific Officer at Sciformix Corporation, looks into the safety and regulatory solutions at biopharmaceutical companies.

DIRECTORS: Martin Wright Mark A. Barker

DESIGN DIRECTOR: Jana Sukenikova www.fanahshapeless.com CIRCULATION MANAGER: Dorothy Brooks dorothy@pharmapubs.com FINANCE DEPARTMENT: Martin Wright martin@ipimedia.com RESEARCH & CIRCULATION: Maria Dominici maria@pharmapubs.com COVER IMAGE: iStockphoto © PUBLISHED BY: Pharma Publications Unit J413, The Biscuit Factory Tower Bridge Business Complex 100 Clements Road, London SE16 4DG Tel: +44 (0)20 7237 2036 Fax: +44 (0)01 480 247 5316 Email: info@ipimedia.com www.ipimedia.com All rights reserved. No part of this publication may be reproduced, duplicated, stored in any retrieval system or transmitted in any form by any means without prior written permission of the Publishers. The next issue of IPI will be published in September 2017. ISSN No.International Pharmaceutical Industry ISSN 1755-4578. The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright. 2017 PHARMA PUBLICATIONS / Volume 9 issue 2 - Summer - 2017

16 The North of England – An Internationally Recognised Health and Life Science Ecosystem The North of England’s profile as a hub of health science has been on an impressive trajectory over the past five years. With some of the most illustrious health science institutions in the world. Analysis funded by the Northern Health Science Alliance (NHSA), and conducted by the think tank IPPR North last year, shows that the health and life science economy in the north is worth over £17 billion to the UK economy, over £10 billion of which is contributed by private sector life science companies. Suzanne Ali-Hassan, Business Development Manager for the Northern Health Science Alliance, discusses the health and life science ecosystem in collaboration with CEO, Dr Hakim Yadi. 20 CpG Oligonucleotide Therapeutics – A History Lesson for CRISPR? When we look at the emerging and likely future battles being fought to establish dominance in the emerging field of CRISPR technologies, it may be too easy to conclude that one has no frame of reference to help understand what the conclusion will likely be. However, as Harry S Truman said; “There is nothing new in the world except the history you do not know”. There have, of course, been many emerging technologies that have been subject to an IP land-grab. One such instance that we will look at in this article relates to CpG oligonucleotides. Craig Thomson, Patent Attorney and Cath Coombes, Senior Patent Attorney at HGF submit an article on Clustered Regularly Interspaced Short Palindromic Repeats. 24 Navigation of Key Regulatory Information for Efficient Life-cycle Management of Regulated Product and Application in SINGAPORE Developing an innovative healthcare product (a drug or a biologic, or a medical device) from the proof-ofconcept stage to the marketing stage is an expensive and complex process. It involves many years of research and

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 1


Contents development work. To save time and money in bringing products to market, product development activities should be conducted in accordance with the related regulatory requirements. These requirements can update development activities and help you to manufacture a product that meets the regulatory standards of your targeted jurisdiction(s) – that is, a quality product that is safe and effective for its intended use. Dr Balamuralidhara V., Assistant Professor at JSS College of Pharmacy with Abhishek B.V. PhD, Research Scholar and Dr Shenaz Z Khaleeli, Technical Director reflects on the Singapore area.

each dose or cohort across one or more sites. Natalia E. Drosopoulou, PhD, Senior Director of Project Management in Neuroscience at Worldwide Clinical Trials, and Henry J. Riordan, PhD, Executive Vice President of Medical and Scientific Affairs and Global Lead for Neuroscience at Worldwide Clinical Trials, focus on technology-assisted cohort optimisation.

DRUG DISCOVERY, DEVELOPMENT & DELIVERY

Quality customer data is foundational to commercial operations, and yet most European life sciences companies are not getting what they need from their customer data. That’s why 78% of organisations have data quality initiatives or will within the next two years, according to a new survey. But as the industry seeks to improve customer engagements through personalised multichannel interactions, the pressure is on for better-quality, more granular customer data. This white paper by Guillaume Roussel, Director of Strategy, Veeva OpenData, Europe Veeva Systems, answers the question of why quality customer data is critical.

30 A Sensitive Tool for Comparing the Stability of Biosimilars Growth forecasts for the global biopharmaceuticals market vary, but headline figures of close to USD 300 billion by the year 2021, rising from an estimated value of around USD 192 billion in 2016, are typical. Furthermore, as patents on large molecule therapeutics expire, and in a regulatory environment that encourages the development of ‘generic’ versions, the market share attributable to biosimilars is expected to increase rapidly. Recent FDA Guidance to Industry sets out an abbreviated licensure pathway for biosimilars, focusing on therapeutic protein products. Dr Lisa Newey-Keane, Life Science Sector Marketing Manager at Malvern Instruments, looks into the stability of biosimilars. 38 Achieving Agility: Real Breakthroughs Belong to the Bold As the old adage goes, if you keep doing the same things it can’t come as a surprise when the outcome doesn’t improve. Organising data differently offers a way to change that, says Amplexor’s Siniša Belina in this editorial. It seems counterintuitive that life sciences companies should strive for operational agility and competitive inventiveness when there are so many regulatory obligations to get past. Red tape is traditionally the enemy of nimbleness, an imposing barrier to innovation; to breaking the mould and doing things differently. CLINICAL RESEARCH 42 Four Easy Steps to Site Optimisation To Get the Most Out of Investigative Sites, Go After the Low-hanging Fruit In today’s clinical development arena, clinical trial sponsors are expected to achieve more with less. The marketplace has become more competitive, regulatory standards are stricter with greater emphasis on trial oversight and patient safety, and study designs are becoming more complex, with the need for more endpoints to demonstrate product value. As there are 58% more sites per trial than five years ago, sponsors have more to monitor and manage to ensure trials stay on track and development programmes succeed. Chris Neppes, Product Manager, Site Optimisation at ERT, guides the readers into the world of site optimisation. 46

Technology Assisted Cohort Optimisation of Early-phase Multi-centre Patient Studies

The common aims of early-phase research centre around helping to define the safety, tolerability and pharmacokinetics of a drug at single or multiple doses (or even multiple formulations) typically administered in ascending doses. These early phase studies are sometimes referred to as “cohort” studies as they are characterised by a relatively small number of subjects being enrolled for 2 INTERNATIONAL PHARMACEUTICAL INDUSTRY

50

HCP Engagement in a Multichannel World: Why Quality Customer Data is Critical

TECHNOLOGY 52

Will Graph Database Technology Uncover Pharma’s Hidden Insights?

By definition, medical research is about dealing with large quantities of data. That’s even truer in the leading edges of the life sciences, where tackling the thorny issues in genomics and personalised treatments has to take place at the petabyte and increasingly the exabyte, rather the mere megabyte and gigabyte level in terms of promising dataset size. Neo Technology’s Emil Eifrem looks at how life science researchers can probe large datasets efficiently and expose new insights with the unique power of graph technology. 56 Propelling Holistic Risk Management Using a Next-generation RBM Approach As the nature of clinical trials grows ever more complex, the requirement for an improved risk-based monitoring (RBM) approach increases. Such an approach improves the quality of clinical studies and facilitates better adherence to new guidelines from regulatory agencies. When implemented effectively, RBM reduces site monitoring costs, enhances oversight and provides a near real-time overview of data. It can enable life science companies to prioritise resources around identifiable risks relating to the safety of participants, and the quality and integrity of clinical trial data. In this technical editorial, Sudeep Pattnaik, President & CEO of ThoughtSphere, analyses holistic risk management. LABS AND LOGISTICS 60 Working with Difficult Preparations – Risks, Regulations, and Considerations Safety testing is a crucial part of drug development and is dictated by pharmacopoeial guidelines, which must be followed when performing each step of the process. Ideally, the method development stage is when any potential sample preparation problems are resolved to make the routine analysis easier; however, depending on the product in question, this can become a lengthy process as preparation methods can vary broadly. John McKenzie PhD, FRSC Chief Executive Officer at Wickham Laboratories Ltd looks at risks, regulations, and considerations. Summer 2017 Volume 9 Issue 2


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Contents 64 The Advantages of LC/MS in Identifying Residual Impurities in Biopharmaceuticals

specifically looks at the approach to PAT implementation on one such process with a sodium borohydride reduction.

Fergus Hall, PhD, Section Manager, Pharmaceutical Chemistry at Eurofins BioPharma Product Testing, looks at the complexity of detecting and quantifying residual impurities which are usually present at low concentrations within difficult sample matrices. He will discuss the broad selection of detection methodologies currently available, specifically focusing on the advantages of high-performance liquid chromatography mass spectrometry (HPLC/MS) for process validation studies.

PACKAGING

68 Environmental Monitoring and Reporting Facilitated by LIMS Environmental monitoring (EM) is an essential part of any pharmaceutical, medical device or biotechnology manufacturing process. It ensures that microbiological and particulate levels in the controlled manufacturing environment are maintained within acceptable limits. The EM programme will involve a regular regime of testing based on location and frequency. The results are used to monitor trends and trigger the appropriate corrective action if a limit is exceeded. Simon Wood PhD, Product Manager at Autoscribe, submits a feature on laboratory information management systems. 72 Future Supply Chain Trends: The Rise of the Full-service CDMO Outsourcing is on the rise, not only among big pharmaceutical firms but also with smaller emerging and even virtual companies, meaning customer requirements are more varied than ever before. As outsourcing continues to gain traction within the pharmaceutical supply chain, companies need to diversify and differentiate their offering to remain competitive. Kevin Cook, CEO of Sterling Pharma Solutions, which develops and manufactures small molecule active pharmaceutical ingredients (APIs), discusses the trends driving the increased demand for contract services partners and the benefits of selecting a full-service CDMO, in place of more niche providers.

86 From Concept to Solution: Designing to Enhance the Multiple Roles of Pharma Packaging When you walk into a store or pharmacy and see multiple similar products in the same competitive space, it is easy to understand the impact that packaging design and branding can make to consumer purchasing decisions. The initial interaction an end-user has with a product – from seeing an eye-catching design and taking it off the shelf to touching the product and reading the information – matters greatly in building a lasting connection. Alan Davies, Global Design Studio Manager for Essentra, brings together a feature on pharma packaging. 90

Crunch Time: The Impact of Serialisation Requirements on Packaging Operations

The November deadline for including unique product identifiers on prescription drugs is putting a strain on multiple parts of the industry, much of which is ill-prepared to meet the target. Here, we look to the experience of a company that is ahead of the curve for lessons on how to manage and ease the transition to serialisation. A Q&A with Allison Gilpin, Business Unit Manager, Global Serialisation, and Ray Hook, Manager Global Serialisation Services, PCI Pharma Services.

MANUFACTURING 76 Innovations for Prefillable Syringes The field of prefillable syringes is constantly turning up new trends and developments, driven by new active ingredients and a desire for patient safety at affordable costs. As a manufacturer of prefillable syringe systems, we respond to these trends with a series of new developments and improvements in accordance with the demands of the pharmaceutical industry, doctors and nursing staff, and the patients themselves. Bernd Zeiss, Manager, Technical Support Medical Systems Business Development at Gerresheimer Bünde GmbH, reviews the innovations of prefillable syringes. 80 Mitigating Risk Roche's Approach to PAT Implementation in a Sodium Borohydride Product Many compounds are synthesised from raw materials in multi-batch and multi-ton quantities over extended time periods. The repetitious nature of the multi-batch business has proven a rich source of opportunity for process analytical technologies (PAT) applications at Roche, for over 15 years in some cases. The key focus has been the integration of the PAT applications into the existing manufacturing systems such as automation, IT, QC, QA, maintenance, and R&D, to mitigate risk and improve process efficiently. This case study, written by Dr John O’Reilly, PAT Technology at Roche, 4 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2017 Volume 9 Issue 2


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Editor's Letter It’s that time of the year when we see long days and the sun at its highest in the sky – the summer equinox is on 21st June. I have just returned from the Anglo Nordic Conference in London, which was a fantastic opportunity to hear what products and services are looking for investment. In this edition of the magazine, you can read about the changing landscape of the life science industry courtesy of Peter Muller of Schlafender Hase. Of course, I am sure the recent general election will bring even more changes over the coming months for the UK life science sector. W i t h mys e l f c o m i n g f ro m Manchester and a big industrial heritage, it’s great to see the Northern Powerhouse being put back on the map. Suzanne Ali-Hassan, Business Development Manager for the Northern Health Science Alliance, discusses the health and life science ecosystem in collaboration with CEO, Dr Hakim Yadi. Analysis funded by the Northern Health Science Alliance (NHSA) and conducted by the think tank IPPR North last year shows that the health and life science economy in the north is worth over £17 billion to the UK economy. Over £10 billion of this is contributed by private sector life science companies. Dr Chitra Lele, Chief Scientific Officer at Sciformix Corporation, has written a white paper which considers

the safety and regulatory solutions at biopharmaceutical companies. Small and medium-sized enterprises (SMEs) are often faced with the challenge of having limited resources which can impact their ability to seamlessly move products through the pipeline from clinical development to launch and post-marketing activities.

dealing with large quantities of data. That’s even truer in the leading edges of the life sciences, where tackling the thorny issues in genomics and personalised treatments has to take place at the petabyte and increasingly the exabyte, rather the mere megabyte and gigabyte, level in terms of promising dataset size.

HCP Engagement in a Multichannel World: Why Quality Customer Data is Critical

Working with Difficult Preparations – Risks, Regulations, and Considerations

Quality customer data is foundational to commercial operations, and yet most European life sciences companies are not getting what they need from their customer data. That’s why 78% of organisations have data quality initiatives, or will within the next two years, according to a new survey. But as the industry seeks to improve customer engagements through personalised multichannel interactions, the pressure is on for better quality, more granular customer data. The following white paper by Guillaume Roussel, Director of Strategy, Veeva OpenData, Europe Veeva Systems answers the question of why quality customer data is critical. Will Graph Database Technology Uncover Pharma’s Hidden Insights?

Safety testing is a crucial part of drug development and is dictated by pharmacopoeial guidelines, which must be followed when performing each step of the process. Ideally, the method development stage is when any potential sample preparation problems are resolved to make the routine analysis easier; however, depending on the product in question, this can become a lengthy process, as preparation methods can vary broadly. Looking further ahead, I will be attending the Nordic Life Sciences on 12–14th September. This year’s event in Malmö is the fifth annual meeting. It is a great networking and partnering opportunity – not only to catch up with contacts, but also to create new relationships, so I hope to see you there.

Neo Technology’s Emil Eifrem looks at how life science researchers can probe large datasets efficiently and expose new insights with the unique power of graph technology. By definition, medical research is about

Glad Sommar from Scandinavia.

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

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

Lucy Robertshaw Director, Lucy J.Robertshow Consulting

Editorial Advisory Board Bakhyt Sarymsakova, Head of Department of International Cooperation, National Research, Center of MCH, Astana, Kazakhstan Catherine Lund, Vice Chairman, OnQ Consulting

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

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

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

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

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

Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group

Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

Francis Crawley. Executive Director of the Good Clinical Practice Alliance – Europe (GCPA) and a World Health Organization (WHO) Expert in ethics Georg Mathis Founder and Managing Director, Appletree AG 6 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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

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

Summer 2017 Volume 9 Issue 2


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Regulatory & Marketplace

Change Management The life sciences industry is currently facing unprecedented turmoil. Peter Muller of Schlafender Hase outlines five trends pharma companies will need to weather in 2017, and the considerations needed for smooth adaptation.

The life sciences industry is in a state of flux for a whole series of reasons, which can largely be traced back to shifting market dynamics and growing regulatory rigour. In a conservative and inevitably slow-moving industry such as this, it can be hard to keep up with the changes. Below are five of the biggest sources of disruption to pharma companies’ equilibrium, which they need to smooth their way through to avoid losing momentum, revenue and market share. Merger and Acquisition Activity The need to respond to changing market demands more swiftly than life sciences firms can manage under their own steam has fuelled merger and acquisition activity in the market in recent years. Analysis of deals in pharma and life sciences by PwC1 revealed that 101 transactions were announced in the sector during Q4 2016, worth $34.4 billion in disclosed value (28 of these deals have already been completed). Seven of the transactions were worth $1 billion+, the highest – Lonza’s acquisition of Capsugel – costing $5.5 billion. KPMG expects more of the same in 2017, with Europe’s largest biotech company, Actelion, the subject of great interest and suggestions that it could be a takeover target for Johnson & Johnson and Sanofi2. It isn’t just that the big brands are keen to take advantage of shortcuts to new innovation. Being acquired by a bigger name is the stated exit strategy for many biotechs bringing hot new products to market. To capitalise on these strategic and often sizeable purchases, the 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

acquiring company must be able to align its branding, content and labelling conventions quickly, reliably and efficiently. This is important if the new parent organisation is to maximise the revenue opportunity while minimising exposure to any risks associated with inconsistent, inaccurate or incomplete consumer messaging in onward packaging, dosage and safety instructions. It isn’t inevitable that the acquired brand will surrender its identity. In the case of Actavis when it acquired Warner Chilcott plc, the better-known brand was kept, but when they subsequently acquired Allergan they decided to rebrand under Allergan. But the need to align content and label assets, update company information and standardise on key wording, registered symbols and logos according to the controlling organisation’s style guide, is clearly an important part of blending portfolios. It is critical to upholding brand image, stabilising compliance efforts and maximising process efficiency – not to mention market opportunity. Comparing content assets manually against an approved master and verifying that they meet the rebranding criteria is a laborious task, which multiplies with each SKU (variation of product). Harnessing automated checking using technology that can compare and accurately spot and highlight anomalies – at high speed across huge batches of content assets – can reduce the time taken by as much as 85 per cent. This can have a marked impact on speed to market with products under new ownership: keeping stock moving while reducing companies’ exposure to issues and providing valuable savings as acquiring companies total up the final costs of the transition of ownership. Over-the-counter Growth and the Rise of Generic Drugs The growing global over-the-counter (OTC) drugs market, and increasing

emphasis on generic medications, is another driver of upheaval for the pharma industry with an impact on the way manufacturers must manage efficiency and the accuracy and consistency of marketing and patient safety information. Pressures on health services in markets such as the UK – whether that’s to get an appointment with a clinician for a consultation about minor ailments, or to qualify for a subsidised or free prescription – are prompting more people to go to local pharmacies, supermarkets and extended-hours convenience stores for the medication they need. Analysis by Technavio 3 suggests the global OTC drug market, which was valued at $120 billion in 2015, will be worth $162 billion by 2020 (a compound annual growth rate of 6.37 per cent). In the intervening period, large volumes of branded drugs will see their patents expire, leaving a gap that could be filled by generic products. If they are paying for their own drugs over the counter, patients are likely to be more cost-conscious, prompting them to choose stores’ own brands. Consumers are becoming more confident about doing this, encouraged by media coverage and consumer studies which have exposed marketing practices designed to get patients to pay a lot more for a recognised name – and for painkillers rebranded repeatedly for specific types of pain4. Reassured that the active ingredients are more or less the same, they are opting for cheaper no-name products that may potentially be made elsewhere, and/or repackaged and distributed by third parties. A report from India, a popular source of outsourced generic drug manufacture, has forecast that the global generic drugs market is on course to grow at a compound annual rate of 10.53% between 2016 and Summer 2017 Volume 9 Issue 2


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Regulatory & Marketplace 20205. Clinical prescribers – hospitals and community medical teams – also have a growing interest in generic drugs, because of the pressure to keep their own costs down. But what pharma manufacturers save in production and marketing costs, they must make sure they are not sacrificing in quality, safety and reputation. The more suppliers/ product handlers there are in the chain, the more critical it is that efficient and reliable quality checks are in place to align labelling and patient leaflets. So that, as information is updated in the light of emerging contra-indications or the discovery of new side-effects, these are reflected throughout. Strict deadlines are applied to these requirements, so companies need to move quickly or risk products being withdrawn from the market until they are compliant again. Again, it comes down to finding reliable automation solutions that can reduce packaging complexity yet instil confidence that nothing is able to slip through the net. Patient Self-service: Putting Information Online As patients are encouraged to take more responsibility for their own health, and are invited to have more involvement in and control of their treatment, drug companies are turning to digital channels to meet that need. Publishing information online is also more cost-effective, and easier to update quickly, so it makes sense for pharma companies to harness these media. In the US, online channels are proving a powerful and effective way of reaching out to and engaging with consumers for promotional purposes. Here it is becoming increasingly common for brands to have productspecific microsites – where they can drive traffic captured via social media, for instance. Surveys suggest that 73 per cent of US adults now use online health information and tools6. For safety’s sake, digital information formats must also include the relevant prescribing dose and safety information, so it is vital that companies are able to manage and coordinate these channels alongside 10 INTERNATIONAL PHARMACEUTICAL INDUSTRY

traditional, physical patient leaflets – ensuring that messaging is consistent and accurate across the board. Practically, this means being able to check content in XML or HTML formats as well as traditional PDFs and text or Word files. Globalisation Although harmonisation of product information is high on the agenda internationally, from the EMA’s IDMP (Identification of Medical Products) efforts in Europe to equivalent plans in the US and Asia, the chances of local variances in information delivery in each country are still quite high – certainly in the short term. The US is currently taking a tough line on off-label claims, affecting the promotional claims and wording used in drug marketing, so this needs to be tightly controlled. International harmonisation efforts are in everyone’s interests and, ultimately, should make life much easier when there are far fewer authorities to publish product information to, but for the time being, global life sciences players still need to put in a lot of work to ensure that they are meeting the quality and safety standards in each individual market. This can be a demanding requirement, given the varying emphases, not to mention language, phrasing and symbol differences between countries. Checking content across different languages and cultures presents its own issues because of the subtle differences in interpretation of particular phrasing. Unless the parties responsible for checking translations are completely fluent in multiple languages, the scope for error is significant, so it is important that teams have the backup of sophisticated software to smooth the process and highlight anomalies. One reliable way to do this is by comparing the code behind the characters to be printed – allowing two files to be compared in any language and any font (as long as these support Unicode). Deloitte advises firms to move away from after-the-fact checks to timely detection and resolution of compliance and quality events,

as a means of reducing the risk that regulatory issues will hamper innovation and slow revenue generation7. In the climate firms are now operating in, prevention (of problems) is more cost-effective than cure, so tools that allow the industry to be on the front foot have much in their favour. Skills Gaps It is becoming more and more challenging for life sciences companies to find and keep the right talent for regulatory and quality purposes. A report published by UK trade association, ABPI, in late 20158 already pointed to challenges with the quality of experienced candidates applying for senior level regulatory roles, which was being cited as a critical concern. More experienced roles require a blend of RA expertise and commercial knowledge, and RA experience that has been too niche has created issues in absorbing other responsibilities easily. Companies we re re p o rt i n g t h at t y p i c a l recruitment times to fill a position were 6–12 months. This situation is worsening now. Brexit and the free movement of labour in Europe; increasingly complex compliance requirements; the expanding presence of pharmacovigilance; and the stress placed on those responsible to be absolutely meticulous in the accuracy of product information, are all factors making it harder to build and maintain teams of regulatory professionals. Manual tasks are unrewarding, demotivating and a poor use of qualified professionals’ time. In a recent study by international people and organisational advisory firm Korn Ferry9, almost three-quarters (73 per cent) of employees cited their number one driver at work was doing a job that had meaning and purpose. Yet pharmaceutical companies don’t typically employ proofreaders; rather they use scientific writers with Masters degrees or PhDs to check over content, at great expense. As they try to plug the gaps, and hang on to the qualified and experienced experts they already have, life sciences companies need Summer 2017 Volume 9 Issue 2


Regulatory & Marketplace

to be clever about how they support those people to make best use of the time, and how they alleviate the aspects of their job which add the least value professionally yet cannot be skimped on. There is no question that 2017 will be a challenging year, but it should be exciting too. Change is necessary, and disruption can bring healthy regrowth – as long as companies see the changes coming and take steps to adapt. In our client work, we see organisations right across the maturity spectrum: as long as companies have the right mind-set and vision, they’re on the right track – even if some will take a bit longer to get to where they need / want to be. REFERENCES 1. Pharmaceutical and life sciences deals insights: Yearend 2016 Update, PwC: http:// www.pwc.com/us/en/healthindustries/pharma-life-sciences/ publications/pharma-lifesciences-deals-insights.html 2. Clarity on mergers & acquisitions 2017, KPMG: https://assets.kpmg. com/content/dam/kpmg/ch/pdf/ clarity-mergers-and-acquisitions2017-en.pdf www.ipimediaworld.com

3. Top 19 Vendors in the Global Over-the-Counter Drug Market, Technavio, August 2016: https:// www.technavio.com/blog/ top-20-vendors-global-overcounter-drug-market 4. Are more expensive painkillers worth the money?, BBC ‘Trust Me, I’m a Doctor’: http://www.bbc. co.uk/programmes/ 5. Global Generic Drugs Market Growing at 10.53% CAGR to 2020, ReportsnReports, May 2016: http://www.reportsnreports.com/ reports/586255-global-genericdrugs-market-2016-2020.html 6. Managing regulatory and legal risk in the digital world, EY, : http://www.ey.com/Publication/ vwLUAssets/EY-Managingregulatory-and-legal-riskin-the-digital-world/$FILE/ EY-Managing-regulatory-andlegal-risk-in-the-digital-world.pdf 7. Simplify compliance, focusing on strategic risks/Navigating the year ahead: Life sciences regulatory outlook 2017, US, December 2016: https://www2.deloitte. com/content/dam/Deloitte/us/ Documents/regulatory/us-lifesciences-regulatory-outlook-2017. pdf 8. Bridging the skills gap in the biopharmaceutical industry: Maintaining the UK’s leading position in life sciences.

November 2015: http://www.abpi. org.uk/our-work/library/industry/ Documents/Skills_Gap_Industry.pdf 9. Korn Ferry Survey: Lack of a Challenge Top Reason Professionals Would Seek New Job in 2017, Korn Ferry, January 2017: http://www.kornferry.com/ press/korn-ferry-survey-lackof-a-challenge-top-reasonprofessionals-would-seek-new-job/

Peter Muller Managing Director, Schlafender Hase, Americas. For the last 20 years, Peter Muller has worked on software and process improvement projects with Fortune 500 companies from various industries: pharmaceutical, consumer goods, food, aerospace and defence. He has a wealth of experience working with international clients to define their organisation's goals and help them leverage new technologies to achieve productivity gains, process improvements and cost savings. Email: peter.muller@sh-p.com

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Safety and Regulatory Solutions to Address the Needs of Small and Medium Biopharmaceutical Companies Small and medium-sized enterprises (SMEs) are often faced with the challenge of having limited resources, which can impact their ability to seamlessly move products through the pipeline from clinical development to launch and post-marketing activities. This is further exacerbated with the growing complexity of regulatory requirements and significant pressure companies face to get their products to market as quickly as possible; balancing these two requirements can be virtually impossible.

Clinical trials are typically outsourced to full service clinical research organisations (CROs) and many SMEs select them based on a CRO’s ability to recruit patients in certain geographies and therapeutic areas. However, some CROs do not have the required level of speciality in other areas, particularly in data management, statistical design and analysis, medical writing and regulatory submissions. Another challenge is that trials may be outsourced to several CROs, resulting in safety and pharmacovigilance (PV) data, along with the technology infrastructure that supports it, being housed at multiple CROs. This often leads to safety data being reviewed and reported separately, rather than being reviewed and analysed at the aggregate (product) level, and data are often collected in different systems. This can put organisations at risk when filing a new drug application, as they will not be able to review and analyse consolidated data to proactively identify and manage safety concerns. Post-marketing activities, including end-to-end safety and risk management for approved products can be very resourceintensive. Many SMEs do not have the internal capabilities to manage these activities as it diverts finances and manpower away from new 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

product development and marketing. Therefore, many such organisations do not have an established safety group and either the clinical development or regulatory groups are responsible for safety activities, leading to lack of focus on critical PV activities. Clinical and regulatory activities in the post-approval phase for registration in different markets and evaluation of safety, efficacy and effectiveness for sub-groups and for other indications can also be quite resource-intensive. New Strategies to Assist with Managing Safety Responsibilities A comprehensive understanding of the safety profile of a product in the clinical trial environment requires evaluation and aggregation of safety data. This is particularly important in real time in order to comply with the US FDA’s guidance for IND safety reporting1. This timely reporting of meaningful safety information allows the FDA to consider whether any changes in study conduct should be made and lets investigators take any essential steps to protect subjects. Establishing a comprehensive PV organisation in-house can be challenging for SMEs. This is because dedicated and experienced professionals are required to manage both PV operations and the enabling technology architecture/ infrastructure. On the technology side, implementing validated, regulatory-compliant PV systems requires significant investment in a robust quality management system (QMS) and the right expertise to select, implement and support the best solution(s). Yet, the volume of the safety data is often highly unpredictable, therefore not always justifying the expenditure. Similarly, on the product safety side, responsibilities such as aggregate safety reporting, benefitrisk evaluation, signal detection and management and development of risk management plans are becoming

more complex and resourceintensive. Across Europe and several other countries, specific regulatory mandates to have a qualified person responsible for PV (QPPV) and local persons responsible for PV pose additional operational challenges to SMEs. SMEs can benefit by embracing newer strategies to manage their responsibilities during clinical development and in the post-approval phase. Using functional service providers (FSPs) that specialise in areas of statistical design and analysis, clinical data management and PV, while using CROs to optimise patient recruitment and manage clinical trial conduct, is an effective strategy that should be considered. This allows a sponsor company to hire specialised skills at different points in time that can provide flexible capacity in a cost-effective manner. Product Lifecycle Regulatory and Safety Related Pitfalls In SMEs, often only a small team is responsible for clinical, safety and regulatory activities. Therefore, they may not have the resources or expertise available to dedicate substantial time to critical safety and regulatory related activities through the product lifecycle from preclinical development to Phase IV, as depicted in Figure 1. However, compliance with safety regulations is of critical importance. If compliance is not upheld, it can lead to extensive financial penalties, re-work of data or low-quality outputs 2. This is more frequent if standard operating procedures (SOPs) and safety management practices are not in place. Regulatory authorities such as the US FDA and MHRA issue warning letters for major regulatory violations observed during inspections. Consequences of the warning Summer 2017 Volume 9 Issue 2


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

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

Research Quality Association 3 Wherry Lane, Ipswich Suffolk IP4 1LG UK

www.therqa.com

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


Regulatory & Marketplace

Figure 3: Companies need to be prepared for planned and unplanned spikes and dips, keeping options open to take advantage of talent pools.

Figure 1: The Product Lifecycle

letters are serious (e.g. loss of trust by patients and HCPs regarding company products, damaging effect on stock prices, and negative impact on approval of future submissions). The FDA’s enforcement actions can include product recall, seizure, injunction, administrative detention and civil money penalties and/or prosecution. During safety monitoring in the product lifecycle, one of the most common pitfalls is a failure to integrate multiple safety databases which are required for comprehensive safety review to have a clear picture of all risks. Managing all submissions to regulators can also be a difficult and complex task for SMEs, including case submissions and DSUR/IND annual reports, as well as ensuring all processes comply with audits and inspections at any time. A failure to analyse, review and document all pertinent clinical safety data (adverse events and events of interest, laboratory data and other investigations) can also be detrimental. Similarly, design, analysis and reporting of clinical trials may not be of the desired quality and may cause inordinate delays in submissions, even if the patient recruitment timelines are met, having serious resource implications for smaller companies. Top Considerations for Outsourcing When evaluating the possibility of outsourcing the clinical, safety and regulatory activities, there are three 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

areas of consideration – people, process and technology – as shown in Figure 2.

Figure 2: Considerations for outsourcing clinical, safety and regulatory activities

People In SMEs, the limited amount of manpower available is an important consideration as inherently, there is little flexibility. Whereas an external vendor is able to supply flexible resources to match fluctuations in demand, with the specialised expertise required to meet the quality and standards needed for compliance. Therefore, companies do not have to invest the time into recruiting and retaining dedicated employees. The fluctuations in workload are a reality in PV, especially of marketed products, as shown in Figure 3. Working with an outsourcing partner allows convenient access to a broader pool of staff within the outsourcing organisation, and can then be withdrawn as needed, providing flexible and cost-effective resourcing solutions for surge management.

Process Developing the right processes to support end-to-end clinical development, regulatory and pharmacovigilance activities is both very costly and laborious. Speciality outsourcing organisations can provide ready-to-go, robust, tested and audited systems and procedures, eliminating the time and expense of starting from square one. These processes can be configured to the company products, processes, and requirements and are updated on an ongoing basis to adapt to changing requirements and technological advances. Technology Information technology is essential to enabling a robust safety and risk management operation, including the aggregation of multiple databases. Outsourcing vendors are able to provide ready-to-go solutions, which have been rigorously tested and proved successful. They are also able to provide experienced staff with in-depth knowledge of the software, removing the need for training. This also ensures strong business continuity and disaster recovery plans. Specialised vendors employ best-in-class quality systems and oversight with well-defined quality management plans, robust SLA compliance frameworks, and metrics, analytics and reporting. Such vendors can help build pragmatic and compliant systems to meet company requirements and development plans. Holistic Specialised Safety and Regulatory Solutions In the area of safety and risk management, PV-in-a-Box (Figure 4) Summer 2017 Volume 9 Issue 2


Regulatory & Marketplace the success rate of clinical trials. Teams which have an understanding of both market access strategies, and an understanding of the regulatory environment in various markets, can advise on submission requirements for regulatory approvals. Such specialised clinical and regulatory support will increase the chances of successful clinical development programmes and ultimately of the commercial success of the products.

Figure 4: Sciformix’s PV-in-a-Box is an integrated regulatory and PV shared services model, encompassing end-to-end activities from safety database implementation, to case processing and medical review, to safety surveillance and risk management. It may include additional services such as QPPV provision (for products marketed in Europe), and call centre capabilities.

is a holistic customer-centric approach that brings together safety, technology and advisory services towards the provision of a full end-to-end PV solution by a single vendor. This integrated, flexible and shared services outsourcing model ensures regulatory compliance, quality data and product safety, as well as mitigating risks and saving money. In turn, this approach allows the sponsor organisations to focus resources on developing and delivering new products to market. The effective combination of domain expertise, agile processes and robust technology results in high-quality and compliant operations, increased efficiency and time savings. At the product level, PV-in-a-Box allows real-time tracking of benefit-risk profile and enables quicker and more informed decisions on risk minimisation, ultimately supporting maintenance of efficacious and safer medicines in the market. An automated technology platform (as part of the PV-in-a-Box solution) plays a key role in effective PV management by fostering collaboration between disparate teams, enabling seamless management and analysis of safety data. Efficient study designs, managing clinical data and the right analysis and reporting can significantly enhance www.ipimediaworld.com

Conclusion Over the past decade, clinical trials and post-marketing activities have continued to grow with more stringent and evolving regulations. While most of the industry’s risk management efforts have focused on post-marketing drug safety, clinical trials also hold the potential for a number of risks which could jeopardise product development investments, including regulatory delays. For SMEs, the ongoing challenge is how to develop and maintain effective clinical, safety and regulatory operations as their portfolios expand. Many companies need assistance to manage these operations, ensure regulatory compliance, produce quality deliverables and remain cost-effective. Employing a comprehensive regulatory intelligence framework and ensuring that best-in-class processes and SOPs are always compliant is challenging, especially with limited resources. Smart outsourcing and quality services are dependent on effective business (scientific) processes, well-defined governance structure and a long-term commitment to continuous improvement. Partnering with a provider who offers a scalable and agile solution with a suite of integrated products will go a long way in enabling sponsor companies to stay ahead of the curve. This strategy will help organisations achieve commercial success, get products to patients faster and remain compliant with regulatory requirements, while being focused on patient safety and benefit-risk evaluation of their products at all times.

REFERENCES 1. FDA. Final Rule: Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans. 2010. (Internet) available at: https://www.gpo.gov/fdsys/ pkg/FR-2010-09-29/pdf/201024296.pdf [accessed 10/05/2017] 2. Deloitte. Pharmacovigilance (PV) outsourcing – Emerging PV business models. 2014. (Internet) available at: https:// www2.deloitte.com/content/ dam/Deloitte/us/Documents/ life-sciences-health-care/uslshc-pharmacovigilanceoutsourcing-021115.pdf [accessed 23/01/2017] 3. European Medicines Agency. Guideline on good Pharmacovigilance practices (GPV). (Internet) available at: http://www.ema.europa.eu/ docs/en_GB/document_library/ Scientific_guideline/2016/08/ WC500211728.pdf [accessed 24/01/2017]

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

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The North of England – An Internationally Recognised Health and Life Science Ecosystem The North of England’s profile as a hub of health science has been on an impressive trajectory over the past five years, with some of the most illustrious health science institutions in the world.

Analysis funded by the Northern Health Science Alliance (NHSA) and conducted by the think tank IPPR North last year1 shows that the health and life science economy in the north is worth over £17 billion to the UK economy, over £10 billion of which is contributed by private sector life science companies. And this area of England, with a 15 million population, is starting to come together to bring its offerings in digital health, personalised medicine, health data and ageing to an international stage. The Northern Health Science Alliance was set up as a body to represent the North’s health science excellence. There are 20 members that constitute the alliance: eight research-intensive hospitals, eight pioneering medical schools and four academic health science networks. When we set up the alliance we knew the North of England had great expertise – but we didn’t realise how much and what depth of it there is. An analysis of all of the health science ecosystem threw up some very clear areas of excellence – which are opening doors to a global audience. Through our work, the strength of the North’s life and health science economy is becoming far more widely appreciated. It is now recognised by government, research funders, trade bodies, and national and international corporations. There are over 570,000 people working in our universities, hospitals and companies, with over 38,000 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

of those jobs being highly-skilled private-sector positions in 1000 companies. Last year, the Bio Industry Association, as well as the then UK Parliamentary Under-Secretary of State, Lord Prior, both formally recognised the North of England as a ‘rapidly developing clinical cluster’. Our mission is to become an ‘internationally recognised health and life science ecosystem’ and we are well on our way to delivering on this mission. Important to this is how closely we work with government and industry. The NHSA has a seat at the UK government’s policy table. Earlier this year, the government brought together a steering group to establish and structure a new life sciences industrial strategy. The group, led by Professor Sir John Bell, includes the Wellcome Trust, Cancer Research UK, other leading research charities, NIHR, NHS England, sector trade bodies, the NHSA, as well as our sister organisation in the South East, MedCity. The group has worked collectively to offer advice and influence the development of the national strategy for the life science sector. Five years ago, at the launch of the last UK Life Sciences Strategy, the North was not at the table - we are now.

they can share information and improve the health of local people. At the heart of the health improvements is the efficient use of health data and technology. These two elements can unlock new meaning and, when analysed between services, can lead to new, more efficient processes and the continuous improvement of public health. The aim of the CHCs is to develop learning health systems that will continually improve care services and health. This system will make healthcare more efficient by providing information to health service managers that can be quickly implemented into standard practice. They are also working with the public to gain their trust that health data is being used responsibly, safely and to improve services for the benefit of all patients. CHCs will also stimulate the UK’s digital health economy by encouraging new technologies to be developed and new services to be created. The project successes will be shared and could be scaled up across the UK.

Connected Health Cities Focus on the North’s excellence in health data has led to the groundbreaking Health North: Connected Health Cities (CHC)2 project, which is seeking to improve the lives of people across the North from Liverpool to Newcastle.

Collaboration as a Catalyst The NHSA has facilitated new conversations and a joined-up way of thinking for some of the largest and most competitive bids in the country, such as: the NIHR biomedical research centres, the NIHR MICs, the new UK Health Data Institute, the Active and Healthy Ageing Reference Sites, and establishing a collaboration between our four NIHR Clinical Research Networks through a signed memorandum of understanding.

The government-funded scheme, delivered by the NHSA, is running across four ‘city regions’ in the North of England, each of which is looking at new ways of using health data. Each local city region will unite health and social care services so that together

While we all recognise areas of competition between the NHSA members, more often than not we are able to identify areas of collaboration and complementary activity. By working in this way, we have been able to demonstrate that the North Summer 2017 Volume 9 Issue 2


Regulatory & Marketplace is at the forefront of a new model of health and research collaboration, designed to benefit patients faster. Waking up the Global Audience to the North It is time the international audience wakes up to health science research in the North of England. Most international corporations have heard of the so called ‘golden triangle’ of London, Oxford and Cambridge, but comparatively few have heard about the North of England. This is despite the fact that the North has world-class research universities, fantastic quality of living and low start-up costs – in fact if the North of England was an independent country it would be the eighth largest in Europe, if measured on the size of its economy. The NHSA has firmly established itself as a go-to point of contact for international companies and companies working across the UK. We act as an independent broker to foster introductions between companies and our research capabilities. The commercial team at the NHSA have created dozens of significant new opportunities for our members in just five years that would not have been available to us without the NHSA. This has meant the NHSA has given a financial return to the region in the form of over £50 million worth of research contracts from the public and private sector in the last three years. Companies are now considering how they work with and most importantly deploy their R&D budgets in the North of England. One example of this is our work with Oxford Nanopore (ONP)3. The MinION, made by ONP, can be used to provide rapid identification of infectious agents and identify genes involved in AMR from clinical samples. through whole genome sequencing. This can be used to identify genes involved in AMR, screen clinical samples and so determine which antibiotic will be effective when treating disease. www.ipimediaworld.com

The NHSA introduced the MinION to clinical researchers across the North. With a trial initiating in Liverpool, it will then expand to centres in Sheffield, York & Hull Medical School, Newcastle and Lancaster. We have achieved all of this in a unique period of political turmoil from Brexit, to the creation of the Northern Powerhouse and a new Industrial Strategy and now a general election. Brexit – an Opportunity? In response to article 50 being invoked, the NHSA has been working on two fronts. We’ve been working to build links back into the EU through the European Active and Healthy Ageing reference sites. We’ve been uncovering opportunities created by Brexit. These opportunities include the possibility of the UK to position itself in a new regulatory environment, developing potentially faster routes for the development of novel therapies and attracting the investment that would follow. There are other opportunities, such as re-establishing links with Commonwealth sister nations, both developed and developing, from whom we have a huge amount to learn, and to whom we can contribute, when it comes to 21st-century models of healthcare research and delivery. We are also developing strong links with Singapore and Australia and continue to foster more relationships. The opportunity here is not just the North, but the whole of the world. A stronger health science cluster in the North means a stronger UK life and health science sector, one that can work collaboratively across the globe to deliver a health and wealth agenda that we all benefit from. How the NHSA helps global industry go North by Suzanne Ali-Hassan Industry needs to consider clinical evaluation of new technology part of their market access strategy. By engaging with the NHS and the health research infrastructure in the UK to do this, they can guarantee the strongest case for adoption of technology by the UK and other international healthcare markets.

Post-Brexit, the NHS will remain the world’s largest single payer for healthcare and provides enormous potential for companies wanting to enter the global market. It also hosts organisations such as the National Institute for Care Excellence (NICE) which provides its desirable gold stamp of approval for new technology. As a result, the UK and the NHS is still prime territory for developing and validating new technology and a spring-board to markets further afield. However, knowing exactly how to engage is hard, and access points can be tricky to find, despite some core pieces of infrastructure in place to help bring innovation to the system. Companies will often approach me to support integrating new technology with the NHS too late in its development, where it is ready to ‘sell’, and consequently uptake is not as quick as first imagined. The NHS is in need of transformative technology; not just technology making up part of a clinical care pathway, but systems and processes which support service delivery and efficiency. Why are in-patient vital signs still taken down by nurses using pen and paper? It is a public sector organisation with limited resource and decisions around budget need to be rigorously appraised, but industry needs to support this as best it can. By including the healthcare system in the clinical validation process, you are making the right connections early on, ensuring there is unmet need and so a route to procurement. Clinical buy-in is the essential precursor for integration of any new technology. With coordinated outreach across our member institutions, it is the first step the Northern Health Science Alliance (NHSA) takes in securing engagement with the healthcare system. The NHSA sits at the interface between the health research infrastructure in the North of England; supporting eight medical schools, eight large research active NHS Trusts and four AHSNs. As a single point of entry to this ecosystem, the NHSA is well placed to assist industry in finding INTERNATIONAL PHARMACEUTICAL INDUSTRY 17


Regulatory & Marketplace the right institutions to evaluate their technology – and at various stages of its development. With our large teaching hospitals bridged with their associated medical schools, they are able to provide translational research capabilities and are primed for partnering with industry. This is further supported by nationally recognised pieces of infrastructure funded by the Medical Research Council  (MRC) and the  National Institute for Health Research (NIHR), for example. Key opinion leaders and clinical investigators from our member institutions engage with industry partners through the NHSA and determine ways of evaluating the new technology in a meaningful way. This has often resulted in several institutions coming together as one and collaborating on a piece of technology with the industry partner, something the North of England is very content to do – perhaps more so than our Southern counterparts. These multi-centre studies mean new technology is assessed in several intuitions at once, maximising the case for unmet need, as well as any outcomes being viewed as institutional preference. In this capacity, working with the NHSA and our 20 members can help establish inter-disciplinary consortiums to support the evaluation. This includes highly regarded health economic groups, NIHR infrastructure set-up to evaluate clinical validity and utility of new medical technology, and of course our four AHSNs who cover larger sub-regional footprints and can latterly support diffusion across their respective regions. The NHSA has worked with large companies through to SMEs, where this multi-centre approach has been valued and resulted in some interesting collaborations. One of the most developed is a Singaporean medical technology company, Biobot, who now have a multi-centre study about to begin with their automated prostate biopsy robot.

Sheffield; but also robust economic modelling from a world-renowned health economics group based at the University of Sheffield, ScHARR. Supporting the collaboration is the Yorkshire & Humber Academic Health Science Network, who are able to ensure engagement with other regional centres post-evaluation. This strong consortium of centres and people means the right type of evidence will be generated for eventual NICE approval, as well as NHS adoption. There is a cost associated with this type of work: engagement with multiple institutions and pieces of infrastructure requires more resource. Although, where the financial investment is considered part of the development process and with the returns almost guaranteed to be fruitful, it is surely a smart way to look at establishing a technology in the healthcare market. Having worked with industry, the NHS and academia for a number of years in this capacity, I urge companies to look at validation of technology and perhaps further iterative development within the NHS itself. As a result, the evaluation will include key components for NICE approval and adoption by healthcare systems worldwide. A win-win situation for everyone. REFERENCES 1. http://www.ippr.org/publications/ health-innovation-breathing-lifeinto-the-northern-powerhouse 2. http://www.connectedhealthcities. org/ 3. http://www.thenhsa.co.uk/2017/01/ portable-technology-fightantimicrobial-resistance-broughtnorth-hospitals/

Dr Hakim Yadi CEO of the Northern Health Science Alliance Ltd (NHSA). He led the formation of the NHSA, bringing together 20 NHSA members as a single health partnership across the North of England, securing over £60m in contracts and raising the profile of the North’s health research at an international level. Hakim is co-founder of two women’s healthcare companies and VicePresident and co-founder of the Global Heart Network. Hakim holds a PhD in the Immunology of Pregnancy from the University of Cambridge and has published a number of peer-reviewed papers as a consequence of his research at the Babraham Institute in Cambridge. He was awarded an OBE in the 2017 New Year’s Honours list for services to healthcare technology and the economy.

Suzanne Ali-Hassan Business Development Manager for the Northern Health Science Alliance, working with SMEs through to big pharma across all industry sectors. Promoting regional capabilities and expertise, she supports industry engagement with the health research infrastructure within the North of England, with a view to set-up of research collaborations with NHSA member institutions. Suzanne holds an undergraduate degree in genetics, and an MPhil in biochemistry & pharmacology from the University of Bath. Throughout her academic studies, she spent several years working in frontline NHS and community services.

This not only includes top urologists from two of our larger teaching hospitals, Leeds and 18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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www.ipimediaworld.com

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CpG Oligonucleotide Therapeutics – A History Lesson for CRISPR? When we look at the emerging and likely future battles being fought to establish dominance in the emerging field of CRISPR technologies, it may be too easy to conclude that one has no frame of reference to help understand what the conclusion will likely be. However, as Harry S Truman said; “There is nothing new in the world except the history you do not know”. There have, of course, been many emerging technologies that have been subject to an IP land-grab. One such instance that we will look at in this article relates to CpG oligonucleotides.

In the 19th century, a clinician called William B Coley successfully treated a number of patients suffering from cancer with bacterial lysates. It took many years to identify the basis for this therapy. In the 1980s, a team of researchers concluded that the ability for the lysates to treat cancer was derived from the nucleic acid content. It was not, however, until the 1990s that the full story began to emerge. Dr Kreig found that it was a specific structure within a bacterial nucleic acid that elicited a powerful immune response. That structure was a cytosine-guanine repeat, with an unmethylated cytosine, when provided with appropriate bases up and downstream from that repeat, ie CpG oligonucleotides. This discovery opened the doors to a new branch of immunotherapeutics and immuneadjuvants. A number of companies sought to exploit the emerging field of CpG oligonucleotides. Two of the companies that were amongst the first to rise to this challenge were Coley Pharmaceutical Group Inc. and Dynavax Technologies Corp. Both were able to raise considerable financial capital on the back of the excitement surrounding the potential for a new range of therapeutics and immune adjuvants derived from CpG oligonucleotides. Each armed with a full war-chest, they both set about laying down a considerable portfolio 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

of patent applications and strategies for restricting the ability of the other to establish a useful monopoly in the field. Both parties wanted to dominate this emerging field. As an indication of how this wish to dominate the field played out with respect to patent protection, we can look to the position in Europe during the period from 1995 to 2005. During this period, 22 European patent applications were published in the name of Coley Pharmaceutical Group, whilst during the same period, 19 European Patent Applications were published in the name of Dynavax Technologies Corp. As both parties were aware that the other was trying to establish a dominance in the field, even when the technology was not fully developed, each party raced to file their applications before the other. Not all CpG oligonucleotides are created equal, and so the accuracy of defining those most effective oligonucleotides in the applications was vital. The need to speedily file applications inevitably resulted in many of the applications being filed with problems that would make their prosecution to grant difficult. Of the 19 European patent applications filed by Dynavax Technologies Corp, four applications had to be withdrawn by the applicant and two were refused during oral proceedings before the Examining Division of the EPO. Coley Pharamceutical Group perhaps fared worse, with seven of their European patent applications having to be withdrawn by the applicant and one being refused during oral proceedings before the Examining Division of the EPO. The cost of prosecution of both portfolios was no doubt considerable, with losses through withdrawal and refusal resulting in a considerable waste of resources. Nevertheless, in a land-grab for an emerging field, this is probably to be expected. The strategy for both parties was, of course, not merely to protect as

much as they could of the emerging field, but also to go on the attack. Of the 13 patents granted in Europe to Dynavax Technologies Corp., four were opposed. The result of these oppositions was that two of the patents were revoked in their entirety, whilst two were maintained with restrictive amendments to the claims. Coley Pharmaceutical Group was an opponent in the majority of these oppositions. A similar situation occurred on the other side. Of the 14 patents granted to Coley Pharmaceutical Group, four were opposed. Three of the opposed patents were maintained with restrictive amendments to the claims, whilst the remaining opposed patent was revoked in its entirety. The position was much more c o m p l i c at e d a n d n o d o u b t considerably more expensive in the US. Indeed, costly and time-consuming interference proceedings were launched and won by Dynavax Technologies Corporation. In these proceedings, Dynavax Technologies Corporation successfully argued that the invention defined in an application – which it had in-licensed from The Regents of the University of California – was invented prior to that of a patent granted to Coley Pharmaceutical Corp. Under the old “first-to-invent” rules in the US, despite the fact that the Coley Pharmaceutical Corp. patent had been filed prior to that of the University, the University patent was able to claim an effective earlier date. A lot of fighting and money was clearly spent, but both parties did come through this period to achieve relative success. Coley Pharmaceutical Corp. went on to list on NASDAQ, raising a reported $96 million, and was later majority purchased by Pfizer for a reported $164 million. Dynavax Technologies Corp. is still operating independently and developing CpG oligonucleotides Summer 2017 Volume 9 Issue 2


1000 Europe’s Fastest

Growing Companies

www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 21


Regulatory & Marketplace for use in multiple cancer indications, as a vaccine for the prevention of hepatitis B and as a disease-modifying therapy for asthma. Their lead product is SD-101, an investigational cancer immunotherapeutic currently in Phase I/II studies, and HEPLISAV-B, a Phase III investigational adult hepatitis B vaccine. Interestingly, after years of opposing each other’s position, it finally became necessary for the parties to collaborate. In order for Dynavax Technologies Corp. to pursue commercialisation of their hepatitis B vaccine, they took a non-exclusive license from Coley Pharmaceutical Corp in 2007. Under the reported terms of the agreement, Coley Pharmaceutical Corp. received a $5 million up-front payment, with a further $5 million upon regulatory approval of the therapeutic. Royalty payment also accrued to Coley Pharmaceutical Corp. from sales of the therapeutic. The two parties were then working together for their mutual benefit. Perhaps the relationship between Coley Pharmaceutical Corp and Dynavax Technologies Corporation would always have ended up taking this route, competition seeming to be the natural order in business. But one does reflect on the story and wonder if a more beneficial route for both parties could have been taken. Ultimately, both parties collaborated to get a product to market, and both parties financially gained from this arrangement. If collaboration had been honestly sought around the beginning of the new millennium, could things have been different? Could both parties have agreed areas of this new field that each could investigate un-hampered by the other, whilst at the same time identifying areas where they could collaborate. In agreeing to proceed in this way, they would no doubt have spent considerably less on legal fees fighting each other, and likely have ended up with broader patent protection in which together they could have better dominated the emerging field. On the other hand, perhaps this story demonstrates that the patent system is working. Two innovators bringing an emerging 22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

technology to the world have been rewarded by the grant of a good clutch of patent rights. However, the breadth of those patent rights has been kept in check by the natural inclination of both parties to compete. Perhaps an even more interesting avenue for reflection is the parallels with the current land-grab we see in relation to CRISPR technologies. The early CRISPR/Cas9 patent landscape for use of CRISPR/Cas9 in eukaryotes is even more complex, with a plethora of interwoven filings by at least six parties. Originally, a number of the early players in the field, including the lead inventors Feng Zhang of MIT/Broad Institute, Jennifer Doudna of UC Berkeley and George Church of Harvard College, collaborated with one another and set up Editas to develop human therapeutics using CRISPR/Cas9. Had this collaboration continued, then today they collectively may have been in a stronger position to dominate this emerging field. Instead, the collaboration fell apart and various companies obtained licences from different early players in the field. The ongoing CRISPR

patent wars have resulted in a replay of the approach for the CpG oligonucleotides technology. There are a number of similarities to be observed here. Like for CpG oligonucleotides, the parties are adopting an approach in which they attempt to dominate this new field, and to go on the attack against the others. This can be illustrated by looking at the patent filings of the MIT/Broad institute of which Feng Zhang is the lead inventor. From the outset the plan was to thicket the field with a number of patent applications and to expedite the process in an attempt to dominate the field. Their earliest patent application was on 12 December 2012, and a year later they divided this out into 10 international patent applications which mostly entered Europe early. These patent applications have been expanded further, so that currently they have no less than 24 European patents/ patent applications in Europe which claim the earliest priority date of 12 December 2012. Armed with a war-chest, they have attempted to dominate the field, whilst attacking the patent applications of the others. And this approach may also be seen to be backfiring in Europe. Eight of their European patents are in opposition and whilst the opponents are mainly anonymous, it is likely that the other parties in the early CRISPR/ Cas9 patent landscape are amongst the opponents. A preliminary and non-binding opinion issued by the Opposition Division of the EPO on one of these oppositions (an opposition to EP 2771468) implies that a number of the granted patents will be severely restricted or revoked during opposition, as the opponents highlight that the formal requirements to be entitled to their earliest filing date have not been met by the patentee. In the US, the situation is just as contentious; the patent interference between the Broad Institute and UC Berkeley over who was the first to invent CRSIPR/Cas9 as a gene-editing tool for eukaryotes has been ongoing, and the decision announced in February 2017 is currently being appealed. Back in August 2016, the legal fees spent by Editas alone (a company having an exclusive licence Summer 2017 Volume 9 Issue 2


Regulatory & Marketplace for human therapeutics aspects from the Broad Institute) on the CRISPR patent battles was reported to be $10.9 million. This will have increased significantly since then. Furthermore, there are similarities between obtaining patent protection for CpG oligonucleotides and for the guide sequences used in the gene editing process. The guide sequence is an RNA sequence which contains a portion of around 20 nucleotides, which is designed to hybridise to a target sequence which you wish to edit. Like CpG oligonucleotides, not all guide sequences are created equal; for example, different guide sequences having different rates of deleterious off-target effects. When CRISPR/Cas9 emerged as a gene editing tool, there seems to have been a follow-on race to seek protection for specific guide sequences which may have utility in human therapeutics. The need to speedily file patent applications to attempt to get protection for guide sequences for use in their treatment of specific diseases has inevitably resulted in many of the patent applications being filed too early, creating problems that will make their prosecution to grant extremely difficult. Whilst the CRISPR patent landscape is still evolving and appears murkier than for CpG oligonucleotides, there may be lessons to be learnt from history. At some point there will be a need for collaboration between the parties involved, whether by cross-licensing between the parties or agreements to areas of therapeutics which each may work within. MPEG-LA has invited the parties involved to consider pooling their foundational CRISPR patent rights under a single non-exclusive, cost-effective, transparent licence on 25 April 2017. It remains to be seen if the parties would be willing to pool their patents under such terms, given the advantages of exclusivity when seeking to provide new medicaments. However, perhaps as with CpG oligonucleotides, we will eventually see some form of collaboration between the parties, which may be to the advantage of all. www.ipimediaworld.com

Craig Thomson Qualified European, UK and Irish Patent Attorney and has considerable experience in providing pragmatic, commercially focused advice to a wide-range of clients and in relation to biotechnological, pharmaceutical and chemical inventions. As well as patent drafting and prosecution, Craig advises on the development of company-wide IP strategies, preparing for or carrying out funding/ acquisition due diligence, and advising on aggressive/defensive strategies in relation to third party IP. Email: cthomson@hgf.com

Cath Coombes Commercially minded European and UK Chartered Patent Attorney with over a decade of experience focussing on the life sciences field. She has particular interest and considerable experience in securing and upholding patent protection relating to CRISPR technology, as applied to bacterial systems and, more recently, as a gene editing tool. The transformation of CRISPR systems from their natural function as part of adaptive bacterial immunity to a tool kit to carry out site specific modifications in eukaryotes has led to an explosion of new applications for such technology. Cath provides a depth of knowledge from working in this highly contentious and constantly evolving field. Email: ccoombes@hgf.co

INTERNATIONAL PHARMACEUTICAL INDUSTRY 23


Regulatory & Marketplace Navigation of Key Regulatory Information for Efficient Life-cycle Management of Regulated Product & Application in Singapore Developing an innovative healthcare product (a drug or a biologic, or a medical device) from the proof-ofconcept stage to the marketing stage is an expensive and complex process. It involves many years of research and development work. To save time and money in bringing products to market, product development activities should be conducted in accordance with the related regulatory requirements. These requirements can update development activities and help you to manufacture a product that meets the regulatory standards of your targeted jurisdiction(s); that is, a quality product that is safe and effective for its intended use. Although information on the regulatory requirements (e.g. laws, guidance documents, international standards) for healthcare product development is readily available, navigating the regulatory system is not simple, and it gets even more complex when dealing with multiple jurisdictions. To help entrepreneurs who are developing healthcare products, the primary aim is to facilitate the regulatory understanding that governs product development and ensures regulatory compliance. It can be used as a starting point to assist you in developing your product. Rather than serving as a compilation of regulations, the guide discusses the fundamental concepts and principles in regulatory affairs. It gives entrepreneurs a road map to follow.

standards of your targeted authority/ ies; that is, a quality product that is safe and effective for its intended use. Although information on the regulatory requirements (e.g., laws, guidance documents, international standards) for healthcare product development is readily available, navigating the regulatory system is not simple, and it gets even more complex when dealing with multiple authorities. Drug regulatory authorities are being established in various countries across the globe. The regulatory body ensures compliances in various legal and regulatory aspects of a drug. Every country has its own regulatory authority, which is responsible for enforcing the rules and regulations and issuing the guidelines to regulate the drug development process, licensing, registration, manufacturing, marketing and labelling of pharmaceutical products.

D ev e l o p i n g a n i n n o vat i v e healthcare product (a drug or a biologic, or a medical device) from the proof-of-concept (idea to demonstrate) stage to the marketing stage is an expensive and complex process. It involves many years of research and development work.

Regulatory authorities and organisations are responsible for effective drug regulation required to ensure the safety, efficacy and quality of drugs, as well as the accuracy and appropriateness of the drug information accessible to the public. For accessing the drug-related information, one needs to know where the regulated information, i.e. Act / Regulations / Guidance, are parked on the regulatory websites. Then, for getting the right information, one needs to know the right information is parked at particular regulatory websites.

To save time and money in bringing products to market, product development activities should be conducted in accordance with the related regulatory requirements. Following these requirements can streamline development activities and help you to manufacture a product that meets the regulatory

This can be accessed by the help of a “navigation pathway� to get regulatory approval from a particular agency. We need to file an application for a particular product and that is submitted to their particular agencies, to market their products and ensure that the products are safe and effective to provide healthcare

24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to individuals around the world. So we need a particular navigation pathway for particular applications or drug products. Implementing a robust regulatory information management (RIM) solution offers a relatively straightforward solution to myriad complex issues. Regulatory agencies have become more safetyconscious and demand more data and regulatory information management (RIM), which leads to increased demand for the navigation pathway. The major challenges of regulatory authorities and organisations around the world are to ensure the safety, quality and efficacy of medicines and medical devices, harmonisation of legal procedures related to drug development, monitoring and ensuring compliance with statutory obligations. If you are not familiar with the healthcare product development lifecycle, please refer to the flowchart given below: Summer 2017 Volume 9 Issue 2


Regulatory & Marketplace

Step

1:

Classify

the

healthcare product

Step 2: Identify the healthcare

Step 3: Determine the

claim and/or product label

healthcare market

\ Step 4: Develop the regulatory strategy

Step 5: Establish the product development plan

Step 6: Execute the product

Step 7: Execute

Prepare

for

a

pre-

development plan

the clinical plan

submission meeting to support the CTA

Step 8: Collect the data for

Clinical

regulatory submission

application Prepare

for

support 10:

Ensure

pre-

submission meeting to

Step 9: Collate the data for regulatory submission

Step

a

trial

Advantages of Navigation Pathway •  Providing an applicant / regulatory expert on the website with the most descriptive path to application / regulatory information is one of the easiest ways to ensure they don't get confused while preparing a regulatory application / dossier.   •  If websites are to attract application / application services, they need easy browsing experience, then the path of navigation of the website will be the main factor in the website design and development process. •  The navigation pathway not only benefits the applicant but also benefits the agency stakeholders, i.e. industry and agency.

licensing

application

post-marketing

surveillance Flowchart to understand development of a healthcare product

Singapore: Factsheets SINGAPORE-MEDICINAL PRODUCTS-CTA REGULATORY FACTSHEET PRODUCT

Medicinal Products

COUNTRY

Singapore

TYPE OF APPLICATION

Clinical Trial Application

LIFECYCLE PHASE

R&D

REGULATORY DEPARTMENT

Science Medicine Health

REGULATORY AGENCY

Health Science Authority

REGULATORY CLASSIFICATION

Medicinal Products

INTRODUCTION •  The Clinical Trials Branch of the Health Sciences Authority has regulatory oversight of clinical trials on medicinal products conducted in Singapore, through evaluation of clinical trial applications, monitoring of clinical trial safety and conduct of GCP inspections. •  Clinical trials on medicinal products conducted in Singapore are regulated under the Medicines Act and its subsidiary legislation.

WEBPAGE CONTENT The webpage of the clinical trials in health science authority concisely describes the overall requirements of a clinical trial application. •  Introduction to clinical trials

• Regulatory guidance

•  Regulatory framework

• Clinical trial register

Introduction to clinical trials: •  A clinical trial is a research study conducted to investigate new treatments such as a new drug compound in human volunteers or research participants. •  Each clinical trial is designed to learn about a potential treatment and its effect on humans. Regulatory framework:

•  Under the Medicines (Clinical Trials) Regulations, a clinical trial certificate (CTC) issued by HSA is required before a clinical trial of a medicinal product can be conducted.

www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 25


Regulatory & Marketplace Products (Clinical Trials) Regulations 2016 include

Therapeutic products

Health Products (Clinical Trials) Regulation

Medicinal products

Medicines (Clinical Trials) Regulation (Revised)

Clinical trials

the following: 1.  Introduction of a clinical trial authorisation (CTA) – clinical trial notification (CTN) system for clinical trials on therapeutic products (TP). 2.  Alignment on consent requirements for vulnerable subjects in accordance with the Mental Capacity Act. 3.  Refinement of labelling requirements for investigational products (IP).

GUIDANCE DOCUMENTS: Sl No.

Current Guidance

Updated Guidance

01

Guideline on Application for Clinical Trial Certificate (CTC)

Guidance on Regulatory Requirements for New Applications and Subsequent Submissions

02

Guideline on Establishment of Refined Workflow for Multi-site Investigator Initiated Trials (IITs)

Guidance for Multi-site Investigator-initiated Trials

03

Guideline on Application for Import of Clinical Trial Test Materials (CTM for Drugs)

Guidance on Clinical Research Materials

04

Guideline for Clinical Trial Advertisement/Recruitment Programme

Guidance is removed

05

Guideline on Extension of Clinical Trial Certificate (CTC)

Guidance is removed

06

Guidelines on Serious Adverse Events (Drug-Related and Unexpected) Reporting in Clinical Drug Trials

Guidance on Serious Adverse Events (Drug-Related and Unexpected) Reporting in Clinical Drug Trials

Guideline on GCP Compliance Inspection Framework

Guidance on GCP Compliance Inspection Framework

08

Guideline on Alternative Measures for Investigational Product Management for Investigatorinitiated Trials

Guidance on Alternative Measures for Investigational Product Management for Investigatorinitiated Trials

09

Guideline for Investigational Product (IP) Repackaging on Site

Guidance for Investigational Product (IP) Repackaging on Site

07

REFERENCE LINK: QUALITY ACCREDITATION: Type of Certificate

Current Guidance

Updated Guidance

GCP

Guideline on GCP Compliance Inspection Framework

Guidance on GCP Compliance Inspection Framework

GCPhttp://www.hsa.gov.sg/content/hsa/en/Health_Products_Regulation/Clinical_Trials/Overview/Regulatory_Guidelines.html NAVIGATION PATHWAY:

HSA Clinical Trial Application Navigation Pathway REFERENCE LINK: http://www.hsa.gov.sg/content/hsa/en.html

26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2017 Volume 9 Issue 2


Regulatory & Marketplace SINGAPORE-MEDICINAL PRODUCTS-NDA REGULATORY FACTSHEET PRODUCT

Medicinal Products

COUNTRY

Singapore

TYPE OF APPLICATION

New Drug Application

LIFECYCLE PHASE

MAA

REGULATORY DEPARTMENT

Science Medicine Health

REGULATORY AGENCY

Health Science Authority

REGULATORY CLASSIFICATION

Medicinal Products

INTRODUCTION •  The NDA application is the vehicle through which drug sponsors formally propose that the HSA approve a new pharmaceutical for sale and marketing in Singapore •  The data gathered during the animal studies and human clinical trials of an Investigational New Drug (IND) become part of the NDA. TYPES OF APPLICATION

NDA-1 NDA

NDA-2 NDA-3

NDA-1: For the first strength of a product containing a new chemical or biological entity NDA-2: For the first strength of a new drug product

1.  containing a new combination of registered chemical or biological entities; 2.  containing registered chemical or biological entity(ies) in a new dosage form (e.g. tablets, capsules, injectables), new presentation (e.g. single-dose vials, multidose vials, pre-filled syringe) or new formulation (e.g. preservative-free); 3.  containing registered chemical or biological entity/ies for use by a new route of administration; or 4.  containing registered chemical or biological entity/ies for new indication(s), dosage recommendation(s) and/or patient population(s). NDA-3: For subsequent strength(s) of a new drug product that has been registered or has been submitted as an NDA-1 or NDA-2. The product name, pharmaceutical dosage form, indication, dosing regimen and patient population should be the same as that for the NDA-1 or NDA-2.

GUIDANCE DOCUMENTS: Sl No.

01

Current Guidance

URL Website

Guidance on Therapeutic Product Registration in Singapore

http://www.hsa.gov.sg/contentdam/HSA/HPRG/Western_Medicine/Overview_ Framework_Policies/Guidelines_on_Drug_Registration/DR_Guide_2016/ Guidance%20on%20Therapeutic%20Product%20Registration%20in%20 Singapore%202016.pdf

DOCUMENTS SUBMITTED: DOCUMENTS

LOCATION IN

MODULE REQUIRED FOR

ICH CTD

ACTD

Full NDA

Abridged NDA

Abridged NDA

Administrative Documents

Module 1

Part I

Yes

Yes

Yes

Common Technical Document Overview and Summaries

Module 2

Incorporated in Parts II, III & IV

Yes

Yes

Yes

Quality documents

Module 3

Part II

Yes

Yes

Yes

Non-clinical documents

Module 4

Part III

Yes

ICH: No ACTD: Overview only

ICH: No ACTD: Overview only

Clinical documents

Module 5

Part IV

Yes

Study report(s) of pivotal studies and synopses of all studies (Phase I-IV) relevant to requested indication, dosing and/or patient group

Study report(s) of pivotal studies and synopses of all studies (Phases I-IV) relevant to requested indication, dosing and/or patient group

CHECKLIST http://www.hsa.gov.sg/content/dam/HSA/HPRG/Western_Medicine/Overview_Framework_Policies/Guidelines_on_Drug_Registration/DR_ Guide_2016/Appendix%202A_Application%20checklist_ICH%20CTD_NDA_GDA.pdf NAVIGATION PATHWAY:

REFERENCE LINK: Quality Accreditation GMP: http://www.hsa.gov.sg/content/dam/HSA/ HPRG/Manufacturing_Importation_Distribution/ Audit%20and%20Licensing%20of%20 Manufacturers/GMP%20Conformity

HSA New Drug Application Navigation Pathway REFERENCE LINK: http://www.hsa.gov.sg/content/hsa/en.html

www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 27


Regulatory & Marketplace SINGAPORE-MEDICINAL PRODUCTS-GDA REGULATORY FACTSHEET PRODUCT

Medicinal Products

COUNTRY

Singapore

TYPE OF APPLICATION

Generic Drug Application

LIFECYCLE PHASE

MAA

REGULATORY DEPARTMENT

Science Medicine Health

REGULATORY AGENCY

Health Science Authority

REGULATORY CLASSIFICATION

Medicinal Products

Mr Abhishek B.V. PhD Research Scholar, Regulatory Affairs Group Department of Pharmaceutics, JSS College of Pharmacy, JSS University, Mysore. Email: abhibv07@gmail.com

INTRODUCTION • •

A generic drug application applies to a therapeutic product that contains one or more chemical entities. GDA is essentially the same with a current registered product with respect to its qualitative and quantitative composition of active ingredients, pharmaceutical dosage form and clinical indication.

Dr

TYPES OF APPLICATION

Balamuralidhara V.

There are two application types for a generic drug application:

GDA-1 GDA GDA-2

GDA-1: For the first strength of a generic chemical product. GDA-2: For subsequent strength(s) of the generic chemical product that has been registered or submitted as GDA-1. The product name and pharmaceutical dosage form should be the same as that for the GDA-1.

CRITERIA: The generic product must fulfil the following criteria: 1. the generic product is the same pharmaceutical dosage form as the Singapore reference product. However, different conventional oral immediate-release dosage forms (i.e. tablets and capsules) are considered to be the same pharmaceutical form; 2. the route of administration of the generic product is the same as the Singapore reference product; 3. the conditions of use for the generic product fall within the directions for use (including indication(s), dosing regimen(s) and patient group(s)) for the Singapore reference product; and 4. the generic product is bioequivalent with the Singapore reference product.

GUIDANCE DOCUMENTS: Sl No.

01

Assistant Professor, Regulatory Affairs Group, Department of Pharmaceutics, JSS College of Pharmacy, JSS University, Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India Email: baligowda@gmail.com

Dr Shenaz Z Khaleeli

Current Guidance

URL Website

Technical Director, Pharmaleaf India Pvt Ltd, Bengaluru.

Guidance on Therapeutic Product Registration in Singapore

http://www.hsa.gov.sg/contentdam/HSA/HPRG/ Western_Medicine/Overview_Framework_Policies/ Guidelines_on_Drug_Registration/DR_Guide_2016/ Guidance%20on%20Therapeutic%20Product%20 Registration%20in%20Singapore%202016.pdf

Email: shenaz.khaleeli@ pharmaleaf.com

DOCUMENTS SUBMITTED: DOCUMENTS

LOCATION IN

MODULE REQUIRED FOR

ICH CTD

ACTD

Abridged GDA

Verification GDA

Verification CECA GDA

Administrative Documents

Module 1

Part I

Yes

Yes

Yes

Common Technical Document Overview and Summaries

Module 2

Incorporated in Parts II

Yes

Yes

Yes

Quality documents

Module 3

Part II

Yes

Yes

Yes

Non-clinical documents

Module 4

Part III

Yes

ICH: No ACTD: Overview only

ICH: No ACTD: Overview only

Clinical documents

Module 5

Part IV

Yes

NAVIGATION PATHWAY:

Study report(s) of pivotal studies and synopses of all studies (Phase I-IV) relevant to requested indication, dosing and/or patient group

Study report(s) of pivotal studies and synopses of all studies (Phase I-IV) relevant to requested indication, dosing and/or patient group

CHECKLIST http://www.hsa.gov.sg/content/dam/HSA/HPRG/Western Medicine/Overview_ Framework_Policies/Guidelines_on_Drug_Registration/DR_Guide_2016 Appendix% 202A_Application%20checklist_ICH%20CTD_NDA_GDA.pd

HSA New Drug Application Navigation Pathway Pathway

28 INTERNATIONAL PHARMACEUTICAL INDUSTRY

GMP: http://www.hsa.gov.sg/content/dam/HSA/HPRG/Manufacturing_Importation_ Distribution/Audit%20and%20Licensing%20of%20ManufacturersGMP%20Conformity

Summer 2017 Volume 9 Issue 2


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Drug Discovery, Development & Delivery

DSC: A Sensitive Tool for Comparing the Stability of Biosimilars Growth forecasts for the global biopharmaceuticals market vary, but headline figures of close to USD 300 billion by the year 2021, rising from an estimated value of around USD 192 billion in 2016, are typical1,2. Furthermore, as patents on large molecule therapeutics expire, and in a regulatory environment that encourages the development of ‘generic’ versions, the market share attributable to biosimilars is expected to increase rapidly. Recent FDA Guidance to Industry3 sets out an abbreviated licensure pathway for biosimilars, focusing on therapeutic protein products. The foundation of the pathway is analytical studies demonstrating that the product is “highly similar” to an existing FDA-licensed biological product (“reference product”). While no single analytical technique can provide all the required data, many advances in instrumentation and data analysis have anticipated the complexities of working with large biological molecules in a commercial environment and have a role to play in supporting such applications.

Crucial to the success of a therapeutic protein product is its stability. This must be comparable in any biosimilar, and a variety of biophysical characterisation t e c h n i q u e s a re u s e d i n i t s a s s e s s m e nt . Howev e r, w h e n characterising thermal stability, a key attribute associated with the inherent conformational stability of a protein, one technique is regarded as the gold standard, and that is differential scanning calorimetry (DSC). This article examines the utility of DSC and its role in accelerating the development of biosimilars. Importance of Protein Stability In terms of a quality by design (QbD) approach to biopharmaceutical development, the stability of a candidate protein is a critical quality attribute because of its ability to directly impact clinical efficacy. Characterising stability is, therefore, a fundamental step in determining 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

‘developability’. There are many stages during the development and manufacture of a biopharmaceutical when a protein is stressed and prone to denaturation. During purification, for example, the protein may be removed from conditions where it is stable and active, while in production and/or formulation it may be exposed to the potentially denaturing effects of heat, chemicals, pH changes, pressure, mixing and high concentration. Furthermore, denaturation and other modifications can lead to aggregate formation, reducing efficacy and potentially triggering a dangerous immunogenic response in the patient. Proteins that are inherently stable are much less likely to be problematic during manufacturing, to lose functionality in formulation and storage, or to be prone to aggregation, thereby increasing the probability of a successful development outcome. Protein stability relates directly to protein structure, the most basic component of which is the linear sequence of amino acids in the polypeptide chain, otherwise known as the protein’s primary (1o) structure. Beyond this is the three-dimensional, or higher order structure (HOS), comprising secondary, tertiary and quaternary structure. A protein’s secondary (2o) structure refers to the local folding patterns of the primary structure and includes α-helix, β-sheet, turns and random coils. The tertiary (3o) structure is the final three-dimensional structure of the protein, arising from an array of secondary structural elements. Quaternary (4o) structures involve the interaction of two or more identical or different polypeptide chains. HOS guides protein function and is a key contributing factor to the quality, safety and efficacy of biopharmaceutical products. Verifying that HOS is maintained throughout manufacture is consequently a crucial aspect of product release.

HOS analysis is performed most commonly during early- and then late-stage characterisation of a protein, in comparability studies and in the ‘fingerprinting’ used for manufacturing support, especially for batch-to-batch comparability, as well as in determining biocomparability and biosimilarity. Regulatory Background for Biosimilars The drive to develop biosimilars is underpinned by the desire to increase access to biopharmaceuticals, while reducing healthcare costs. In 2010, the Biologics Price Competition and Innovation (BPCI) Act, part of the Affordable Care Act in the USA, created a new abbreviated licensure pathway for biological products that are demonstrated to be similar to or interchangeable with an FDA-licensed biological product. This parallels the long-established generics route for small molecule drugs, but while small molecule generics have active ingredients that are identical to the innovator drug, the complexity and inherent variability of biological materials and their production means that a biosimilar will never be an exact replica of the original product. There is a degree of protein variation even between batches of the same product, and this can include differences in post-translational modification and HOS. The FDA defines biosimilarity to mean “the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components and that there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product”3. Demonstrating biosimilarity requires wide-ranging physicochemical, analytical and functional comparisons of the reference protein and the biosimilar. In a 2016 paper explaining the “FDA’s Approach to Regulating Summer 2017 Volume 9 Issue 2


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Drug Discovery, Development & Delivery Biosimilars”4, the authors point to the foundation of a biosimilar development programme as being “an analytic similarity assessment that directly compares the structural/ physicochemical and functional properties of the proposed biosimilar with the reference product.” To obtain regulatory approval, additional non-clinical and clinical studies are also required, but these are informed by the analytical testing. The European Medicines Agency’s “guideline on similar biological medicinal products” 5 likewise recommends this stepwise approach, beginning with a comprehensive physicochemical and biological characterisation. This analytical characterisation of a biosimilar includes primary and HOS (secondary, tertiary, and sometimes quaternary) assessment, and the analysis of product and process impurities. The guidance documents are not prescriptive as to which analytical techniques should be used. However, when addressing the assessment of physicochemical properties, the FDA expects that appropriate analytical test methods will be selected based on the nature of the protein being characterised, its structure and heterogeneity, and those characteristics that are critical to performance. The value of orthogonal techniques in providing independent data to support a particular attribute is also highlighted. DSC is among the core analytical techniques used in biosimilar development to meet this need. DSC and What It Delivers DSC is a microcalorimetry technique that is widely used to characterise the thermal and conformational stability of proteins and other biopolymers. It directly measures the heat absorbed as a protein denatures with the application of increasing temperature, detecting the heat changes that occur when hydrogen bonds break and unfolding takes place. It can ‘see’ the unfolding of all proteins and all domains and requires no labels or probes of any kind. Regarded as a ‘forced degradation’ technique, DSC measures heat capacity (Cp) as a function of temperature. Protein in solution 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

is placed in the sample cell of the microcalorimeter and a matched reference cell is filled with buffer (Figure 1).

TM is considered a reliable indicator of thermal stability: the higher the TM, the more thermally stable the protein. Multi-domain proteins generally exhibit more than one peak on a DSC thermogram, allowing determination of the TM of different domains, as illustrated in Figure 3. DSC also delivers other parameters that are used to characterise and rank protein stability, including unfolding enthalpy (∆H), which is measured as the area under the curve, Tonset (see above), ∆Cp, the heat capacity change of unfolding, and T½, which is the width at half the peak height and is indicative of the shape of the unfolding thermogram. A full DSC analysis can therefore include determination of any combination of these parameters.

Figure 1: Thermal core of a differential scanning calorimeter

The calorimeter is designed to maintain both cells at the same temperature. As the cells are heated at a constant scan rate, the absorption of heat that occurs when a protein unfolds causes a temperature difference (∆T) between the sample and the reference cells. This results in a thermal gradient across the Peltier units of the microcalorimeter, setting up a voltage that is converted into power. This power is used to drive the Peltier to return ∆T to 0°C. The temperature difference between the reference and the sample cells is continuously measured and is calibrated to power units. As the applied temperature increases, the protein starts to unfold (Tonset) and the Cp increases (Figure 2).

Figure 3: DSC thermogram of a monoclonal antibody with CH2, Fab and CH3 domains identified. The dashed red lines are the deconvoluted peaks of each domain transition, with the three TM values indicated6

Via the measurement of these parameters, DSC is extremely sensitive to changes in HOS and it can therefore be used as a universally applicable HOS biophysical assay. Using DSC, it is possible to demonstrate that a biosimilar has a thermal stability profile ‘fingerprint’ and thermodynamic parameters which are highly similar to those of the reference product, supporting claims of equivalence. As the pace of biosimilar development steps up, so too does the evolution of

Figure 2: Output from DSC6 Summer 2017 Volume 9 Issue 2


Drug Discovery, Development & Delivery DSC instrumentation, with modern systems making measurement faster and more automated, and offering the capability to quickly and objectively interpret and compare thermograms for rapid feedback and high productivity comparability studies. Application to Biosimilars The natural variability of biological molecules and their sensitivity to production methods and conditions raises the question of what constitutes ‘similar’ or ‘highly similar’ biopharmaceuticals. In this still rapidly evolving field, continuing advances in the sensitivity and reproducibility of the analytical technology used are helping developers to become more exacting in their definitions and requirements. Examining the natural variability of the reference product is a prerequisite to developing a biosimilar, which must then fall within the same range. The more robust the data, the more it becomes possible to remove subjectivity from the equation.

DSC can be applied as a key assay in comparability and HOS analysis, from product evaluation during manufacture, through to

the comparison of protein variants and modified products, and the development of biosimilars. Using this technique, analysis of a protein in defined conditions is reproducible and quantitative if the protein is the same or highly similar (Figure 4), and data from DSC are now being used in regulatory support documents for both HOS characterisation of new drugs and in biosimilar submissions. Indeed, three of the four biosimilars approved by the FDA in 2016 included DSC as one of the HOS assays in their FDA filing6. An example of such DSC data is shown in Figure 5.

Figure 4: Nineteen DSC thermograms of bovine serum albumin6

Figure 5: DSC thermograms compared for reference drug Neopogen and its biosimilar Zarzio7

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Drug Discovery, Development & Delivery Manufacturers of the latest 21 CFR Part 11 compliance-ready DSC systems have made considerable strides in meeting the needs of biopharmaceutical development and manufacture, improving accessibility to the technique, reducing sample requirements and accelerating throughput. Importantly for biosimilar applications, advances in automated and quantitative analysis tools allow maximum information to be extracted from the data produced. Conventionally, TM and ∆H are used in comparing the thermal stability fingerprints of biosimilars with those of reference proteins. Gaining the additional ability to directly, quantitatively and objectively compare the shape of the thermograms allows the discernment of subtle differences in peak height and shape. This improves the sensitivity of DSC in detecting changes of HOS in a protein and, for routine analyses, offers the possibility of setting pass/fail criteria. Transferability of protocols means that HOS can be compared consistently from lab-tolab and site-to-site, right through to manufacturing. Hand-in-hand with the gains in reproducibility delivered by automation, these capabilities substantially enhance the value of DSC as a manufacturing support tool. In Conclusion As biosimilar development gathers pace, so too does the requirement for robust analytical tools. As well as the emergence of novel technologies, there is a significant focus on making proven characterisation tools even better fitted to the biopharmaceutical environment. DSC is the recognised gold standard technique for characterising the thermal stability of proteins and is widely used in biopharmaceutical development, from candidate selection through to manufacturing and the development of biosimilars. The latest advances in 21 CFR Part 11 complianceready DSC instrumentation allow direct and automated comparison of thermograms in a way that significantly enhances the technique’s use for fingerprinting and comparing biosimilars and reference proteins, for faster processing and improved productivity. 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

REFERENCES 1. Global Biopharmaceuticals Market Growth, Trends & Forecasts (2016 - 2021) https:// www.mordorintelligence. com/industry-reports/globalbiopharmaceuticals-market-ind ustry?gclid=Cj0KEQjwzpfHBR C1iIaL78Ol-eIBEiQAdZPVKgw noZx2V7UT8uJEEAojuBf9CoF4Mq2i_Jmd1ANsv0aAo5r8P8HAQ (Accessed 7 April 2017). 2. The Global Pharmaceuticals Market – Trends, Drivers and Projections (May 2015) http://www.strategyr. com/MarketResearch/ Biopharmaceuticals_Market_ Trends.asp 3. Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product. Guidance for Industry. April 2015. (Accessed 7 April 2017). https://www. fda.gov/downloads/Drugs/ ComplianceRegulatoryInformation/ Guidances/UCM291134.pdf (Accessed April 2017). 4. Lemery, S.J., Ricci, M.S., Keegan, P., McKee, A.E. & Pazdur, R. FDA’s Approach to Regulating Biosimilars. Clinical Cancer Review. December 2016. http:// clincancerres.aacrjournals.org/ content/early/2016/12/29/10780432.CCR-16-1354 (Accessed 7 April 2017). 5. Guideline on similar medicinal

products. European Medicines Agency. October 2014. http:// www.ema.europa.eu/docs/en_GB/ document_library/Scientific_ guideline/2014/10/WC500176768. pdf (Accessed April 2014). 6. Characterization of biopharmaceutical stability with Differential Scanning Calorimetry, Malvern Instruments (2016) http:// www.malvern.com/en/support/ resource-center/Whitepapers/ 7. John F Carpenter. Differential scanning calorimetry: robust and powerful physical characterization of therapeutic protein products. University of Colorado (2017) https://www.brainshark.com/ malvern/

Dr Lisa Newey-Keane The Life Sciences Sector Marketing Manager for Malvern Instruments, based at Malvern's head office in the UK. She holds a PhD in Microbiology/ Protein Biochemistry from the University of Birmingham, and her industry background is within contract manufacture and research, primarily for biopharmaceuticals and anti-infectives. Email: lisa.newey-keane@malvern.com

Summer 2017 Volume 9 Issue 2


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Advertorial

Systems Engineering for Complex Portable Drug Delivery Device Development Bill Welch, CTO, Phillips-Medisize Corporation explains how a systemsengineering approach provides an efficient method of developing smaller, smarter and more complex inhaler devices. With the ever-growing requirements for these devices, systems engineering can address the whole device system and reduce the risk of technical or schedule risk.

As the demand for complex, portable drug delivery devices continues to grow, reducing risk and increasing efficiency during the development of these products should be paramount. Taking a systems-engineering (SE) approach to development provides a holistic, organised and deliberate method for identifying, as well as reducing, both patient and business risks early in the process. When we talk about “smaller and smarter”, smaller relates to the patient expectation of devices engineered to be compact and portable in order to allow discreet usage and improve adherence. To take a look back 14-15 years at a well-known example, the Exubera dry powder insulin device was considered large and bulky and definitely not discreet. The system failed to gain acceptance among patients and physicians and was discontinued after a short period on the market. Meanwhile, if we take a look at some of the new inhalation devices that are reaching the market today, those that are electromechanical in nature, they are getting down to the size of a deck of playing cards and that is similar to the size of the mechanical-only devices. There are things in clinical trials today that are in that form factor. Being small in size does not guarantee clinical, regulatory and market success for the entire system, which of course includes the drug. However, getting the device down to the size of a mobile phone, which does have consumer acceptance, may translate into patient acceptance on healthcare devices. 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Addressing the “smarter” aspect, there are different dimensions of this to talk about, based on the device and the use needs. The first dimension of “smarter” is the creation of more intuitive devices – not necessarily electronic, but intuitive – that will help decrease patient error while increasing adherence, and also the desirability of the therapy in order to gain patient engagement. The second dimension is to improve the device’s primary intended function: more effective, targeted delivery of the drug and greater efficiency of delivery, such that less drug product is required to obtain the desired benefit. So this area provides cost savings that will support improvements in other parts of the system, such as the inclusion of electronics and software. This leads to the third and fourth dimensions of “smarter”. The third is the integration of electronics to improve functionality via an electromechanical delivery system. The big benefit of electromechanical systems, even not connected, is to be able to use sensors and software to time the delivery of a dose, rather than depending on a purely mechanical device with which, study after study show, there are adherence problems even with patients who make a sincere effort to follow the prescribed regimen. There are inhalers in clinical trials today that use electromechanical systems, and measure the patient’s tidal breathing, to potentially gain increased delivery effectiveness while protecting against device misuse. Then, the final dimension of “smarter” is wireless connectivity that allows the device to communicate – smartphone apps, cloud databases etc – to share information with both patient and caregivers to improve adherence. The latest inhalers on the market reflect the relentless industry-wide drive towards smarter, smaller and more portable drug delivery

devices. To ensure reliability and repeatability, however, such complex devices demand a greater number of requirements, as well as more testing and validation during their development, than do the larger, simpler devices of previous decades. In turn, they also carry with them greater technical and schedule risk. Applying systems-engineering to the development of these devices addresses the whole device system and determines the following features: •

• •

All subsystems (a discrete selection of components that work together to per form a function) that make up the full system Each subsystem-to-subsystem dependency All of the rules that will need to be drawn up in order for the subsystems to work together, or integrate The order in which those rules will be drawn up so that subsystem integration occurs correctly.

This approach differs from the traditional linear product development approach, typically in that it breaks the whole product idea into subsystems and – beyond simply establishing requirements for those subsystems – devises an order in which each subsystem must be defined. It also determines which dependencies between subsystems are needed for proper operation. Systems engineering requires both subsystem-specific engineers and the overall systems engineer, who focuses on establishing the requirements for the interactions and integration of the subsystems – that is, what makes the whole system work together. Systems Engineering Step by Step To kick off the SE process for a complex, portable inhaler, the user and stakeholder needs must first be determined by the client (the device company), then communicated to Summer 2017 Volume 9 Issue 2


Advertorial the product development (PD) team. Once the PD team has a firm grasp of what the client wants, the team members will typically brainstorm ways in which those wishes can be fulfilled. Illustration of Systems Engineering with an Automatic-dosing Inhaler The SE approach can be illustrated using a hypothetical, complex, portable drug delivery device: an automatic-dosing albuterol inhaler, which represents an upgrade of the traditional manually dosed albuterol inhaler. This mechanical upgrade features automatic dosing triggered by the user’s inhalation, as well as a dose counter that tracks the number of doses that have been administered. In early brainstorming, the team decided the order of operation would occur as shown in Figure 1. Several subsystems are present in the entire device, including canister design and drug formulation, user interface, drive-mechanism cocking, drive mechanism (spring), stem and opening, canister activation, dose-counter mechanism and an inhalation-activated trigger. Rather than jumping right to the creation of a total-product concept that incorporates all of these subsystems at once – thereby making it difficult to define what is critical about each subsystem and its components – the SE approach first establishes the individual subsystems, determines the links between them, prioritises those links, defines and tests in a logical order, and then finally, integrates the subsystems. Figure 2 depicts the links that have been established between the subsystems of the hypothetical automatic-dosing inhaler, along with how the links have been prioritised. As is illustrated, the PD team has determined that defining the requirements for the canister design and drug formulation are the most important, followed by the stem and opening from which the drug will exit the canister. These two subsystems and their interaction can then be studied on their own, independent of other variables, such as the drive mechanism. Subsystems 1 and 2 are used to define the requirements for subsystems 3, 4, and 5. www.ipimediaworld.com

Finally, Figure 3 illustrates the structured, deliberate manner in which integration of the inhaler’s subsystems occurs. Fig 1

Fig 3

device makers should have faith that the extra up-front costs required by SE will pay off in reduced risk, more timely development schedules and greater efficiency. Medical device makers that understand SEs’ high value should listen carefully to the language potential vendors use. Such SE terms as subsystem, integration, subsystem interactions, and systemlevel requirements and specifications indicate that the vendor’s SE approach is sound and credible. Additionally, when asked about how it approaches proof of concept, the vendor should be able to explain that its engineers work out the functional aspects of the device in question “on Fig 2

Advantages of SE While adopting an SE approach to product development does not totally eliminate development risk, it does reduce risk significantly. By defining each subsystem and specifying the order in which those subsystems must be characterised, troubleshooting during subsystem integration becomes more efficient and straightforward. Engineering teams can work backwards through the system, if needed, to determine where gaps may have occurred. Patients, ultimately, will benefit from a product that does not cause harm and that functions as intended, while the manufacturer will benefit from a timely product launch. “Learn early and inexpensively” is a useful mantra here: by focussing on subsystem- and system-level requirements during the proof-of-concept phase, the team will set up a solid foundation for the more expensive development work that follows. Understanding and Trusting Systems Engineering´s Value Although SE for complex portable drug delivery devices demands a greater expense up front, it is well worth it in the long run. A less-seasoned drug delivery device manufacturer that has no experience with problematic late-stage PD issues, for example, may not immediately understand the value of the SE approach. However, medical

the bench” first, rather than jumping straight to a fully integrated product concept. SE for Future Delivery Devices Healthcare products continue to shrink, feature greater connectivity and grow more complex. These trends are not going away, and the SE approach to development is the best choice for firms creating these devices. Delivery device manufacturers can stay current and competitive by taking the SE approach to product development for reduced user, patient, product, financial and schedule risk and improved PD lifecycle efficiency. Those who don’t, may find themselves falling behind.

Bill Welch CTO, Phillips-Medisize Corporation. Over 25 years of contract design, development and manufacturing experience, primarily serving customers in the drug delivery, health technology and diagnostics markets. In his current capacity as Chief Technical Officer at PhillipsMedisize, he leads a global, over-500 person development, engineering, tooling, program management and validation organisation with more than 75 concurrent schemes.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 37


Drug Discovery, Development & Delivery

Achieving Agility: Real Breakthroughs Belong to the Bold As the old adage goes, if you keep doing the same things it can’t come as a surprise when the outcome doesn’t improve. Organising data differently offers a way to change that, says AMPLEXOR’S Siniša Belina

It seems counterintuitive that life sciences companies should strive for operational agility and competitive inventiveness, when there are so many regulatory obligations to get past. Red tape is traditionally the enemy of nimbleness, an imposing barrier to innovation; to breaking the mould and doing things differently. It is hard to be responsive to new opportunities when there are so many is to be dotted and ts to be crossed. Yet the call to transform and innovate is clearly being heeded. Current merger and acquisition activity1 is a clear sign that companies are reviewing and honing their portfolios to stay ahead or establish an advantage. In an industry that, by necessity, moves so slowly (inventing and developing new medicinal products is hardly something that can be executed overnight), acquiring attractive product lines or promising start-ups, or merging with businesses that can fill emerging gaps, is organisations’ best bet at keeping pace with market change. For these investments to start paying their way, the process of absorbing those acquired entities needs to be smooth and efficient. Beyond structural and financial considerations, and branding realignment, product data from the merged lines needs to be assimilated. The vast majority of life sciences organisations are already struggling with huge volumes of data however, which is strewn across their operations, collected and used for a range of different purposes. With each merger or acquisition, this situation is further exacerbated, and data becomes even more unwieldy. 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

So if companies are to truly capitalise on their new ventures to get ahead of the curve, they need to get all of this data under control. The challenge for most companies is that there are so many different software tools, each using their own data set, to support a particular function and task. Not only does this singular application limit the return on investment of each software system, it also creates additional work if data needs to be re-used elsewhere – in manual re-entry, in de-duplication/checking it is the most up-to-date version of the ‘truth’, and in reformatting or data adjustments to meet the current need. Each new process takes time, costs money, and introduces new risk – of human error, for example, or that the information being used may be incomplete or out of date. All of which is likely to lengthen the time to market, and with it the time to market advantage and the time to revenue. 2017 Budget Priorities In almost every industry that is being digitally transformed or disrupted, it is data that provides the all-important differentiator – the key to new discoveries, insights and opportunities, and the ability to turn these into new services. The ability to collate, consolidate, cross-analyse and readily access and repurpose data is at the heart of some of the most ambitious and successful new business models – from Google and Facebook; to Uber and Airbnb; to IoT apps, including those involved in pre-emptive health monitoring. If exploiting data strategically was easy though, all businesses would be doing it. Yet information management is highly complex, particularly in life sciences, and bringing multiple sources together in an intelligible form is no mean feat. These might range from structured database files to spreadsheet entries, manual

notes, emails, and PDF scans or attachments. It is hard enough to combine these assets, let alone interrogate them reliably for the insights they might contain. If this wasn’t enough of a challenge, companies’ data alignment projects need a clear and specific driver and a robust financial case. The hope was that the regulatory requirements around IDMP would provide that, giving life sciences organisations the strongest reason yet to get their data assets in order. However, repeatedly shifting deadlines2 and a lack of specific enough guidance have caused companies to lose momentum with associated projects. Here was a chance to get everyone behind data transformation, and the benefits of a streamlined, consolidated, digital-first approach to product information – a chance to secure budget to put behind the big dream of transforming the way they manage data. Without a hard deadline and fixed terms to meet, however, upper management teams have become distracted, prioritising other more urgent projects instead. Lamentably, as companies take their foot off the pedal with IDMP and associated data transformation initiatives, they risk jeopardising their responsiveness to new opportunities because they will continue to lack the agility required to capitalise on them. The more pressing compliance issues which are consuming their attention in the meantime include updated EU pharmacovigilance legislation, which has brought about significant changes to electronic reporting requirements for suspected adverse reactions, to support better safety monitoring for medicines and a more efficient system for stakeholders. EMA aims to launch a new EudraVigilance system with enhanced functionalities in November 2017. New requirements include using the ISO/ICH E2B (R3) Summer 2017 Volume 9 Issue 2


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Drug Discovery, Development & Delivery data structure (an update from the current R2 format) for individual case safety reports3. In the US, eCTD (the electronic common technical document standard) continues to be a priority as electronic marketing submissions become the default4. eCTD requirements for submissions to CDER and CBER will come into effect on May 5 this year. From that date, new drug applications (NDAs), abbreviated NDAs (ANDAs), biologics licence applications (BLAs), and master files must be submitted using the eCTD format. A year on (from May 5, 2018), commercial investigational new drug applications (INDs) will also need to be submitted in this form. Following those deadlines, submissions that do not use eCTD will not be accepted. Beyond pharma, other life sciences sub-sectors including medical devices, cosmetics and food supplement manufacturers are also under increased pressure to get their product data in order. Here too now, regulatory bodies are placing more emphasis on electronic submissions and information management processes as part of their efforts to increase safety and improve traceability. As the affected manufacturers start to distance themselves from paperand spreadsheet-based information management, it makes sense that they look laterally at the wider opportunities this introduces, rather than buying into targeted, singlepurpose systems. Cloud Could Prove a Distraction Many of the more exciting innovation imperatives for life sciences involve dynamic collaboration through secure and strategic data-sharing with complementary service providers across the wider ecosystem or supply chain. This becomes easier once data is managed systematically across an organisation in such a way that supports multiple uses, including those not yet imagined. The point is that companies need to leave themselves open to the wider potential, rather than box themselves into a corner. The less of an IT legacy there is to begin with, the greater the 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

scope for companies to plan for the bigger picture. Changes in technology deployment models can help with some of this – cloud models, or centralised data management (which can be achieved virtually, without the need for data to all reside in one place) can make it easier to make data accessible and shareable across geographical locations, for instance, and to keep affiliate/small satellite operations in sync. But companies should not see the cloud as a panacea. Without some hard work and investment at a grass roots level, to get fundamental data in order so that it tells a story that can be relied upon (a consistent ‘truth’), and so that it is sufficiently accessible and intelligible to support decision-making, then whether or not companies harness the cloud to store it, amalgamate it, share it or analyse it will make very little material difference. In short, there is no avoiding the important groundwork. Without robust, complete, good-quality data that is captured, held, managed and accessed in a consistent and reliable way, any other investments, efforts, systems and processes will be undermined. This is why companies, in their drive to be more agile, need to return to the premise of IDMP and continue to focus on the spirit of the initiative, even while some of the final dictionary-definition detail is still being agreed. Why IDMP is Still the Best Guide of What to Aim For The vision of IDMP, and its standardised data formats, is to make the life sciences industry safer, more efficient, and more transparent and traceable. As a programme of change, it has implications for everything from pharmacovigilance and batch recalls to e-prescriptions and product shortages, with expected benefits for everyone concerned. The emphasis on high-quality master data aligns with every organisation’s need to more effectively manage all information considered to play a key role in the core operation of a business – data that can and should be re-used for multiple purposes. Although the latest timelines for IDMP compliance stretch into 2019, there

is much that life sciences companies could be doing now to get themselves into a robust, optimised position. In 2017, as firms review and replace older IT systems, they would do well to think laterally about what else they could be enhancing or adding, rather than merely looking for an improved like-for-like capability. What’s missing from that current system, and how might that be holding back productivity or performance? What are its limitations, and might there be another, better way of delivering what’s needed? Having time on their side before IDMP compliance becomes mandatory buys companies time to get the basics in order – those fundamental aspects of data management that are intrinsic to the ability to adapt, transform, innovate and deliver. Ideals to work towards include transforming information management from something that’s document-based to something that is data-oriented – i.e. from something static and relatively impenetrable to something more dynamic, granular, structured and searchable. A 100-page PDF, for example, would become something more componentbased, broken down, stored and recallable as a series of reusable information assets. ‘Data’-based information management makes it easier to observe, analyse and report patterns, and draw conclusions, without the need for someone to manually sift through and compare different content sources. It would mean companies are able to spot patterns in queries received from the authorities in relation to products or submissions, so that these could be pre-empted and delays avoided. As long as records of previous questions are confined to email trails or scanned letters, those trends will be far harder to identify and prepare for. Any time saved in responding to regulators and navigating the review and decision process increases a company’s speed to market, and time to revenue. Quick responses, and getting more marketing applications right first time, could take weeks or even months off the submissions process under a given procedure. Summer 2017 Volume 9 Issue 2


Drug Discovery, Development & Delivery As evident as the efficiency benefits might seem, the scenario painted above is far from the norm. Today, ‘good data’ scenarios are a rarity, accounting for less than 10 per cent of companies’ information management practices. In-house systems are typically proprietary, built internally to bespoke requirements, and a lot of content remains locked in static documents. This reality is a long way from the vision of a centralised, structured master data resource that people with an interest in quality and safety can access readily. Without an immediate compliance focus, it is somewhat forgivable that organisations have taken their eyes off the prize – after all, it’s probably a lot cheaper to get someone to go to the archives and open six months’ worth of letters than to invest in a data management project that would address all of this once and for all. But in the context of agility and market responsiveness, the existing and desired scenarios don’t bear comparison. As the industry takes stock of where it needs to be over the next decade, openness needs to play a key role: from openness to new ideas, business models and ways of doing things, to openness in data standards and data sharing. In an article published by World Economic Forum last year, Stephen Caddick, Wellcome Trust’s director of innovation, called for greater support for open innovation across life sciences – specifically a commitment to “sharing methodologies, data, hypotheses and outcomes” to enable faster progress1. But as long as companies remain wedded to legacy systems and processes, and fragmented data sources, it’s hard to see how things will move forward. REFERENCES 1. Life Sciences M&A boom is far from over as the industry deal market 'renormalizes', EY, May 2016: http://www.prnewswire. com/news-releases/life-sciencesma-boom-is-far-from-over-asthe-industry-deal-marketrenormalizes-300275615.html www.ipimediaworld.com

2. Implementation of ISO IDMP standards, EMA latest: http:// www.ema.europa.eu/ema/index. jsp?curl=pages/regulation/ general/general_content_000645. jsp 3. EudraVigilance change management, EMA: http://www. ema.europa.eu/ema/index. jsp?curl=/pages/regulation/q_ and_a/q_and_a_detail_000165.jsp 4. Electronic common technical document (eCTD), FDA: https://www.fda.gov/Drugs/ DevelopmentApprovalProcess/ FormsSubmissionRequirements/ ElectronicSubmissions/ ucm153574.htm 5. 9 innovations needed in life science, World Economic Forum, March 2016: https://www. weforum.org/agenda/2016/03/9ways-life-science-innovation-isabout-to-change/

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

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Clinical Research

Four Easy Steps to Site Optimisation To Get the Most Out of Investigative Sites, Go After the Low-Hanging Fruit

In today’s clinical development arena, clinical trial sponsors are expected to achieve more with less. The marketplace has become more competitive, regulatory standards are stricter with greater emphasis on trial oversight and patient safety, and study designs are becoming more complex, with the need for more endpoints to demonstrate product value. As there are 58% more sites per trial than five years ago,1 sponsors have more to monitor and manage to ensure trials stay on track and development programmes succeed.

In a trickle-down effect, sites are becoming saturated and overburdened, asked to tap into their investigator and patient resources for more and more studies in addition to their already busy clinical and patient care workload. As a result, many sites end up underperforming – with nearly 50% of sites failing to meet enrolment targets.1 These underperforming sites are not only expensive – such sites resulted in a wasted $2 billion in startup costs between 2006 and 20102 – they also extend study timelines and, in many cases, produce poor-quality trial data.

All of this can seem overwhelming, but many of these issues can be addressed via practical, easy-toimplement approaches that help investigative sites succeed – and can have dramatic and immediate impacts on a trial. Here, we discuss the opportunities that represent the “low-hanging fruit,” enabling sponsors to achieve the most with their sites at minimal cost and with little-to-no disruption to current operations. Identify the Most Productive Sites: Benefit from Historical Data Across Multiple Sponsors Although this might seem like a logical first step, it can often be difficult and time-consuming to determine which sites are most likely to successfully enroll patients and provide timely, quality data. Considering that it costs $30,000 for site initiation alone and, on average, 30% of clinical trial patients drop out,1 a site’s ability to enroll and retain patients can significantly affect trial costs. Many sponsors make site enrolment decisions based only on how a site has previously

performed on their studies. But, today’s advanced solutions enable sponsors to make these important decisions based on the investigative site’s historical performance across all studies from numerous sponsors. With the right solution and technology partner, sponsors can rely on algorithms based on behavioural and performance data that score a site’s historical performance relative to other sites using criteria integral to each study, including patient enrolment scores, site quality scores, site operational efficiency scores and site overall scores with indication and phase specificity. In this manner, site-specific study data – across all sponsors – are stored in a centralised, cloud-based repository that can be accessed with proper credentials from anywhere at any time. The comprehensive data set shows which sites have a proven track record for enrolment and patient retention per therapeutic area, giving sponsors a better foundation from which to make informed site enrolment decisions.

Figure 1: Easy-to-adapt technological implementations represent the low-hanging fruit in site optimization; delivering significant cost, time and data quality benefits with minimal investment and disruption. 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2017 Volume 9 Issue 2


Clinical Research

Train Sites Effectively: Improve Data Quality through Consistent Rater Training Even after enrolling the most productive sites, sponsors may still be faced with sites that don’t always perform as expected. Therefore, sponsors require more oversight capabilities throughout the entire trial to proactively identify sites that would benefit from additional training. Using traditional paper-based methods, sponsors must rely on site visits and monitors’ reports to identify underperforming sites. Paper lag time contributes to the detriment of the study timeline and budget — as much as an underperforming site. Using an electronic approach that integrates recruitment and data collection into a single view gives sponsors a leg up in actively monitoring sites to mitigate risks and identify site training needs in near real-time without the need for costly site visits. Progressive, consistent delivery of study-specific training improves data collection practices and is critical to study success. This is especially true www.ipimediaworld.com

for studies that require the collection of clinician-reported outcomes (ClinRO) and patient-reported outcomes (PRO) data, as inconsistent ClinRO and PRO measurements result in poor data quality and missing data, which may compromise regulatory submissions. Effective rater and subject training is a key contributor to therapeutic efficacy and/or safety as it ensures that each assessment is consistently administered across sites — a fact often overlooked by trial managers. The Food and Drug Administration (FDA), European Medicines Agency (EMA) and International Society for Pharmacoeconomics and Outcomes Research (ISPOR) recommend that site personnel (raters) and subjects capturing assessment data receive training in the correct use of each instrument (questionnaire), as well as training on the data collection device. Just as electronic data capture accelerates and improves ClinRO and PRO data collection accuracy, linking rater and subject training on the same data capture platform

enables a number of improvements in training quality, ease of use, cross-talk between eCOA and rater environments and single sign-on for both eCOA and rater functions. Rater training deployed on the study device or web can be accessed on-demand in proximity to the eCOA assessments, and gating can be used to restrict assess such that only trained raters or subjects can begin completing eCOA assessments. On-demand, interactive modular training that can be accessed in its entirety or as chapters to refresh proximal to a study visit is vital; it is especially helpful in solving the common time-lapse between investigator meeting, site staff turnover and first patient in. Automated quizzing for rater certifications and training are provided, including the maintenance of real-time rater reporting with certified, trained, remediated and/ or failed raters, including training expiration dates where applicable. Best of all, since electronic rater training is integrated into standard workflows, there is minimal disruption to site staff – allowing them to INTERNATIONAL PHARMACEUTICAL INDUSTRY 43


Clinical Research focus on maintaining efficient and consistent trial operations. Improve the Patient Experience through Electronic Clinical Outcome Assessments (eCOA): Increase Enrolment and Retention: Trial success relies on enrolling and retaining the right patients. However, the pool of trial participants is becoming smaller owing to the growing number of global trials, and there is increasing burden on sites to identify eligible patients for multiple studies. In addition, patient drop-out and non-compliance with the study protocol compromise data quality, extend study duration and increase costs. Engaging these patients and/ or their caregivers in the study is necessary for retention, particularly for those with debilitating diseases where frequent clinic visits are difficult. Unfortunately, accessing historical data to determine eligibility for each individual patient is not feasible and would be very resource-ineffective. Instead, a clear, up-front definition of patient eligibility criteria enables accurate, consistent measurements of those criteria during the enrolment process. The use of electronic enrolment, which is often based on validated, standardised tools and processes, reduces subjective eligibility assessments. During the start-up period, tech-based enrolment and its associated processes reduce both patient and site burden and can be tailored to the local environment and language – engaging patients well before they even consent to participate. Then, because electronic enrolment is typically recorded directly in a centralised database, all enrolment data are available to easily track recruitment progress. Once the right patients are enrolled, the next challenge is keeping them involved in the study. Designing assessments that are easy for patients to access, complete and submit can be accomplished through electronic clinical outcome assessments (eCOA). Through eCOA technology, sponsors can also effectively provide clear instructions and alerts on what to do and when 44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to do it, with patient portals enabling reminders, schedules and relevant educational content and training to keep patients engaged in the study. Other data capture technologies for cardiac, diabetic, respiratory and other clinical measurements simplify patient participation. These directto-patient technologies (e.g., devices, activity meters and sensors) transmit clinical-grade data directly to a centralised database that eliminates data transcription errors and ensures data completeness. Electronic assessment implementations facilitate tailoring to disease burden and translating to different languages. Even better, they eliminate human errors and increase data quality. Empower Sites: Provide the Ability to Collect and Manage Patient Performance and Compliance Data At best, paper-based data collection can provide clinical sites with preliminary study analysis within 60 days of study close. Whether the study has achieved appropriate power cannot be learned until after all data have been processed, limiting the site’s ability to intervene if necessary to make sure that all data are coming in as expected. Furthermore, patient safety is at risk because safety signals must be observed at the site visit or reported by the patient. Electronic data collection expedites intervention decisions relating to patient compliance or to improve patient safety. Sites gain greater autonomy and accountability for their study contribution with role-based permissions to access data collected. Standardised and/or customised reports and alerts can notify sites of patient non-compliance or lacking data, empowering sites to initiate appropriate remediation. This is an effective use of resources and essentially eliminates the middleman. Through electronic data collection, sites become true partners in study conduct and outcomes to help ensure the study’s success. Conclusion Investigative sites are critical study stakeholders and significantly contribute to trials that are on time,

on budget and continue to progress through the approval pipeline. Providing sites with the resources and tools they need to effectively recruit and retain patients and collect high-quality data can go a long way to improving a company’s competitive edge. The technological implementations described here represent the low-hanging fruit that, if reached for early, can replace current time-intensive, manual methods and deliver significant cost, time and data quality benefits to sponsors with minimal investment and disruption. Driving change in any organisation can seem daunting. But, if sponsors approach the site optimisation challenge with practical, step-wise improvements, they stand to realise significant benefits that will continue to accrue over time. REFERENCE 1.  Treweek, S. ‘Meeting the challenges of recruitment to multicentre, communitybased, lifestyle-change trials: a case study of the BeWEL trial,’ Trials. 2013; 14: 436. Published online 2013 Dec 18. doi: 10.1186/1745-6215-14-436 2.  Outlook Report: Tufts Center for the Study of Drug Development, Phase II & III Enrollment Performance on a multi-center study, Tufts University, 2014

Chris Neppes Product Manager, Site Optimisation, ERT. As Product Manager, Site Optimisation, Chris Neppes is responsible for ensuring ERT’s eClinical solutions reduce burden and enhance the investigate site experience during clinical trials, while ensuring sponsors can effectively select and train sites to optimize higher quality data collection and more effective clinical development. Email: chris.neppes@ert.com

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

LEADERS IN PHARMACEUTICAL ANALYSIS Telephone: +44 (0) 20 8977 0750 Email: info@butterworth-labs.co.uk Website: www.butterworth-labs.co.uk

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Clinical Research

Technology-assisted Cohort Optimisation of Early-phase Multi-centre Patient Studies The common aims of early-phase research centre around helping to define the safety, tolerability and pharmacokinetics of a drug at single or multiple doses (or even multiple formulations) typically administered in an ascending manner.

These early-phase studies are sometimes referred to as “cohort” studies as they are characterised by a relatively small number of subjects being enrolled at each dose or cohort across one or more sites. For example, a single ascending dose (SAD) study will classically enroll subjects in four to six independent cohorts in a sequential manner with each cohort being initiated following completion of data review at a certain time point of the current cohort; while a multiple ascending dose study may require even more cohorts. More recently, there has been an effort to ensure a seamless transition from single to multiple dose cohorts (SAD-MAD) within a single study often consisting of up to 10–12 cohorts across as many sites. Of note, some sites may be engaged early on in the enrollment process while others are activated in a staggered approach. Unlike studies seeking to enroll normal healthy volunteers at a single site, the majority of early-phase cohort studies in patient populations are conducted across multiple sites with the number of sites being dependent upon sample size, length and complexity of the study, and the recruitment potential of the indication of interest. For patient studies it is common for multiple sites to be engaged in the simultaneous enrolment of patients into a single cohort. Therefore, it is imperative to ensure the accurate and timely assignment of patients into each cohort while guaranteeing that all screened patients who are eligible for study participation are actually randomized, and that there is no chance of over-enrolment. This requires the centralised monitoring of rapidly changing recruitment efforts 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and notifying sites of fluctuating accrual speed and limits in real time. This monitoring may involve moving some patients from screening to randomisation, holding others back, and opening/closing recruitment across multiple sites simultaneously. Tasks such as these lend themselves to a technological solution such as interactive response technology (IRT). Much like interactive voice response systems (IVRS), IRT, sometimes called IWR for interactive web technology, uses the internet instead of the phone to serve as a gatekeeper and data tracker, and has obvious advantages over IVRS in terms of speed, accuracy and ease of use. Battling Recruitment Fatigue In early-phase drug development there are multiple strategies which may be employed to help ensure successful cohort study conduct all requiring a high level of data tracking and operational acumen. In order to be both efficient and successful, a unified approach must be undertaken not only to ensure that timelines are met but also that the study enrolls appropriate patients and yields high-quality data. Each study therefore requires a well-defined and unique strategy which can leverage enhanced technology to ensure rapid and proper enrolment of patients, the seamless collection of data, and the timely scheduling of safety review meetings complete with relevant outcomes in the most efficient manner possible1. These strategies can also be utilized to help combat recruitment fatigue as cohort studies across numerous patient populations often suffer from sluggish enrolment as site staff can become resistant to sponsor demands to repeatedly commence and halt their recruitment efforts. Additionally, site staff are particularly sensitive to situations in which a potentially eligible patient is actually overlooked due solely to the timing of cohorts or other procedural delays. This interruption in recruitment and

inability to randomise every eligible patient may result in recruitment fatigue, with poor and variable enrolment at a site that cannot be forecasted accurately. The Virtual Patient Waiting Room In an effort to increase the predictability of timelines, stabiliseenrolment fluctuations, master the timing and unpredictability of complex cohort designs, fight recruitment fatigue and ensure that all eligible patients who can be randimised actually are randomised, a technology-assisted “virtual patient waiting room” was created. This virtual waiting room permits investigators to recruit patients on an ongoing, rolling basis in a “next in line” approach that permits multiple sites to simultaneously enroll patients into a single cohort, while continuing to recruit for the upcoming cohorts. Patients recruited who meet eligibility criteria when randomisation is closed for a specific cohort are simply placed in the virtual patient waiting room while screening activities continue for the subsequent cohorts. This simple maneuver stabilises recruitment efforts and patterns such that sites do not have to be shut down and started back up multiple times. By utilising this strategy, the appropriate enrolment of each individual cohort can be more easily managed simply by proper programming of the IRT to ensure that all eligible patients are randomised, that there is no over-enrolment within the cohort, and that the time between cohorts is minimised. Importantly, forecasting important metrics such as last patient visit in each cohort can be easily achieved. As many sites requiring local IRB/EC approval take longer to start up, they are at a disadvantage in enrolment compared to sites who use central review; and utilising an IRT-assisted cohort optimisation strategy will permit an equal opportunity for all sites to enroll in a particular cohort despite regulatory disadvantages. Summer 2017 Volume 9 Issue 2


OFFERING DEEP INSIGHTS INTO KEY AREAS OF CLINICAL DEVELOPMENT Bioclinica is specifically structured to create clarity in the clinical trial process — so you can make better decisions.

eHEALTH SOLUTIONS eClinical Solutions Randomization & Trial Supply Management Safety & Regulatory Solutions Financial Lifecycle Solutions

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Clinical Research Advantages of IRT In addition, IRT can be utilised to successfully manage the appropriate dosing and often complex timing/ tracking requirements mandated per protocol. For instance, in a classic cohort study design which requires sentinel dosing, the first one to three patients dosed within each cohort are more strictly monitored to determine tolerability for a given time period prior to administration of the next dose. In this situation, the IRT can be designed to effectively halt enrolment not just within a site but across sites, to ensure that there is no additional enrolment until the requisite time period is met2. Additional “breaks” may be implemented to ensure that all safety parameters are observed, i.e. no further dosing proceeds until a one-week period has occurred following the dose of the nth patient in each cohort, depending upon study specifications. The IRT can simply restrict further randomisation until this or any time parameter is met. Cohort Modelling Importantly, information that is typically used to generate enrolment curves across an entire study can also be modelled to reflect a specific cohort, and this model can vary from cohort to cohort. For example, enrolment rates may be very low in the first cohort but peak by cohort number three or four as the “virtual waiting room” fills with appropriate patients. Screen failure rates also vary with cohort succession with the highest rates usually evidenced in the first cohorts and then continually declining over successive cohorts or until the investigators’ patient database is exhausted. These cohort metrics can be used to estimate the number of sites needed to enroll at any one time period, noting that not all sites need to be actively recruiting at the same time. For example, in a common SAD-MAD study of 10 cohorts enrolling eight patients per cohort (six drug and two placebo) it may be necessary to launch at least 12-16 sites overall, although only six to eight would be active at one time with three to four utilised for the last two cohorts only, especially if the last cohort is expanded in terms of sample size or treatment duration. It is important to note, however, that 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

those sites activated last should not be viewed as “back-up” sites as it is imperative that they are initiated and fully ready to screen early on in the timeline. Of course, using this IRT-assisted cohort optimisation strategy requires adding screen time for patients currently in the virtual waiting room, with an average screen time of 42-49 days recommended. The benefit of this increased screen time is that it allows patients to be in the virtual waiting room for longer periods of time and not be screen failed simply due to the screening time elapsing. Even though this recommendation of 42-49 days may be two to three times longer than the screen times in typical SAD/MAD studies, this time is more than recompensed over the length of the entire study conduct. In fact, our experience in a recent set of Alzheimer’s disease studies suggests that the use of the IRT-assisted cohort optimisation saves an average of 2.9 weeks per cohort. In a 10 cohort SAD-MAD study, the overall timelines were reduced by over six months compared to studies conducted using a standard approach to recruitment. Increased Safety Data Vigilance In addition to promoting continuous recruitment efforts across sites, IRT also permits increased data vigilance enabling more accurate and timely review of safety data. In cohort studies, a review of safety data is typically required prior to escalating to the next cohort and the parameters for the advancement to successive cohorts can be incorporated into the IRT specifications. For example, once the nth patient in a cohort completes a certain visit (nominally week four or six visit), the site is required to enter all data into the electronic data capture (EDC) system within 24 hours of the patient completing that visit. Haematology and chemistry lab results should be returned to the site minimally two days after being drawn and therefore would be available for monitoring by the designated site monitor and/or physician. The regional monitor could then plan their visit to the site two days after the patient completes the week four or six visit. This would ensure

that all relevant data is monitored, cleaned and available prior to the cohort safety review meeting. Once analysis of any pharmacokinetic, pharmacodynamics or biomarker variables have been completed, data management can run the appropriate patient profiles or listings required for the cohort safety review meeting. Examples of Cohort Optimisation An example of the benefits of optimising cohort management via IRT is evidenced by the recent conduct of two separate Phase I, doubleblind, placebo-controlled studies designed to establish the safety and tolerability of both single and multiple ascending dose(s) of blinded verum in patients with Alzheimer’s disease (AD) across similar SAD to MAD settings. A total of 80 patients for the first study, and a total of 57 patients for the second study, were enrolled across 10 dose-ascending cohorts for each study. Screen failure rates were 54% and 45%, respectively. For the first study, patients were enrolled across twelve sites in the US and Europe, while patients were recruited from nine clinical sites across five countries in Europe for the second study. For both studies, the main objective was to assess the safety and tolerability, and pharmacokinetics across SAD and MAD cohorts. Having appropriate Phase I facilities and experience, access to neurologic imaging centres, and familiarity with cerebrospinal fluid (CSF) sampling procedures were critical factors in the site selection process for both of these studies. One primary challenge shared by both of these studies was related to the method of cohort management and escalation requirements. The complex design of two component sub-studies (SAD and MAD) resulted in the implementation of a unique strategy to support study screening and enrolment activities and direct escalation to subsequent cohorts. Importantly, in one of the studies, patients were able to roll over from the SAD to the MAD cohort; and in the other study, patients that discontinued early were replaced rendering accurate tracking via IRT obligatory. In both studies, the project team worked closely with the IRT staff Summer 2017 Volume 9 Issue 2


Clinical Research to program and successfully leverage the technology necessary to support these trials, permitting vigorous and competitive enrolment to occur across multiple site simultaneously, and importantly providing an equal opportunity to enroll patients across selected cohorts. Cohort transition was determined by a series of programmable criteria based upon the unique protocol requirements. Medical monitoring staff were responsible for authorising dosing of patients within a cohort via electronic approval, while the project management staff were responsible for the activation and closure of given cohorts based upon the outcome of each safety review meeting via IRT. The combined efforts across all functional groups and implementation of this technology facilitated continuous study management in which recruitment into a fixed cohort of patients could be controlled centrally across multiple site locations. One key factor in the successful conduct of these cohort studies can be attributed to the speed and accuracy of data collection as well as efficient cohort management. The project team created a streamlined, effective process specifically tailored to these studies that was designed to facilitate an ongoing review of patient eligibility on the part of the study medical monitor.

Allison House Served dual roles at Worldwide Clinical Trials as Executive Director of Global Operations, Neuroscience and Director of Business Development. She received her B.S. in Biological Sciences from North Carolina State University. With a tenure of over 20 years within the clinical research industry, Ms House’s experience includes programmes in both CRO and pharmaceutical environments across all phases, with a specific focus upon studies of complex design, requiring innovative technological solutions. Email:  allison.house@worldwide.com

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Information was gathered from various data sources and compiled for easy review and confirmation of patient status. Ongoing details were provided to ensure patient wellbeing was maintained throughout the treatment period. Routine contact with sites coupled with a rolling data review resulted in the successful achievement of having over 90% of data clean at all times. This in turn permitted timely scheduling of the intra-cohort safety review meetings, saving even more time. Notably, a detailed written cohort management plan not only supported protocol compliance, the realistic opportunity for enrolment of eligible patients across sites, the consistency in patient visits, but also importantly the optimisation of the management of the various cohorts, saving time and costs while safeguarding patient safety and quality. Conclusion The ability to facilitate the uninterrupted recruitment of patients across multiple sites results in a continuous screening process, alleviating disruption in momentum and recruitment fatigue in cohort studies. This use of an IRT-assisted cohort optimisation strategy allows each site an equal opportunity to enroll patients, decreases burden upon sites by providing a tiered screening approach, and allows for more accurate study planning and

Natalia E. Drosopoulou Senior Director of Project Management in Neuroscience at Worldwide Clinical Trials who leads the International Clinical Project Management Team. She received her PhD in biochemistry, specialised in developmental neurobiology from King’s College of London. With over 16 years in the clinical research industry, Dr Drosopoulou’s experience spans from small intricate Phase I studies to large global Phase III programmes.

preparation for both patients and caregivers (i.e. accommodation for travel plans/vacations). Safety and data review committee functions are also managed within this technology driven methodology, yielding high quality data while minimising review timelines and transition between cohorts. In summary, the technology-assisted cohort optimisation strategy outlined above results in faster progression through cohorts while preserving study data integrity in early phase multi-centre studies saving both time and money. REFERENCES 1.  Morissey, M., Roberts, R., O’Gorman, B., Wells, D. Applying New Technology to Randomization, Cohort Management and Dosing in Multicentre Early Phase Trials. Applied Clinical. Trials, Jan 15. 2015. www. appliedclinicaltrialsonline.com 2.  Byrom B. Using IVRS in clinical trial management. Applied Clinical Trials. 2002; 10: 36-42

Henry J. Riordan is Executive Vice President of Medical and Scientific Affairs and Global Lead for Neuroscience at Worldwide Clinical Trials. Dr Riordan has been involved in the assessment, treatment and investigation of various CNS drugs and disorders in both industry and academia for the past 20 years. He has over 100 publications, including co-authoring two books focusing on innovative CNS clinical trials methodology. Email: henry.riordan@worldwide.com

Email: natalia.drosopoulou@ worldwide.com

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Clinical Research

HCP Engagement in a Multichannel World: Why Quality Customer Data is Critical Quality customer data is foundational to commercial operations, and yet most European life sciences companies are not getting what they need from their customer data. That’s why 78% of organisations have data quality initiatives or will within the next two years, according to a new survey. But as the industry seeks to improve customer engagements through personalised multichannel interactions, the pressure is on for better quality, more granular customer data.

In the era of personalised medicine and rapid drug innovation, sales and marketing teams are challenged to get the right information through the right channels at the right time to healthcare professionals (HCPs). At the same time, rep access to HCPs is changing. For example, the Global Data Protection Regulation (GDPR), which comes into effect in May 2018, will place much greater emphasis on consent to receive marketing data. Life sciences companies are constantly navigating evolving regulations to stay compliant. The result is that the ability to reach, educate, and inform HCPs

50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

is getting more complicated and difficult. Consequently, the industry is focused on improving engagement with HCPs through more personalised interactions. Delivering relevant content, in a timely manner, via the right communications channels is the new imperative. Of course, detailed, up-to-date customer data is crucial. The right customer data in the right people’s hands means more effective and more efficient pharmaceutical sales teams. But getting that customer data right in the first place is no easy task. In fact, 87% of respondents in the recent Veeva 2016 European Customer Data Survey say they face customer data quality challenges. Sales reps often have wrong addresses, don’t know which HCPs to contact, or have outdated data about a physician’s speciality and licence status. Data quality is an important issue – and one that is being taken seriously by the industry. Today, nearly three-quarters of life sciences companies either have customer data quality initiatives in place or will within the next two

years. Quality customer data is now widely recognised as key to effective commercial execution, so the need to improve customer data quality has climbed in priority on the corporate agenda. For years, the industry has had access to customer data from a range of sources, both internal and external. However, it’s often quickly outdated. Physicians frequently move practices or hospitals, and these changes are difficult to keep current. Today it takes around 10 days for a data-change request to be processed; however, the majority of companies say four days would be acceptable. More than two-thirds want customer data-change requests actioned within one day. Inaccurate or incomplete customer data is not only a commercial hindrance, but also a compliance risk. For life sciences organisations, having a complete, real-time view of their customers is critical for meeting European physician payment-transparency requirements stipulated by the European Federation of Pharmaceutical Industries and Associations (EFPIA). Companies

Summer 2017 Volume 9 Issue 2


Clinical Research without streamlined, Europe-wide systems to track and aggregate spend at the HCP level will struggle to accurately report regional and local HCP engagement activity. However, less than half of the life sciences companies surveyed say they are satisfied that their customer data provides a complete and real-time customer view. The problem is twofold: volume and infrastructure. In today’s hyper-connected world, customer data is everywhere. Every department – from sales to medical affairs to marketing – routinely collects customer data. But it is not only the volume of customer data that is growing; so is the number of stakeholders and channels used to engage them. Accurate, quality customer data is crucial, yet all too often the industry struggles to efficiently consolidate and analyse it. There is simply too much information for even the most experienced operator to absorb, comprehend, and quickly act on. Many life sciences companies still rely on a variety of methods to source and manage their customer data. Just less than half of organisations solely source and manage their customer data in-house, while just over one-third rely on a blend of in-house and third-party sources. But the complexity of maintaining current and accurate customer data puts a burden on organisations to manage customer data themselves. The industry trend is more towards outsourcing customer data, as 57% of life sciences companies now rely on third-party vendors to supply their customer data. The current infrastructure to manage customer data is often a patchwork of disparate data systems and siloed organisational structures. With multiple systems working in isolation, the most recent information and intelligence are not evenly shared across the company. There is no single version of the “truth” about the customer. Without complete, up-to-date customer data accessible from one source, different departments of the same company might inadvertently www.ipimediaworld.com

contact a customer several times, leading to brand fatigue at best and damage to the company’s reputation at worst. For sales and marketing to be truly effective, it is vital to precisely coordinate outreach and determine what message to send, when, and through what channel to each individual HCP. Quality data must be quickly accessible. This is where the industry is demanding that customer data is seamlessly integrated into CRM systems so reps can focus on what matters the most: productive engagement with HCPs. In fact, 68% of respondents say integration of customer data with current systems, including CRM, is a key factor in selecting a third-party data vendor. With real-time access to accurate, up-to-date customer data, reps are more likely to use their CRM systems. And as companies seek to leverage the power of digital communications channels, the need for more granular customer data is only increasing. Digital engagement means life sciences companies can increasingly reach and deliver more relevant, tailored information. But that, of course, relies on more detailed customer and email data. Currently, less than half of life sciences companies can uniquely identify customers across systems and geographies, more than two-thirds of respondents say they will need greater segmentation in the future, and more than half cite customer email data as a key future requirement. Across the industry, the drive is on to improve customer data quality. While the desire is to improve customer engagement through multichannel communication, there is still a gap between where the industry is and where it wants to be. More life sciences companies realise their approaches to customer data must change if they wish to increase personalised multichannel communication with HCPs. Life sciences may well be in the process of digital transformation, but customer data still lags behind.

State of Customer Data Today Key Findings from the Veeva 2016 European Customer Data Survey • The majority of respondents (73%) say that having a complete and real-time view of the customer is a top customer-data priority, while less than half (40%) say they are satisfied that their data provides this view today. • Only half (50%) say they are satisfied with the quality of their data in general. • The speed at which data changes are processed is a major limiting factor to data quality, with the average reported time being 10 days to process data-change requests, compared to an average desired time of four days. • More than four out of five (87%) say they face challenges to improve customer data quality, citing key reasons that include data-vendor limitation (41%) and siloed data across multiple systems (38%). • The industry is moving towards improving the quality of customer data, with 78% of respondents noting that they have a customer data-quality initiative under way, or will within the next two years. • Respondents are looking for much more from their customer data in the future. Seventy per cent say they need more detailed segmentation of customers, while 58% say they need email addresses for HCPs.

Guillaume Roussel As Director of Strategy for Veeva OpenData in Europe, Guillaume Roussel brings with him more than 15 years of experience within the life sciences industry, and the perspective born of a truly international career. With his unique experience spanning life sciences, information technology, business development and healthcare compliance, Guillaume is set to drive the industry towards greater transparency, agility and global harmonisation by delivering a world-class master-data solution to the cloud.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 51


Technology

Will Graph Database Technology Uncover Pharma’s Hidden Insights? Neo Technology’s Emil Eifrem looks at how life science researchers can probe large datasets efficiently and expose new insights with the unique power of graph technology

By definition, medical research is about dealing with large quantities of data. That’s even more true in the leading edges of the life sciences where tackling the thorny issues in genomics and personalised treatments has to take place at the petabyte and increasingly the exabyte, rather the mere megabyte and gigabyte level, in terms of promising dataset size. With Big Data one also has to assume that’s going to be less structured information. So Big Data life science research demands we go beyond the simplistic managing, analysing and storage of data – which means we have to take a hard look at the tools we’ve historically used to model data, namely SQL and relational database technology. That’s because traditional relational database methods struggle with the sheer volume, as well as the unstructured nature, of the data we want to work on. But a realistic answer is emerging in the shape of graph databases. An approach opened up by social web giants Google, LinkedIn and Facebook, graph database technology is an approach based on the insight that when it comes to data, it’s the relationships that are all-important and of interest to the researcher. The power of graph databases recently came to the world’s attention due it being behind the world’s largest investigative journalism project, The Panama Papers [https:// panamapapers.icij.org] – a probe of a 2.6 terabyte dataset that would not have been possible using traditional database means, says the global team of researchers that mounted it. 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Limitations of SQL In fact, the Panama Papers is the biggest data-based investigation so far conducted, and the body that led it, the ICIJ, has stated that, “It wasn’t until we picked up a graph database that we started to really grasp the potential of the data.” Investigators like the ICIJ are among many who say that graph databases are not only great at handling a lot of data, but are uniquely able to uncover the patterns difficult to detect using SQL-based rdbms (or even other approaches, like NoSQL and Hadoop). The reason is that the high-volume, highly-linked dataset the Panama Papers represent is too hard for SQL to easily work with. That’s an issue of fundamental architecture. Relational databases model the world as a set of tables and columns, carrying out complex joins and self-joins to action queries when the data becomes more inter-related. But the interesting questions we need to ask in areas like the life sciences are technically challenging to construct and expensive to run in this form, while making them work in synchronous time is a challenge, with performance degrading as data volume increases. The relational data model also doesn’t match our mental visualisation of the application (technically defined as “objectrelational impedance mismatch”). As people, we instinctively like to model connections between data elements visually, creating an intuitive model as we whiteboard a problem – so attempting to take a data model based on relationships and forcing it into a tabular framework, the way a data platform like Oracle asks us to do, creates a needless disconnect that can waste time and potentially miss useful patterns and leads.

Relationships in Data Conceal Possible Insights By contrast, the USP of graph database technology lies in discovering relationships between data points and understanding them – and at huge scale. That’s why it is ideal at allowing the medical researcher to uncover hidden patterns when they are looking at the hard problems out there, like new molecule research and big clinical trial work. Medical and Pharma Use Cases of Graph Technology Emerging with Greater Rapidity Tim Williamson, a data scientist at Monsanto whose role focuses on coming up with ways to help the firm get better research inferences out of genomic datasets, is a graph database convert. He says that his team had previously managed its data problems in a classical, relational way. However, “Every question we would want to ask needed lots of real-time analysis to be run and it would take us seconds to minutes to hours to perform one round of analysis, which doesn’t scale.” Monsanto is continually researching the best possible plant varieties and what genetic traits cause them to thrive in different climatic and environmental conditions. There are genetic problems that rely on being able to treat a dataset as an ancestor family tree. Williamson discovered that these family tree datasets naturally have a graph structure – and it was really easy to write graph queries instead. Now, he says, analysis that used to take minutes or hours took seconds. “This was really cool, because then we could do it across everything; I could ask the same question of several million objects instead of one at a time.” Summer 2017 Volume 9 Issue 2


Technology That frees Williamson and his team to make abstractions around important genetic features, such as which plant ancestors continually form the most productive cross-breeds. That means the biotech leader is starting to get much quicker at spotting which plant varieties are the most productive, so the firm can spend its resources researching those rather than less promising options. Another great graph medical research example is the EU FP7 H O M AG E c o n s o rt i u m [w w w. homage-hf.eu], which is all about early detection and prevention of heart failure. Working with a dataset from 45,000 patients from 22 cohort studies covering patient characteristics, clinical parameters such as medical history, electrocardiograms and biochemical measurements, all this great data is now being connected with existing biomedical knowledge in public databases to create an analysis platform so implicit and explicit

relationships can be more easily exposed and explored. That really helps, as this is complex; the graph database for just one heart failure network analysis platform contains over 130,000 nodes and seven million relationships alone, for instance. One more use case is provided by Stephan Reiling, Senior Scientist at Novartis Institute for Biomedical Research. Novartis has created a large graph database of all kinds of heterogeneous biological data, which his team is combining with text mining results. Currently with half a billion relationships in the database, with plans to triple this number, Novartis is looking to create one database to better understand biology and how they can use this scientific knowledge to develop the next generation of medicines. “There is a huge amount of biological data available, along with incredible data sources,” he says. “By really bringing all this data together, for the first time we can say, ‘I want

to find compounds that are similar to this compound that have annotations about this disease.’ “To have the flexibility to navigate all of these data sources is really powerful.” Discovering the Unknowns at Big Data Scale As integrating data and knowledge in life sciences involves the modelling of an incomplete and ever-changing model of how our bodies work, we need a better way, then, for modelling this complexity. And as our knowledge improves, these models continuously need to change – to take just one example, large human DNA sequences we originally thought were just 'junk' turn out to be an important component of our genomes. So everything is connected – and those connections change depending on context, time and environmental triggers. To be able to deal with this reality, researchers need tools

Product News Sartorius Stedim Biotech introduces new BIOSTAT STR® bioreactor range •  New generation of bioreactors combined with new Flexsafe STR® bags offer a fully scalable, single-use system •  Systems enable significant reduction of bioprocess development timelines and costs Sartorius Stedim Biotech (SSB), a leading international supplier for the biopharmaceutical industry, announced the launch of its next generation BIOSTAT STR®, a fully scalable, singleuse bioreactor family based on a conventional stirred-tank design. This new bioreactor range featuring upgraded hardware and software, as well as a fully integrated, new design of Flexsafe STR® single-use bags, ensures quick and easy bioprocess scale-up of biologics and vaccines.

process transfer from 250 mL to 2,000 L can be achieved in weeks rather than months using this innovative technology platform. The new bioreactors and the newly introduced single-use Flexsafe STR® bags are a perfect match. The bags with advanced single-use sensor solutions are manufactured from a proprietary, robust multilayer S80 polyethylene film. The formulation of resins and additives for the film are fully characterized, and extrusion process parameters are controlled within established ranges, providing consistent batch-to-batch extractable and leachable profiles. The fully self-contained design of the new bioreactor with its single-use bag prevents product cross-contamination, saving time in set-up, validation, clean-in-place procedures and sterilize-in-place operations.

The BIOSTAT STR® bioreactors are equipped with an improved stainless steel bag holder for userfriendly installation of the single-use Flexsafe STR® bag. The bioreactor series consisting of five systems in different sizes offers working volumes from 12.5 L to 2,000 L. Because the bioreactors are designed with the same geometries as SSB’s ambr® 250 mini bioreactor, the industry gold standard for scale-down, linear scale-up and

Besides using bags of the highest purity, the system is designed for efficient oxygen transfer, mixing and CO 2 stripping. These combined features ensure excellent cell culture performance with reproducible high-density growth of even sensitive cell lines. As a result, BIOSTAT STR® bioreactors are ideal for achieving very high cell densities in continuous processes and for safe manufacture of vaccines and recombinant proteins in cGMP environments.

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Dr. Thorsten Adams, Director of Product Management for Fermentation Technologies at Sartorius Stedim Biotech, stated: “Direct linear scalability is crucial for ensuring the efficiency and costeffectiveness of bioprocess development campaigns. Compared with conventional stainless steel vessels, our next generation BIOSTAT STR® bioreactors in combination with the ambr® 250 technology will help reduce process development timelines significantly. These highly scalable, single-use bioreactors are an intelligent, low-risk bioprocess development solution for use in multi-product facilities, as well as at contract manufacturing organizations, for the production of biologics and vaccines.”

Contact: Sartorius Stedim Biotech GmbH August-Spindler-Str.11 7079 Göttingen www.sartorius.com/biostat-str www.connect-upstream.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 53


Technology adept at discovering ‘the unknown unknowns’ at mass scale in order to make those serendipitous discoveries and which are able to handle dynamic and constantly evolving data. Clearly, graph databases are helping life science make real advances. Could it help your life sciences project, too? Cross-Disciplinary Is Where Science Happens Best Neo Technology’s Petra Selmer explains how exposure to graph databases changed her career – and put her on a mission to explain the approach’s time-saving and complexity-defeating benefits I’m a software engineer by training who has worked on life sciences and healthcare-related projects at a medical research centre and a major university. I did a long stint developing software for clinical trials and national medical audits, combining NHS and private healthcare patient datasets, for the Intensive Care National Audit & Research Centre. I also worked at a multi-participant academic project centered at University College London’s Wellcome Trust Centre for Neuroimaging. In both cases, I was tasked with helping on the data management side of the projects. What I found: medical data is very heterogeneous. It can range from cell-level, hugely detailed data to macro-scale disease network tracking, often in the same research. Very often, you want to link the two ends of the spectrum, as that’s where the interesting results tend to lie, but it can be a real challenge to model that. Biologists and physicists, to name but two fields of scientific endeavour, think they inhabit different worlds, but often they are looking at the

same thing, just from different perspectives. What’s frustrating is the breakthroughs will often come from the interface between the two sides, or multiple sides. Cross-disciplinary working across all scientific fields is the place where the best science happens, many believe. What hampers this collaboration is that IT is not seen as a useful participant in these conversations. Working out the smartest way to model the complexity discussed and to find ways for multiple actors to find ways to engage with the same information doesn’t happen enough. Scientists love data, but they are a bit casual about the modelling of it, so you may have a lot of Master’s degree students and post docs scrabbling around with Excel and basic approaches to getting the dataset into a viable shape to be looked at. That’s not efficient. The key thing is that the relationships in data conceal the actual breakthroughs. I think that’s worth elaborating, and it needs recording. Research is about exploring the unknowns. The easier it is to expose that darkness to light, the better the chances of success. Data provenance is vital here; for example – it’s crucial to know exactly where data came from and what might be affecting it, as more and more researchers need to back up their claims through the veracity of their data (and repeatability of their experiments). Meanwhile, visualising complexity, being able to use the amazing human pattern recognition system we call ‘sight’, is also a real aid. In the course of working on these projects, I became convinced graph database technology could help. In the clinical trials project, we were getting confused by the complexity of participant and stakeholder identities – they had multiple roles we needed to be aware of. It was only when I modelled these areas in a graph database that we made any headway. Mapping all this in Excel and SQL, as we’d been battling to do, just wasn’t effective. A similar leap forward came with the neuroscience work. We had to

54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

collect a wide range of attributes for people in various concurrent projects, which meant a lot of shared participants whose identity and relationships needed to be carefully and accurately tracked. I tried to do this in a relational database – and it proved to be a disaster! But using graph was a quantum leap in terms of clarity, depth and ease of maintenance. That experience – and what I hear from other researchers and data modellers in life sciences – has convinced me of two things. One: graph database technology, thanks to its innate ability to model complexity, scale and connections, is the only data tool for serious medical research. And two, positive help from developers to build graph-based data structures for research would make a huge difference, as well as allow a lot of highly-trained specialists get their hands-on information in a form they can work with a lot sooner.

Emil Eifrem CEO and co-founder of Neo Technology. Previously CTO of Sweden’s Windh AB, where he headed up the development of highly complex information architectures for enterprise content management systems, Emil famously sketched out what today is known as the property graph model on a flight to Mumbai in 2000. Since then, Emil has devoted his professional life to building and evangelising graph databases, and jokes that, as a result, he plans to save the world through graphs and own Larry Ellison’s yacht by the end of the decade. He is a frequent conference speaker and a well-known author and blogger on NoSQL and graph databases, as well as co-author of the agreed Bible on graph databases, O’Reilly’s Graph Databases. Email: emil@neotechnology.com

Summer 2017 Volume 9 Issue 2


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Technology

Propelling Holistic Risk Management Using a Next-generation RBM Approach As the nature of clinical trials grows ever more complex, the requirement for an improved risk-based monitoring (RBM) approach increases. Such an approach improves the quality of clinical studies and facilitates better adherence to new guidelines from regulatory agencies. When implemented effectively, RBM reduces site monitoring costs, enhances oversight and provides a near real-time overview of data. It can enable life science companies to prioritise resources around identifiable risks relating to the safety of participants, and the quality and integrity of clinical trial data.

Biopharmaceutical companies and CROs currently use a number of electronic systems to support their RBM solutions, but these systems are often inefficient and do not utilise centralised and on-site tactics. Globally, the Good Clinical Practice (GCP) standard has recommended that monitoring activities and managing data need to be accomplished more effectively. The ICH E6 (R2) addendum to GCP places more responsibility with sponsors, investigators and CROs, making a risk-based approach a requirement rather than optional. In doing so, sponsors must assume proficient trial monitoring, cross-site communication and data integrity maintenance. On-site monitoring costs are one of the leading expenditures contributing to the increasing costs of clinical trials, so an RBM strategy which reduces these would be hugely beneficial to the industry. What Are the Requirements? The expectations of CROs and sponsors have risen, and documentation of a monitoring plan is now required which states the methods, responsibilities, requirements and the strategy. The sponsor’s chosen approach – on-site, centralised, or a combination of both – must be stated and reported on in a monitoring plan. To help reduce 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

risk during the trial, the guidelines suggest that protocol design and implementation, standard operating procedures (SOPs) and training are all documented. A thorough re-evaluation of industry standard practices is needed in order to improve RBM across the board. The goal of the addendum is to encourage biopharmaceutical companies and CROs to adopt a more efficient approach to RBM, which combines centralised and on-site tactics. Integrating all critical data sources, irrespective of format, in near real time will lead to a new, superior, holistic approach. The overarching aim is to move RBM from a reactive to a more proactive system. By using a centralised, near real-time RBM solution, the industry can effectively manage clinical trials more proactively. Quality management activities need to be documented and communicated to all those affected, to facilitate risk review and appropriate action.

The FDA and EMA, under their RBM guidance, identify the siloed approach of various clinical research activities, as well as the siloed nature of supporting platforms, as a key issue. Availability of data in an organisation is often reflective of its siloed structure and, for effective RBM, access to all the necessary data sets and the ability to integrate them is required. Data integration mobilises risks which are not obvious when the data is examined from a single source (i.e. eCRF and audit trail, drug safety database, etc.), and with more data comes more knowledge, which helps site sponsors make better informed decisions. RBM Solutions: Where Are We Now? Despite many vendors claiming they have solutions for RBM, multiple existing RBM solutions are primarily simple analytic or reporting tools which do not aggregate data in near real time, nor perform interactive

The Importance of Data Integration A current problem facing sponsors and CROs is the siloed nature of data collection. The ability to access and manage a diverse array of documents or data, such as metadata, case report forms, data from interactive response technologies (IRT), protocol deviation reports, central laboratory reports, trial master files (eTMF) and quality metrics, is a potential drawback to current RBM implementation1. Because RBM draws upon a wide variety of data sources, the technology solutions required must have the flexibility to load data from any application, database, file, EDC or report, for example. Integrating disparate data sources is costly and time-consuming, and the clinical medical review process is prone to error and is labourintensive. The integrated data structure gap in clinical research must be bridged before RBM can be used as a robust management platform. Summer 2017 Volume 9 Issue 2


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Technology data discovery or RBM functionality. Custom solutions offered by CROs to sponsors can also be inflexible as they are often built as data warehouses that are not sourceagnostic. Such solutions are not equipped for effective RBM, and cannot grow with the needs of the organisation as their RBM usage develops. As it stands, there are three main categories which RBM solutions can fall into: 1. CRO solutions Many CROs have built their own RBM solutions, in order to apply RBM to the trials they are conducting on behalf of the sponsor organisations that they are running trials for. These are built around data warehouses. 2. RBM offerings by major clinical informatics vendors Clinical informatics vendors that sell their own solutions are developing RBM solutions, but they often have limited functionality and lack data aggregation technology. 3. Statistical-based RBM solutions Data must be manually mapped nto the stats system where the

data is run against statistical models to determine the best course of action according to the risk mitigation strategy. However, they cannot easily integrate data and perform operational RBM functions. Using a data warehouse is cumbersome, as the entire clinical system must be re-validated if data sources are changed or added (e.g. if additional EDC systems are added or a CTSM system is replaced), or data is changed, such as fields in a CRF being added. Defining a schema upfront in such a relational database-oriented way is extremely limiting. Novel solutions coming onto the market are re-defining this approach. This is to leverage a document-oriented database which enables clinical development teams to analyse clinical, operational or other data of interest, thus, leveraging visualisation-based data discovery to drive rapid data analysis. What Does Effective RBM Look Like? Despite the leaps that have been taken in terms of technology, one of the biggest issues holding back the effective use of RBM is data

Figure 1: The role of data integration in eective RBM 58 INTERNATIONAL PHARMACEUTICAL INDUSTRY

integration. Integrated data collected for the purpose of clinical research is the first step in providing an effective risk management solution. By powering reporting and analytics to identify and monitor risks, this approach helps to allocate resources and manage issues more effectively. Identifying risk signals early on in a clinical trial process is critical, so the ability to obtain timely, quality connected data from the various sources helps eliminate late-stage risk identification. This type of integrated system is built on big data technologies using the data lake concept, which enables loosely coupled data ingestion that is not hardwired with any of the source systems. The traditional approach uses an ETL (extract, transform, load) methodology to ingest data into a predefined common structure. Data is extracted from sources, transformed, and then loaded (ETL) into a common structure that can only accommodate a certain level of variability. Data lake-based systems invert the process, extracting and loading data first. Then, end users can transform the data on a near real-time basis for analysis and signal/risk/issue detection. As modern clinical research advances, new solutions with capabilities such as these will be a fundamental requirement. As well as risk identification, the ability to view data across sources and sites will facilitate improved remote monitoring – a step forward from focusing on reducing the amount of source document verification (SDV) and visits to potential problem sites. In addition to allowing users to better understand and categorise risk, update monitoring plans and create trial-specific key risk indicators (KRIs), a next-generation RBM tool could draw on machine learning technology and include a deep learning algorithm that could track user activity and predict risk and behaviour based on past experience. Other areas of the clinical research process, such as performance-linked payments to sites based on triggers, could be integrated, to incentivise sites and potentially drive better efficiency and data quality. Summer 2017 Volume 9 Issue 2


Technology Conclusion The ideal RBM platform should continuously and automatically bring data together from the numerous distinct sources used to collect clinical trial data, allowing trial oversight through risk assessment. Th e t e c h n o l o g y re q u i re d t o accomplish this level of risk-based monitoring is already available on the market and is being used by the world’s leading companies, enabling RBM workflow processes, budgeting, contracting, clinical data review and payments. By making interactive visualisation-based data discovery available, information from multiple sites can be easily interpreted and evaluated. Visualising outliers and trends in clinical data is crucial, and is made easier through the standardisation of data with a next-generation holistic RBM solution, in addition to data flexibility to accommodate multiple source systems and formats. New best-practice regulations suggest that sponsors and CROs

adopt RBM that includes systematic, o n g o i n g a n d p ro a c t i v e r i s k assessment, on both an organisational and trial level, which is embedded in a quality-by-design and risk-based approach. By using a combination of centralised and on-site monitoring, biopharmaceutical companies and CROs can proactively identify and eliminate inadequate site behaviours, therefore managing risk rather than simply monitoring it. Since comprehensive RBM is now a recommended approach, it is time to re-evaluate the industry standard and to expect more from RBM solutions, leveraging a holistic RBM solution driven by an integrated data solution. REFERENCES 1. Schwartz, G. “Any Pitfalls in RBM Implementation? The Perspective of the Regulators” The Federal Institute for Drugs and Medical Devices, 3rd European Conference of Clinical Research (2016)

Sudeep Pattnaik President & CEO of ThoughtSphere. Prior to founding ThoughtSphere, Sudeep was the global leader of products for Quintiles, the largest CRO Fortune 500 life science company in the world, creating and leading the strategy team behind a $60M integrated healthcare data hub. He also played a key role in defining the risk-based modelling approach for optimising the clinical development process and helped develop a best-of-breed RBM platform for the industry. He holds an MSc in computer science from Uktal University (India) and an MBA from Leeds School of Business at the University of Colorado, Boulder. Email: sudeep.pattnaik@ thoughtsphere.com

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Working with Difficult Preparations – Risks, Regulations, and Considerations Safety testing is a crucial part of drug development and is dictated by pharmacopoeial guidelines which must be followed when performing each step of the process. Ideally, the method development stage is when any potential sample preparation problems are resolved to make the routine analysis easier, however, depending on the product in question, this can become a lengthy process as preparation methods can vary broadly.

The type of test in question may also affect whether a sample is challenging to prepare as any number of roadblocks can occur during the testing process. It can be difficult to determine which method is suitable for each type of product without familiarity with regulatory guidelines and an awareness of how the available methods work with specific product types. The best place to start is by examining the material safety data sheet (MSDS), which should contain any specific details of the composition of the product and safety concerns. Drawing on any relevant personal experience, either with a similar sample type or from other types of testing completed with that product already, can also be useful, as well as consulting with other experts such as the manufacturer, or if the sample has already undergone any tests with a different facility, comparing any methods used for that prior testing. Each product is unique and there are an infinite number of issues related to product type, composition, appearance, sampling size, and hazardous samples that might arise during the testing process. Inhalation & Aerosol Products Inhalation products, for example, along with pressurised aerosols can pose an issue with extraction as the extraction method must not affect the natural bioburden or the composition of the product in any way. 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Part 2 of the current Ph Eur 2.6.12 Microbiological Examination of Non-Sterile Products: Microbial Enumeration Tests starts with stating that the testing is to be performed under conditions designed to avoid extrinsic microbial contamination of the product to be examined. This includes the area in which the testing is performed but also how to remove the sample from the container and how the subsequent testing is performed. While extracting the product from its final container, it is important that aseptic technique is applied. One possible extraction method for fluids in aerosol form is to first chill the sample in its container in dry ice for around one hour. The container can then be aseptically cut open at room temperature, allowing the propellant to escape before collecting the sample. However, what impact freezing has on the product must be considered, as well as whether the composition may be altered. Whichever approach is chosen must be qualified during method development or if transferring methods, during validation. To achieve the best results, ideally the manufacturer and technicians conducting the testing should work together to determine a suitable extraction method, ensuring that microorganisms or other contaminants are not introduced in to the test and that the chosen extraction method is safe to perform with that particular product. It is, therefore, vital to ensure risk assessments for the components

are in place to minimise exposure to propellants and potentially harmful substances during handling, storing and testing of the product. Insoluble Products Solubility issues are another factor to consider, as these can affect various tests including microbial limits, sterility and pyrogen testing. The desired outcome of the test itself must be considered, particularly with in vivo testing and the route of administration of the sample. Examples of solubility issues include water soluble products (which may not dissolve completely) and fatty versus non-fatty products which require different approaches to prepare. With a non-fatty product that is insoluble in water, emulsifying agents will need to be added to your diluent to aid in homogenisation of the sample preparation. The pH might also need to be adjusted using sterile acid or alkaline solutions. W i t h fatt y p ro d u c t s , t h e preparation will need to be dissolved in isopropyl myristate or polysorbate 80 or some other emulsifier, and may need to be heated as well but to not more than 40°C or, in exceptional circumstances, to not more than 45°C as detailed in the pharmacopoeias (to ensure that the bioburden is not affected) to aid in preparation of the sample for testing. Preparation of samples for toxicology testing poses a different set of challenges, given that the dose in the syringe must be a representative dose and therefore issues with solubility cannot be addressed by continued dilutions. Summer 2017 Volume 9 Issue 2


Labs & Logistics It is a very careful balancing act which requires not only an understanding of the drug product being tested and technical expertise with the test, but also a thorough familiarity with all factors affecting animal welfare. At all stages, particularly in microbiology and toxicology testing, aseptic technique must be observed and any solution used to dissolve the substance should be demonstrated not to alter the composition of the product, provide any potential for growth of microorganisms, nor add to the bioburden of the product. When acid-based solutions are used in preparation, it’s important to be aware of potential issues, as these are used to prepare some of the more insoluble solutions for testing but can inhibit microbial growth, as many organisms prefer to grow in more neutral pH environments. This could impinge on method suitability and cause inaccuracy in reporting of results, so it is vital to ensure you put in place appropriate steps to minimise or negate these effects. In the case of toxicology samples, the acid / alkali balance must be very carefully controlled due to the nature of the testing with both the active dose of ingredients and the dosage rate taken into consideration. It is essential that no more than the maximum human dose is utilised, requiring representative concentration levels prepared specifically for the size / weight of the test subject. This is an issue that must be considered throughout the toxicology testing process, not just when assessing pH levels, as the dosage size must be calculated correctly to be representative for the size of the laboratory animal versus the human dose, but also must not be so small that there isn’t enough drug to challenge the system. This is relevant with medical device testing as well – the key consideration must be whether the testing is representative of how the drug or device would be used in the end patient, and the test sample should be representative of how the final product will be manufactured and used. www.ipimediaworld.com

Products Requiring Filtration Filtration can also pose problems as a filter or filtration apparatus that is compatible with the product must be chosen. Acidic solutions do not mix well with a dissolvable filter, for instance, as any microorganisms that should be captured on the filter surface could be washed away to waste along with the filter as it disintegrates. Some samples may also react with the plastic of the filtration apparatus causing it to melt and warp, so in certain instances a glass filtration apparatus might work better. Additionally, samples may need to be pre-filtered prior to testing to remove ‘lumps’ or, in the case of cell banks, to remove the cell bank cells to prevent blocking of the filter, leaving the smaller microorganisms to pass through and then be captured on the microbial retention filter. It is also important to consider factors that may be specific to the type of test performed; for example, the microbial limits test. In the microbial limits test, products that are highly antimicrobial or have a high binding ability may result in the product binding itself to the pores of the filter membrane using electrostatic charges. Such a product may not be able to be washed out of the filter matrix and may then exhibit inhibition to any microorganisms present in the product, giving a falsely low result. This can be overcome by using low binding filter membranes. The container used for testing must also be considered, such as how a new container might interact with the sample. Whether the material of the container or lid will interfere with the product, including the preservative system, must also be determined in advance of testing. Other concerns to resolve in advance are whether the product is required to be stored in the dark and whether evaporation of the product is likely to occur.

Antibiotic Preparations Microbiological assays are another challenging series of tests which provide a collective assessment of the potency of the overall biological activity of an antibiotic preparation as compared to a reference microorganism, or standard. An example of an issue that might need to be considered in this case is whether the sample is hygroscopic, or absorbs water from the environment. These types of samples must be handled minimally in “sealed” environments where it is possible to minimise the opportunity for water uptake. It may also be prudent to use desiccation sachets. This should be discussed with the manufacturer to ensure the method chosen will not affect the properties of the product. In addition to environmental controls, you should consider the effect of disinfectants and chemical agents on the sample preparation process. At many other testing facilities, it is usual to decontaminate or sterilise products in their packaging before they are moved into a sterility testing isolator for sterility testing. It is, therefore, important to consider whether a sample container is permeable, for example if using hydrogen peroxide equipment for decontamination purposes, as the hydrogen peroxide in the gassing cycle could potentially permeate into the test sample and adversely affect the sample composition. In any instance where permeability is a concern, per MHRA and FDA guidance it must be shown through validation that there is no effect on the sample. In some circumstances, the sterility test itself may be insufficient in proving the impermeability of the sample and a longer-term stability programme may be required. Coloured Products Another aspect of the composition of the product which can affect such tests as the bacterial endotoxin or monocyte activation test, is appearance. For example, the kinetic chromogenic endotoxin test is a quantitative kinetic assay based on the development of a yellow colour after cleavage of a synthetic peptide complex. In this test, a coloured sample may provide a false result INTERNATIONAL PHARMACEUTICAL INDUSTRY 61


Labs & Logistics and therefore must be diluted and re-assayed to avoid interference with the test, or a different method such as the kinetic turbidimetric endotoxin test chosen instead.

Product Availability While not an issue with the sample itself, another aspect of testing that might need to be considered would be if there is only a small sample size available for testing due to manufacturing issues, or limited availability of materials such as a small batch or small amount of product per test item. In some circumstances, a reduced number of samples can be used for validation or method suitability but it is essential to put in place a robust justification for ‘scaling down’ any testing that doesn’t meet pharmacopoeial regulations. Although price is always an issue from a commercial standpoint and it might therefore be tempting to consider this in assessing sample sizes for testing, it is not a reasonable excuse to scale down samples in the eyes of regulators for most pharmacopoeial testing. Hazardous Products Cytotoxic, carcinogenic and other teratogenic substances can be difficult in a different way, as the preparation of the sample itself may not be inherently difficult, but there are specific safety precautions which must be followed given these drugs affect normal cells alongside the tumour cells they are targeted toward. These substances can produce significant side-effects in anyone exposed to them and their preparation and administration must be carefully considered. When working with laboratory animals, the risk to staff is heightened as working with hazardous substances in a live system has additional risk and complications versus a cleanroom environment. 62 INTERNATIONAL PHARMACEUTICAL INDUSTRY

One such issue is dosing, as this can be a difficult process regardless and requires good control at all stages to avoid additional risk to technicians. These types of products must be tested in a safety cabinet and may be restricted to testing by only technicians of a certain age or gender. A code of practice should be put in place that covers the safe handling of these drugs, including sample receipt, testing and disposal, which are all considerations which should be evident from a thorough review of the MSDS. Any such code of practice for cytotoxic substances should require all samples to be marked clearly as such and that appropriate personal protective equipment be in place at all times during handling. All workspaces and materials should be thoroughly cleaned to ensure neutralisation of any cytotoxic material once the sample is dealt with (booked in or tested) and such samples stored securely and separately from other samples to avoid cross-contamination. Additionally, with these types of teratogenic drugs, any laboratory animals used for their safety evaluation or the waste produced from such tests must not be handled by any staff who are pregnant, planning a pregnancy or breastfeeding due to the increased risk. These steps must be taken to ensure that the testing can be carried out effectively with no harm to any personnel involved. Product Method Transfer It’s also important to mention the potential testing and sampling issues that can arise when transferring methods, particularly from in vivo to in vitro tests such as the rabbit pyrogen versus the monocyte activation test, where there may be a different metabolic effect. An example of this would be a sample contained within a liposomal sheath requiring toxicology testing. The difficulty lies in how to determine when the drug breaks down as if it hasn’t broken down completely, the full potency of the drug may not have been tested. While this may seem like a testing issue rather than sampling, when

switching from using a live system to an in vitro method, it must be considered what needs to be done to the drug in the preparatory stages to make it break down fully with the exact same mechanism as would happen in the body. There can be no changes to the chemical makeup and no reduction of the reaction that would occur in the original test. These examples illustrate that a vital part of any drug development lifecycle is conducting a risk assessment of the product and any potential sampling issues in advance of initiating actual testing or method development. The process of preparing a risk assessment can be difficult and time-consuming, which is why many manufacturers and drug developers choose to outsource this to an experienced laboratory facility. The human element of this is particularly important and the risk to the workforce must be considered in advance when dealing with high-risk samples such as toxic or cytotoxic substances, given that accidents do happen, no matter how much care is taken. A thorough examination of any relevant safety information and product details in combination with reliance on the technical expertise gained through familiarity with common sampling issues can help to ensure that you avoid costly delays due to testing failures.

John McKenzie Chief Executive Officer, Wickham Laboratories Ltd. He has an extensive background in the life sciences industry with over 20 years of management experience across the European and Asian continents.

Email: mail@wickhamlabs.co.uk

Summer 2017 Volume 9 Issue 2


Labs & Logistics

The Advantages of LC/MS in Identifying Residual Impurities in Biopharmaceuticals The identification of impurities and their subsequent removal constitutes one of the most critical process steps in the development of biopharmaceuticals. The presence of residual impurities has the potential to affect the safety and efficacy of products. As a result, their levels must be effectively controlled and are considered as critical quality attributes.

Fergus Hall, PhD, Section Manager, Pharmaceutical Chemistry at Eurofins BioPharma Product Testing, looks at the complexity of detecting and quantifying residual impurities which are usually present at low concentrations within difficult sample matrices. He will discuss the broad selection of detection methodologies currently available, specifically focusing on the advantages of high performance liquid chromatography mass spectrometry (HPLC/MS) for process validation studies. Process-related Impurities in Biopharmaceuticals Biopharmaceuticals make up a class of drugs which are generally produced in living organisms and used for the treatment of a wide variety of diseases, including cancer and diabetes. Examples of biologic products include hormones, enzymes, monoclonal antibodies, vaccines and blood factors, and each present different challenges during drug development and manufacturing. The growth of the biologics market can be attributed to the many advantages they offer over small molecule drugs, such as reduced safety/ toxicity issues, the potential to treat complex diseases and high target specificity. The challenges of developing biopharmaceuticals arise from the structural complexity of these large molecules and their production processes which introduce a range of additives that have the potential 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to become residual impurities in the process stream. These impurities are potentially toxic and have no benefit to the patient. Consequently, implementation of analytical characterisation processes at each stage of manufacturing is necessary to ensure product efficacy, quality and purity. Process impurities are related to the manufacturing process and may include cell substrates, such as host cell proteins, host cell deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Other impurities occur as a result of cell culture steps, such as inducers, antibiotics and media components, as well as residual impurities that are introduced downstream from resins, residual solvents and surfactants. There can also be residual impurities that are introduced through chromatographic media used in purification and buffer components, while others are present due to extractable and leachable substances. These include impurities that can migrate from pharmaceutical container closure systems, process equipment and packaging. In order to protect patients, the level of impurities in biopharmaceuticals must be reduced to acceptable safety limits. However, these process-related impurities are typically present at trace levels in complex sample matrices which makes quantification a challenge. Regulatory View The regulatory authorities have introduced extensive guidelines which set out the highly specific and sensitive techniques which offer robust quantification to support process validation and ensure that products meet specification limits for process residuals. The testing of biopharmaceuticals must be conducted in accordance with the International Conference

on Harmonization (ICH) Technical Requirements for Registration of Pharmaceuticals for Human Use Q5A to Q5E (Quality of Biotechnological Products) and the Code of Federal Regulations (CFR) Title 21 parts 600, 601 and 610. Since residuals are typically present at varying levels throughout the process, method development and optimisation can be difficult. For example, extraneous proteins which are known to produce allergenic effects in humans should not be added to the final virus medium of cell culture produced vaccines that are intended for injection. If serum is used at any stage, its calculated concentration in the final medium should not exceed 1:1,000,000 (CFR 21 part 610.15). Multiple Analytical Techniques Multiple detection techniques can be used to characterise and classify residual impurities. The most commonly relied-on methodologies utilise liquid chromatography (LC) or gas chromatography (GC) combined with a range of detection methods, such as charged aerosol detector (CAD), evaporative light scattering detector (ELSD), mass spectrometry (LC-MS, GC-MS), flame ionisation d et e c t o r (G C / F I D) , e n z y m e linked immunosorbent assay; and quantitative polymerase chain reaction (qPCR). Th e va r y i n g p ro p e rt i e s of residual protein contaminants in biologic drugs mean that different methods may be used to detect and monitor each. For example, the presence of residual solvents and volatile molecules are frequently determined by GC/FID, while proteins are detected using qPCR. The analysis of compounds where UV detection might be a restriction, e.g. sugars, antivirals, antibiotics, lipids, phospholipids, terpenoids, and alcohols, are typically measured using ELSD. Summer 2017 Volume 9 Issue 2


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Labs & Logistics core business, all while reducing costs and the need for capital equipment. Final Thought As the biologics market continues to strengthen, there is a growing need for manufacturers to take measures to prevent the formation of residual impurities in products, with these being identified and characterised u s i n g a p p ro p r i at e d et e c t i o n methods. However, the complexity of new process matrices together with growing demand for increased sensitivity presents a multitude of challenges and calls for advances in detection technologies.

Improved Detection Using LC-MS The industry is continuously exploring more advanced techniques for the detection of residual impurities, particularly at the low concentration levels required for biopharmaceuticals testing. Typically, LC/CAD and LC/MS are used for biologic products. As a cost-effective universal detector, LC/CAD is well suited to limit tests and screening. Highly sensitive and possessing a broad dynamic range, it offers real advantages in the analysis of compounds that lack UV chromophores. It is, however, less robust than other methods and limited by the need for the compound of interest to be non-volatile. LC/MS, on the other hand, is being widely used to characterise impurities due to exceptional sensitivity down to the picogram (10-12) level. The technique provides high-resolution, accurate mass, selectivity, as well as specificity, positioning itself as a superior detection method that provides more detailed information and a better indication of purity. Additionally, it is able to detect multiple types of impurities. The only stipulation for the use of LC/ MS is that the residual impurity being analysed must be ionisable. When compared to LC/CAD, LC/ MS can provide considerably more 66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

information on analyte identification. It is one of the most widely-used tools for monitoring and identifying residual impurities and yields both qualitative and quantitative information. It is also the only technique that provides the capability to both identify and quantify residual impurities. Industry Preference for Outsourcing Models One area in which LC/MS demonstrates significant drawbacks is the costs associated with implementing the technique. The expense of procuring the instrumentation alone is in the region of $600,000, and this is without even considering the costs associated with the installation, qualification, software validation, and on-boarding of an in-house team to operate the equipment and interpret the resulting data. Due to the high expense, many manufacturers are turning to third-party vendors that can provide residual impurities analysis using LC/ MS as a service. While the choice to outsource can be somewhat of a difficult decision, it is one that can be both analytically and financially rewarding. By carefully considering the services procured and choosing an appropriate outsourcing partner, manufacturers can access expertise and proven experience that offers them the freedom to focus on their

LC/MS represents the most robust analytical technique available and provides the necessary sensitivity and selectivity to detect a broad range of impurities. By identifying and quantifying residuals in biopharmaceuticals with the highest degree of precision, specificity and accuracy, it can help manufacturers streamline their analysis processes and simplify compliance with regulatory guidelines.

Fergus Hall Ph.D., Section Manager, Pharmaceutical Chemistry, Eurofins BioPharma Product Testing. Fergus is Section Manager for Pharmaceutical Chemistry at Eurofins BioPharma Product Testing in Dungarvan, Ireland. He is responsible for the management of five analytical teams, testing sample material on behalf of global biopharma and pharmaceutical clients. He has specialist expertise in contract testing, method development, transfer and validation. With a PhD in analytical chemistry, Fergus has spent more than 11 years working for contract research and contract testing organisations in managerial positions. Email: fergushall@eurofins.ieÂ

Summer 2017 Volume 9 Issue 2


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Environmental Monitoring and Reporting Facilitated by LIMS Environmental monitoring (EM) is an essential part of any pharmaceutical, medical device or biotechnology manufacturing process. It ensures that microbiological and particulate levels in the controlled manufacturing environment are maintained within acceptable limits. The EM programme will involve a regular regime of testing based on location and frequency. The results are used to monitor trends and trigger the appropriate corrective action if a limit is exceeded. The use of a LIMS (laboratory information management system) is commonplace in QA/QC labs to ensure quality in the manufacturing process. However, added value can be gained by using LIMS to manage environmental monitoring protocols as well; including definition and management of the sampling plans, testing schedules and associated result limits. LIMS can readily manage the potentially large volume of data generated and can report the results and analyse underlying trends and patterns.

Manufacturers of drugs and medical devices will follow the appropriate Good Manufacturing Practice (GMP) guidelines issued by the regulatory agency for their location. Production must take place in a controlled manufacturing environment where microbiological and particulate contamination levels are maintained below pre-defined levels. Anything that can come into contact with the product is a potential source of contamination. This includes active ingredients and excipients, process water, air and personnel, as well as containers, tools, instruments and work surfaces in the production and storage areas. Acceptable limits for each production area will be based on its specific role in the production process. Particulate contamination is important because particles may contaminate the product physically or act as a vehicle for microbial contamination. As there is no correlation between particulate count and airborne microbiological contamination, separate microbiological testing 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

must also be carried out. In addition, personnel are a major source of contamination of cleanrooms and special regard should be given to their behaviour with regard to hygiene, infectious diseases, open wounds, etc. The education and training of personnel, the garments used, dressing procedures, rules for entry and behaviour are all important factors in maintaining an acceptably clean environment. Environmental Monitoring Programmes Environmental monitoring allows the efficacy of contamination control procedures in a production facility to be measured. It can cover areas such as cleanrooms for drug fill/finish, formulation tank rooms, laminar flow hoods, biological safety hoods, isolators, glove boxes, moulding machines, kit assembly lines, intravenous (IV) compounding areas and sterile packaging. Environmental monitoring defines and documents the state of control of the facility and highlights possible threats to the purity of products, but it does not determine the actual quality of the finished product, which is a quality control / quality assurance function. There are a number of key steps involved in establishing an environmental monitoring programme: 1. Define the critical areas of manufacture 2. Identify the potential contamination risks 3. Specify the locations at which samples should be taken 4. Specify the tests to be used to measure contamination levels 5. Specify the frequency with which measurements should be made 6. Establish the acceptable measurement limits in line with the appropriate regulatory requirements 7. Determine how test results should be monitored and reported

8. Establish specific corrective action procedures to be implemented in the event of any measurement exceeding its defined limit The above steps will identify deviations from the defined limits. However, if such deviations occur it is important to identify the root cause of the problem in order to eliminate it. It is often only by observing trends in the measurements that the complete picture needed for root cause analysis can be seen. Applying LIMS to Environmental Monitoring LIMS is a well-established tool in QA/ QC Labs, and the extension of a LIMS to manage environmental monitoring is entirely logical. However, the extension of the functionality does place significant demands on the LIMS itself. To support an EM workflow, the LIMS must be able to associate multiple sampling points, the frequency of sampling and the testing required with multiple controlled environments (CE). A graphical representation of each CE should be displayed by the system with the individual sampling points identified. It is essential that different alert and action limits can be entered for every sample point and for every test within each CE, and that these limits can be easily changed if the testing protocol changes. The system must be able to capture the results and metadata associated with microbiological testing, which are usually quite different to a classic analytical or physical test. When samples are taken according to the defined protocol (Figure 1) the system must be able to produce labels, including barcodes that uniquely identify the sample. If an alert limit or action limit is violated, specific triggers must make responsible staff aware of the condition so that corrective action may be taken. The system must be able to produce trend plots and summary reports on Summer 2017 Volume 9 Issue 2


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Figure 1. Sample registration screen

demand according to user-definable criteria. Typical trend reports might include: trends for a specific CE over a chosen time period, trends for a specific batch/lot or product, or trends for specific analysts which may reveal specific training needs. For some organisations it could also be a distinct advantage to have the ability to view EM results from different locations, using web-based technology. In addition, the system must be validated for use in the particular regulated environment. Although most LIMS, in principle, provide the capability to handle the requirements of environmental monitoring, many are too inflexible to do so without extensive customisation or integration with a specialised third-party EM package. Such software will need to be customised to meet an organisation’s specific user requirements in terms of workflows, screen designs, menu designs, terminology, numbering schemes, report designs and much more. Such customisation can affect the future supportability and upgradability of the product, as well as raising validation issues; all of which affect the long-term viability of the solution. LIMS that provide true configuration tools using an interactive configuration interface and where the supplier’s code remains unchanged, offer an alternative approach. Here the implementation of an environmental monitoring programme based on an existing environmental monitoring application and using the configuration tools 70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

allows configuration for any facility and monitoring programme. Sampling point locations, test results and corrective action plans can be linked in a single graphical environment. Detailed Environmental Monitoring Workow The following shows how a detailed workflow for an environmental monitoring programme could be implemented in a LIMS configured to meet specific requirements: 1. Sampling plans that clearly identify the exact location for each sampling point in a CE are entered together with the required tests and sampling frequency. The alert and action limits for each sampling point and test combination are also defined. The location of sampling points are mapped on a stored image or diagram of the production area being monitored. Multiple CEs per facility may be configured, each with multiple sampling points. 2. When the protocol calls for a sample to be taken, the appropriate samples are created in the LIMS and the tests assigned. The sample test combinations are linked to the appropriate alert and action limits. 3. The LIMS can print the appropriate labels for each sample, with barcodes if required, and the physical sample can be taken. 4. Th e a n a ly t i c a l wo r k m ay b e assigned to a specific analyst. If required, the system can check

that this person is currently certified to carry out the test. 5. Actions carried out on the sample can be recorded in the LIMS and relevant metadata recorded, such as incubator and other equipment used, temperature records and media. 6. If an automated instrument is used, the results should be imported directly into the LIMS database to prevent transcription errors. 7. Once entered into the database, the results are automatically compared to the limits set for the CE, sample point and test combination. If the result exceeds the alert or action limit, the relevant people are alerted in real time. While information such as analytical results can be changed once entered, the details of the changes are recorded in an audit trail to provide complete traceability of the sample. 8. When the test results have been entered, they may be reviewed and validated by a different analyst or supervisor. After validation, the results may further be approved by a qualified, senior person, before any official results are reported. The entire process from sample planning to reporting should be done in a secure, compliant system. Reporting and Reviewing Results LIMS can maintain a clear, audit-trailed, searchable record of all samples, test results (Figure 2) and reports issued. Information available within the system should include the date/time of sampling and result entry, together with the identity of the person who entered the results and information about any changes made. Details of how/ when results were reported, by whom and to whom should also be recorded. By graphically linking the environmental monitoring test results to the sampling location, the results of each sample location can be shown in chart and tabular form simply by clicking on that location. A graphical chart view can show the results over time so general trends can be quickly identified. The tabular view shows all test results for that sample location for more detailed investigation. A clear visual indicator, Summer 2017 Volume 9 Issue 2


Labs & Logistics

reactive response to a problem. Root cause analysis allows a preventative action policy that should allow the identification of improvements and the sources of non-conformities. Any preventative action plans that are developed in this way should also be documented and monitored in the LIMS. Figure 2. Sample test result report

such as a green check or red “X”, can be shown for each sampling point on the graphical view of the CE to denote the status of results over a selected time period. This allows the location of any test failures to be quickly identified and corrective actions to be implemented. In many organisations, reports and data may need to be accessed by personnel across multiple sites, or perhaps on the move. Many LIMS allow web-based access to the system. However, a separate web portal can allow staff, who may not be regular users of the LIMS, controlled access to appropriate information. This may be the best way of disseminating result

information across an organisation as access to such a web portal, controlled by password protected login, is available from any internetconnected device. The information available to individuals can be limited to what is relevant to them. Corrective and Preventive Actions (CAPA) Any out of specification results can trigger the appropriate corrective action(s). The severity of incident may be classified and responsible personnel assigned for various tasks. Investigative files may be attached for complete documentation. Users can also view all past corrective actions for tracking and audit purposes. Corrective action is, by definition, a

A suitably configured LIMS can offer a powerful way of simplifying and automating environmental monitoring in production facilities. LIMS can help to define and implement a rigorous sampling regime (frequency and location), record the test results, monitor the programme to identify trends, log corrective actions and maintain an audit trail of the entire programme. It can drive good practice and help organisations to document preventive controls to avoid product contamination. A LIMS that integrates environmental monitoring with QA / QC management provides a complete solution for controlling today’s manufacturing process.

Dr Simon Wood Product Manager at Autoscribe Informatics, has almost 30 years’ experience in the commercial LIMS environment. He is an acknowledged expert in the field of scientific and laboratory informatics. Autoscribe is a global supplier of LIMS to both the laboratory and the wider business markets, with distributors in every continent offering localised technical support. Email: simon.wood@autoscribe.co.uk www.autoscribeinformatics.com Figure 3. Linking of sampling locations, test results, corrective actions, etc.

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 71


Labs & Logistics

Future Supply Chain Trends: The Rise of the Full-service CDMO In the last ten years, the pharmaceutical industry has changed exponentially for contract development and m a n u fa c t u r i n g o r g a n i s a t i o n s (CDMOs). With an increased demand for reduced costs driven by price pressures from governments, CDMOs are being challenged to improve project efficiencies and offer a more cost-effective solution. Rising customer expectations when it comes to the range of capabilities and capacities contract partners can offer is also shaping the landscape, with consolidation becoming a major trend.

Outsourcing is on the rise, not only among big pharmaceutical firms but also with smaller emerging and even virtual companies, meaning customer requirements are more varied than ever before. As outsourcing continues to gain traction within the pharmaceutical supply chain, companies need to diversify and differentiate their offering to remain competitive. Kevin Cook, CEO of Sterling Pharma Solutions, which develops and manufactures small molecule active pharmaceutical ingredients (APIs), discusses the trends driving the increased demand for contract services partners and the benefits of selecting a full-service CDMO, in place of more niche providers. Industry Challenges and the Rise of Outsourcing In recent years, the pharmaceutical industry has had to adapt to a changing economic environment and the evolving drug pipeline. For example, advances in areas such as immunology and oncology have driven the need for manufacturing facilities that can handle high-potency drugs safely and efficiently, leading to a reliance on contract partners with the infrastructure and expertise to meet this need. In addition, pharmaceutical companies need to find ways to remain cost-competitive in a highly-populated market, without 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

compromising on the quality of the final product. Whereas in the past they have looked to emerging markets in the east to generate cost savings, this has often proven more expensive in the long run due to quality concerns and long transport times in order for products to reach the intended market. As a result, more companies are bringing their manufacturing projects back to the west where they can access reputable CDMOs that comply with stringent quality standards.

The growth in the generics market due to the fact that many patents are expiring is also driving the outsourcing trend. It is clear that many pharmaceutical companies are looking to outsource the manufacture of these drugs so they can focus their efforts on other areas, such as research and development. And, while emerging pharma companies, particularly in the US, are dominating the development pipeline, they have little or no manufacturing capabilities of their own. As such, these companies rely on contract manufacturers to provide this service.

In general, pharmaceutical companies are moving away from tactically outsourcing specific projects when their internal capacity is stretched, to a more strategic model. By developing long-term partnerships with contract manufacturers with a breadth of capabilities and a detailed understanding of the project goals, they can experience added value and ultimately bring drugs to market more efficiently. The Benefits of a Full-service CDMO There are many reasons that full-service API manufacturers are becoming the go-to choice for pharmaceutical companies looking to outsource, not least of which is the rising cost pressures associated with developing and manufacturing drugs. Selecting a CDMO that offers a start-to-finish service for the development and manufacture of APIs mitigates the need for movement between sites, helping to reduce time to market. This in turn increases cost-efficiency. Transferring a process between a developer and manufacturer, or between manufacturing sites for scale-up purposes, can have a direct impact on project timelines and costs. Selecting a full-service API developer and manufacturer that carries out its operations on one site can simplify the supply chain by reducing the need for multiple tech transfers.

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Labs & Logistics An integrated approach will also help to ensure high quality standards and consistency of manufacture. The industry standards for quality are high and manufacturers must be agile enough to cater for dynamic projects, while ensuring they meet the required Good Manufacturing Practice (GMP) guidelines.

Added to this, full-service providers by their nature have a wide variety of capabilities, meaning they can handle complex chemistries and molecules that would be costly for pharmaceutical companies to handle in-house. For example, in order to implement the engineering proficiencies and equipment necessary to handle high-potency APIs, pharmaceutical companies would need to make a significant upfront investment, whereas a CDMO may already have this technology and expertise in place. The demand for such a variety of capabilities is driving what was once a fragmented sector to consolidate. Large CDMOs are now acquiring smaller niche providers with specific expertise in order to expand their service offerings and increase capacity. For example, whereas in the past a larger CDMO might have focused on commercial quantities, they can now cater for the smaller batches associated with clinical trials and research, and then scale up to mass production when required. This is simplifying the supply chain for the customer accessing these services. What to Look For in a CDMO So, what should you consider when choosing a contract partner? It’s important that it can offer a multitude of capabilities, however, a CDMO should go beyond having an extensive offering. M&A activity can help a company to expand its portfolio, but if the facilities that are acquired are not fully integrated with the rest of the company’s operations, this can cause delays in the supply chain. As such, you should look for a CDMO that has a cohesive approach to its development and manufacturing services. 74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The ability to manage complexity is also key as increasingly challenging, and often highly potent molecules, are entering the supply chain. So, for example, if you’re developing and manufacturing a complex molecule which requires hazardous chemistry, then it is important that your CDMO is equipped to manage this and that they have the expertise to do so safely. There is no substitute for good people, with strong experience. Selecting a CDMO with a rich heritage in the API space will go a long way to ensuring you receive seamless service as well as a high-quality product. A comprehensive understanding of API projects will also allow your CDMO to tailor its solution to suit your project requirements. As well as providing an extensive range of capabilities, your contract partner should also be committed to continuously developing, and investing in, its technology and innovation strategy. It’s important to select a CDMO that is not only technically agile but also capable of implementing innovative process engineering solutions.

Final Thought As a result of changing customer requirements, full-service CDMOs that both develop and manufacture APIs are coming to the forefront of the market. An industry-wide demand for lower prices, increased efficiencies and the need for complex technologies are all driving the demand for these full-service providers that help to simplify the supply chain. Selecting the right CDMO can improve cost-efficiencies as well as reduce the time to market. However, it is important to ensure that your CDMO’s offering goes beyond an array of capabilities. Namely, experience, track record and a seamlessly integrated service are also of vital importance.

Kevin Cook CEO of Sterling Pharma Solutions and is responsible for strategically ensuring compliance, growth and profitability for the UK-based contract development and manufacturing organisation (CDMO). He has over 30 years’ experience in the pharmaceutical industry, having worked at a number of pharmaceutical companies and CDMOs before joining Sterling in 1993. In January 2014 Kevin was appointed as president and in 2016, he led the business through a management buy-out (MBO) to form Sterling Pharma Solutions, which is now the largest independent API CDMO in the UK. Email: kevin.cook@sterlingpsl.com

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 75


Manufacturing

Innovations for Prefillable Syringes

The field of prefillable syringes is constantly turning up new trends and developments, driven by new active ingredients and a desire for patient safety at affordable costs. As a manufacturer of prefillable syringe systems, we respond to these trends with a series of new developments and improvements in accordance with the demands of the pharmaceutical industry, doctors and nursing staff, and the patients themselves.

Pharmaceutical customers are interested in syringe systems that fulfill extremely strict requirements in terms of quality and can be filled without any problem, thus keeping additional costs to a minimum. In particular, current approaches include ways of adapting syringe systems to the requirements of new formulations, most of which are produced using biotechnology. Development is focusing on facilitating higher dosage volumes per injection, dealing with higher viscosities and overcoming the sensitivity that the liquid formulation has to some of the syringe’s individual components. Patient safety when using the syringe system is always at the forefront of all research: technical properties such as break resistance and reliable force regulation when emptying the syringe are deal-breakers, especially when it comes to integration in automatic injection systems. The Effective Dosage, Injected Safely Modern injectables in prefilled syringes are classed as “combination products.” Prefillable syringes are filled with a variety of medications – most of which are relatively expensive and produced using complex biotechnological processes. The additional therapeutic value for this process is closely linked to ensuring that the injectable and the syringe system work together smoothly. As such, the requirements placed on the syringe as an “interface” between the medication and the 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

patient are becoming increasingly demanding. The effective dosage needs to be injected safely. All the more important, then, to ensure that the syringe itself is of consistently high quality – after all, it needs to be able to store the medication safely (primary packaging) and make the injection itself safe, patient-friendly and as painless as possible (injection device). With this in mind, our company has extensively investigated the functionality – i.e. the break-off and slipping forces – with a number of stoppers in order to help pharmaceutical customers choose the appropriate injection system. The functionality of the syringe is also essential to its integration in automatic injection systems, a factor which is becoming increasingly important. High-volume Syringes of Up To 2.25 ml In addition to the “traditional” 1 mm long syringe, a second important format – the 2.25  ml syringe – is now becoming more established for certain applications. High-volume syringes mean that injections do not need to be carried out as frequently. They also allow patients to be injected with medication that acts as a deposit for a long-term effect, or based on a number of reasons, for which higher concentrations

2.25 ml needle syringe

are unfeasible or impossible. In all these cases, high-volume syringes represent a significant expansion to the range of therapies a doctor can offer. Among other products, we offer a 2.25 ml syringe that allows subcutaneous injection for such applications. Together with the matching stopper, this syringe is the perfect packaging and device for volumes of up to 2.25 ml. A variety of caps and stoppers are available from many different manufacturers.

Figure 1, High-volume prefillable syringes – 2.25 ml needle syringe Summer 2017 Volume 9 Issue 2


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Manufacturing for our customers and drastically minimise rejection rates among our pharmaceutical customers.

G3 camera system for maximum quality

Injecting Highly Viscous Medication Painlessly Increasing numbers of biotechnologically produced medications are highly viscous. When the syringe is emptied into the tissue through the cannula, this leads to high backflow forces, making injection more difficult. The aim of making injections quick and painless can be achieved using needles with a larger inside diameter: “thin-walled” cannulas allow a higher flow rate per unit of time, at a lower pressure. They also reduce shearing forces, which can sometimes impair the often-sensitive liquid formulations. The company caters to the requirements of modern injectables with its range of thin-walled cannulas. In addition to the traditional 27G cannulas, we also have 29G, 26G and 25G thin-walled cannulas. We also offer a 23G thin-walled cannula for extremely viscous medications. Minimising Interactions with Active Ingredients Two components of the syringe are of particular significance when it comes to interaction with sensitive medication: silicone oil, which is used as a lubricant in prefillable syringes, and residual traces of tungsten, which can remain in the syringe from the manufacturing process for the glass body. Silicone oil can be kept to a m i n i m u m u s i n g b a ke d - o n siliconisation, a process that Gerresheimer has offered for many years with its Baked-on RTF® syringes. Baked-on siliconisation ensures that far fewer silicone oil particles remain in the syringe. Traces of tungsten can be significantly reduced using a special washing process, or avoided 78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

completely by using a special ceramic as an alternative pin material. These production techniques enable Gerresheimer to meet the strict requirements of its pharmaceutical customers. Extremely High Break Resistance We have carried out extensive studies on the break resistance of glass syringes. In addition to the break resistance of the

Looking to the Future Our company is constantly working in close collaboration with its pharmaceutical customers in its own labs to further develop and improve existing injection systems. Highly viscous and high-volume injections are just two examples of the developments in the administration of modern medication, and the solutions a packaging manufacturer can offer in this field. Both our labs and our production teams are staffed with experienced, highly trained workers and are fitted with the latest equipment. In addition to our own ideas, our company can also implement customer concepts within a predefined schedule and cost framework.

G3 camera system for maximum quality

finger flange, it is also possible to significantly improve the stability of the shoulder area and the cone. The newly developed Valor glass also offers further improvements in terms of break resistance. High break tolerance and compact dimensions are important parameters for a prefilled syringe, especially when using automatic injection systems. High Process Quality = High Product Quality The modern production technology used for glass forming, needle mounting and the “ready-to-fill” (RTF) process ensures extremely high product quality. Sophisticated camera technology (G3 camera system) and transporting syringes individually during the RTF process to avoid glass-to-glass contact are just two examples of the measures we take in order to improve quality

Bernd Zeiss Manager Technical Support Medical Systems Business Development. Gerresheimer Bünde GmbH Dipl.-Biol. Bernd Zeiss studied biology, microbiology and chemistry at Goettingen University, Germany. Today Bernd Zeiss is part of the Center of Excellence for Prefillable Syringes in Buende. As Manager Technical Support Medical Systems he concentrates on drug-container interactions, new developments in the field of prefillable syringes (e.g. materials like COP), on technical studies related to PFS and on technical documentation. Email: b.zeiss@gerresheimer.com

Summer 2017 Volume 9 Issue 2


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 79


Manufacturing

Mitigating Risk Roche's Approach to PAT Implementation in a Sodium Borohydride Product Roche Ireland is a manufacturer of active drug substances. Many compounds are synthesised from raw materials in multi-batch and multi-ton quantities over extended time periods. The repetitious nature of the multi-batch business has proven a rich source of opportunity for process analytical technologies (PAT) applications at Roche, for over 15 years in some cases. The key focus has been the integration of the PAT applications into the existing manufacturing systems such as automation, IT, QC, QA, maintenance and R&D, to mitigate risk and improve process efficiency. This case study specifically looks at the approach to PAT implementation on one such process with a sodium borohydride reduction.

The Opportunity Methylfuranoside is a starting material in the synthesis of an anti-cancer drug, manufactured on a large scale in Ireland. The manufacturing of the methylfuranoside involves a hazardous reduction of the thermally labile tosylfuranoside with sodium borohydride reagent as shown in Figure 1. The reaction is carried out near 80 °C with hydrogen gas evolution, foaming, and the precipitation of tosylate salts. The sodium borohydride is converted to a borohydridetriethylamine complex during the reaction, with the temperature strictly maintained at less than 90 °C due to the thermal instability of the tosylfuranoside. Unreacted sodium borohydride (up to 20 % by weight) accumulates naturally during the reaction. Safety First In the original process for the reduction of the tosylfuranoside to methylfuranoside, the sodium borohydride was added to the reaction in 15 kg aliquots as a safety measure to reduce the risk of excessive sodium borohydride accumulation. The reaction of the borohydride was confirmed by 80 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 1. Reaction Scheme

Figure 2. Mid-IR spectra observed following the aliquot additions of sodium borohydride in a laboratory reduction experiment.

the heat-spike/temperature rise observed after each addition. The next aliquot of borohydride was only added when the reaction temperature had fallen to a predetermined level.

borohydride could be followed in great detail using inline Mid-IR without interference from the evolved gas, foaming, and precipitated sodium tosylate (Figure 2).

The Problem In a new optimised process, the heat-spike which signalled the reaction initiation had been observed in the laboratory during process development, but not to the same extent as found at production scale. The lack of a reliable heat-spike in the new process is related to the levels of isopropanol solvent entering the reaction with the undried tosylfuranoside. After risk assessment, it was decided that an alternative risk mitigation solution was required before the new process could be used.

ReactIR™ was equipped in the laboratory with a silicon crystal (SiComp™) ATR probe and a K4 light-guide in order to detect the borohydride peaks which occur above 2000 cm-1, and to achieve optimum sensitivity. Each of the key reaction steps are clearly detected by the Mid-IR system. These key events include the sharp increase in the dissolved sodium borohydride peak at 2216 cm-1 after each aliquot addition, the subsequent slow decrease in the sodium borohydride peak and triethylamine peak at 2799 cm-1 as they react, leading to an increase in the borohydride-TEA complex peak at 2385 cm-1, and reduction of the tosylfuranoside peak at 1600 cm-1.

A PAT Solution Mid-IR had been used in the laboratory to investigate the original process (during technology transfer), and in the development of the new process. The reaction of the sodium

PAT Implementation All PAT solutions start as feasibility studies; a positive outcome of a Summer 2017 Volume 9 Issue 2


All NEW


Manufacturing feasibility study can lead to a business proposal. The business case decision is made with reference to all aspects of the drug substance manufacturing business including safety, return on investment (ROI), site development, regulatory impact, etc. In-process Mid-IR was investigated for use as a possible process safety risk mitigation technology, which was proven and accepted. Extensive risk assessments, FMEA, HAZOP, LOPA, etc. were carried out to ensure the revised process would deliver the product safely. The Mid-IR system was installed in October 2012, and has been operating continuously and successfully since (Figure 3).

Figure 3. Installation of the METTLER TOLEDO ReactIR 45P system at the bottom of the Tosylfuranoside reduction vessel (15,000 L). MidIR operation is continuous 24/7.

Seeing the Chemistry Mid-IR is ideally suited as a PAT tool. It provides readily interpretable spectra with peaks directly associated with specific chemical components. It is rugged and relatively immune to physical interferences caused by bubbling and particulates, which severely impact the measurements from other spectroscopic techniques. Mid-IR is almost universally applicable to all chemistries, both inorganic and organic, and provides both quantitative and qualitative information on the chemicals as they change in response to the physical processes applied to them. All PAT Data is Useful Figure 3 shows the installation of the in situ Mid-IR directly into the 82 INTERNATIONAL PHARMACEUTICAL INDUSTRY

borohydride reduction vessel. The recycling of the reactor contents during the borohydride addition was not an option because of safety reasons, in particular possible line blockages. The instrument is cooled with instrument air and the light-guide is flushed continuously with process nitrogen (cryogenic, oil free). The instrument is controlled by dedicated METTLER TOLEDO iC process control software, and integrated with the manufacturing DCS process control system. The Mid-IR process data is delivered to the site process information (PI) database, and integrated with all process data for general access. The instrument is permanently on and acquiring spectra continuously. As a general rule, the changes observed in the spectra of the Mid-IR can be correlated to the changing conditions in the reactor, such as filling and emptying at the beginning and end of the reaction, and during solvent washes and reactor cleaning. The responses of the Mid-IR to process change can be used to evaluate and confirm the operational status of the PAT system. Match the Probe to the Process Figure 4 shows the Mid-IR spectral data translated into changes in the relative amounts of some of the chemical components during the borohydride addition and the reaction. The rapid increase in the sodium borohydride (light blue) in the solution is always followed by a slower exponential decay in the borohydride peak as it reacts. The decrease in the borohydride peak coincides with the previously seen

heat-spike. This decrease also coincides exactly with a dramatic decrease in the triethylamine peak (orange) and the tosylfuranoside peak (green). The increase in the borohydride–triethylamine complex (dark blue) is less dramatic, but follows closely the reaction of the borohydride. The reaction proceeds with the same profile as each aliquot is added, but with the accumulation of more borohydride after each addition. After the last aliquot is added, the reaction is aged. Process Knowledge Must Lead to Process Control In the single isolation process, the in situ Mid-IR showed an unexpectedly large decrease in accumulated sodium borohydride during the reaction age, which was not observed in the original process. This disappearance of the accumulated borohydride during the age was also associated with persistent gas evolution and foaming. There was little or no foaming or gas evolution observed during the aging in the original double isolation process. Further Mid-IR studies in the laboratory have shown that an isopropanol (IPA)-borohydride complex is formed during the reaction. The IPA solvent from the undried tosylfuranoside reacts further with the unreacted borohydride, and also with the borohydride-triethylamine complex during the age (higher temperature) liberating hydrogen and triethylamine. The reaction completion and downstream processing proved problematic in the initial batches from the single isolation process. The loss of accumulated sodium borohydride as evidenced by the Mid-IR was key to understanding

Figure 4. Mid-IR trend data for output to the process control system (PCS) and the process information (PI). Summer 2017 Volume 9 Issue 2


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 83


Manufacturing the root cause of these process problems. The in-process Mid-IR system was instrumental in providing a solution to the process problems. The goals for throughput, plant usage, and manpower were achieved within a few weeks. Eliminate the Sample At the end of each borohydride reduction, the batch is physically sampled to confirm reaction completion. This sampling involves the recycle of the thick reaction slurry through the reactor recycle loop (acceptable levels of tosylfuranoside at this stage). If the sample completion check fails, then the batch is heated further to effect completion. A safety sample is also taken at the start of the reduction reaction prior to borohydride addition, to ensure that sufficient triethylamine is present. Early in the original double isolation process it was found that failed completion checks were caused by small amounts of residual tosylfuranoside left in the recycle loop after the initial safety sample. This problem was solved in the double isolation process by recycling the reaction mixture through the recycle loop toward the end of the reaction age in order to bring any unreacted tosylfuranoside into the vessel, to react it with the excess sodium borohydride still present in the reaction. However, in the new single isolation process, up to 20 % completion check failures were observed even when this recycle was carried out. The Mid-IR clearly showed that in the new process there was little or no unreacted borohydride remaining by the time the recycle operation was carried out. It was considered an unacceptable change to recycle the batch earlier in the reaction. It was decided to replace the initial physical safety sample with an in-process Mid-IR measurement of the triethylamine level in the vessel (Figure 5). This approach was successful and eliminated all completion check failures. PAT Sustainability Figure 6 shows the yield improvement and batch consistency since implementing the new single isolation 84 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 5. A typical borohydride reduction reaction Mid-IR trend over a one-week period demonstration of the rhythmical nature of the process from batch to batch.

process supported by in-process Mid-IR and QC-PAT. The average yield increased from 69 % to 77 %. The elimination of the completion check failures was a contributor to the improved yields through the elimination of prolonged age times. The single isolation process delivered the throughput increase of four batches per week, (instead of 2.5/ week) with zero failed batches (25 % failure rate before QC-PAT).

The Mid-IR has been used for additional MeF (methyl furanoside) campaigns over two years. The system has performed well over that time, requiring only preventative maintenance/ calibration and yearly IQ/OQ. The PAT system is fully integrated into manufacturing operations, the IT network, and QC procedures. The direct benefits from the single isolation process have been further consolidated:

Since the new process started, over 200 successful batches have been completed with zero failed batches since the introduction of the QC-PAT virtual sample at batch 60. The new process led to an improvement in manpower by going from an eight-person operation per shift to a six-person operation. In addition to much-improved worker safety, the implementation of the new process achieved a reduction in mass intensity (i.e. all materials used in the synthesis of the product) of 15 % (primarily from a 3000 L reduction in solvent per batch).

•  8 % yield increase •  15 % reduction in mass intensity factor (all materials used in the process) •  25 % reduction in equipment •  40 % reduction in manual handling operations •  Elimination of significant site safety risk by removal of drying step •  14 % improvement in production reliability •  € 60,000 reduction in energy costs per campaign •  Use of PAT to: •  Continuously monitor the reaction to ensure process

Figure 6. Benefits of new single isolation process. Summer 2017 Volume 9 Issue 2


Manufacturing safety • Eliminate IPC failures • Eliminate physical QC sample • Reduce exposure risk to a hazardous material • Implement the new process safely • Increase process understanding • This process change resulted in an overall favourable profit impact of € 3.8 million in one year vs. target due to yield and throughput improvements. • The single isolation process recently received Roche global green chemistry and innovation awards.

The Future for PAT at Roche Ireland Bridging the Gap Between QC and Real-time Process Control QC-PAT moves the QC function closer to the manufacturing process and closer to real-time process analysis. QC-PAT provides an independent expert evaluation of PAT raw data using proven analytical methodologies. QC-PAT verifies the quality of PAT raw data, upon which process decisions may be made in real time. An interesting feature of the QC-PAT concept is the possibility that a QC-PAT virtual sample analysis required by the production site may be performed by any QC-PAT individual from any

other location, no matter how remote they may be. This feature may be of interest to those sites where the availability of analytical support is limited in number or even restricted to particular times. Toward Continuous Process Verification The borohydride reduction described here is a striking example of the effect PAT can have on an individual chemical process, and on the systems and organisations required to carry out that process. The ability to “see” individual chemicals non-convoluted with other chemistries as they progress along a desired reaction path in a complex reaction mixture using in-process Mid-IR is a tremendous advance in PAT. This is in contrast to the traditional manufacturing approach where we infer the process path by reference to external process parameters such as temperature and pressure, and then verify the process performance much later through downstream analysis. For the process discussed here, it is planned to define the relative kinetics of the reaction and to monitor the chemical path followed by each chemical component in real-time batch reactions using the in-process Mid-IR. The adherence of the chemistry to the desired reaction path may be defined as a process quality (PQ) parameter. It is hoped that through such continuous process verification efforts, the requirement for downstream analysis will be reduced or even eliminated, and that a given minimum acceptable value of PQ may be specified for a process. Downstream QC analysis will not be required for values above the specified PQ, only for batches where the PQ value is below the specified value.

Dr John O’Reilly PAT Technology, Roche Email: joreilly@nuigalway.ie

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 85


Packaging

From Concept to Solution: Designing to Enhance the Multiple Roles of Pharma Packaging When you walk into a store or pharmacy and see multiple similar products in the same competitive space, it is easy to understand the impact that packaging design and branding can have on consumer purchasing decisions. The initial interaction an end user has with a product – from seeing an eye-catching design and taking it off the shelf to touching the product and reading the information – matters greatly in building a lasting connection. It is important to recognise that this process does not just occur when looking at FMCG purchasing decisions, but in every market where packaging is concerned. Additionally, packaging design doesn’t just contribute to that first moment of purchase, but throughout the whole customer journey. How a product is stored, presented and organised in its packaging affects its entire usage.

In the healthcare and pharmaceutical industry, packaging design is crucial as the customers are patients, who rely on the medication the pack contains. Healthcare packaging must therefore be simple to open, convenient to use and easily distinguishable. It also plays an important role in increasing patient adherence, which the World Health Organisation (WHO) defines as the extent to which a person’s behaviour – for example taking medication, following a diet, or executing lifestyle changes – corresponds with agreed recommendations from a healthcare provider. Patient adherence is currently one of the biggest challenges that the industry is facing, resulting in a growing number of pharmaceutical companies amending their packaging to try and help improve levels of adherence by patients. In addition to low patient adherence levels affecting healthcare efficacy, it is also extremely costly to the industry. In fact, research shows that patients not taking their medicines in line with agreed recommendations from the healthcare provider costs the 86 INTERNATIONAL PHARMACEUTICAL INDUSTRY

NHS £500 million annually which, in context, is equivalent to 30,000 kidney transplants or an extra 21,000 qualified nurses.

home environment, that they are equipped with all the packaging and information required to support proper usage.

Breaking down all the roles that packaging plays in a patient’s journey, a number of features that can encourage patient adherence at each stage can be identified. Packaging can be designed specifically to:

Communication and Information Of the five roles listed above, arguably the most important in terms of improving patient adherence is the range and depth of information provided. In fact, in its ‘Adherence to Long-Term Therapies: Evidence for Action’ report, the WHO references “the resources, knowledge, attitudes, beliefs, perceptions and expectations of the patient” as key drivers of improving adherence. Packaging and literature must help to communicate all the information needed in order for patients to be able to successfully take their medicines, ranging from simple dosage instructions on over-the-counter drugs to comprehensive directions for carers or medical professionals. With the latter, communication is particularly important, as there are several layers of information exchange that must occur; from the prescription to the carer, and then from the carer to the patient. By understanding these potential barriers to communication, it becomes clear that the packaging serves as an integral part of the communication process, aiding the medical professional to quickly recall key information about the product and its usage to share with patients.

• Contain its contents • Physically protect its contents • Communicate information about its contents • Provide security to its contents • Aid in the transportation of its contents

It is essential to keep these five roles in mind when thinking about design, applying concepts such as semiotics, ergonomics, colour and trends to each one where appropriate. To explain this in more detail, this article will review examples based on in-home medical devices and over-the-counter drugs, to illustrate some of the ways that incorporating good design practices into packaging can benefit multiple stakeholders. Containment and Accessibility On a basic level, packaging is a means of containing and delivering a product to a user. Thinking carefully about accessibility is essential; something as simple as how a carton opens can make a considerable difference to the end user. Using the hypothetical situation of an in-home medical product that is delivered to the patient at a pharmacy, if the dispensing clinician cannot access the product inside, they will not be able to successfully provide an appropriate explanation to the patient. A pack that allows the medical professional to demonstrate the item, easily re-pack it and issue it to the patient helps ensure that the product and related information stay together. This gives the patient and caregiver confidence in their

I n o r d e r t o e n s u r e t h at information is as clear as possible, pharmaceuticals need to provide detailed literature that is available in multiple languages, catering for all audiences. Text should be printed in a legible font face and size, with colours used if appropriate. Information should be delivered in an easily-digestible format – including features such as images, graphs or infographics in addition to blocks of text – to help aid understanding and reassure patients. Images are particularly important for those who are illiterate. According to Summer 2017 Volume 9 Issue 2


A GLOBAL LEADER IN MULTI-PAGE LABELLING

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Packaging use thermochromic inks that are activated by high or low temperatures to help patients monitor the storage conditions that may impact the efficacy of the drugs. Summary Every one of these basic elements has the ability to add value and increase patient adherence by utilising intelligent targeted design practices. Though these design tools may not completely solve the issue of patient adherence, employing these package design practices should not be overlooked. As pre-existing components in the delivery of drugs, the financial implications of the addition of information or protective structural elements to secondary packaging and literature is minimal. However, these adaptations are proven to substantially increase levels of patient adherence. Overall, developing a successful product should not end there, but should also enhance the delivery of that solution with effective and relevant packaging.

the UNESCO Institute of Statistics, in 2013 the global illiteracy rate was 15.9%, or one in six people. In addition, for those suffering with sight loss, or who are partially or fully blind, braille should be used. According to the WHO, 285 million people are estimated to be visually impaired worldwide; 39 million are blind and 246 million have low vision. If the packaging is too small and there is not enough space on the carton or bottle to supply the large volumes of information required, pharmaceutical manufacturers can employ features such as booklet or leaflet labels or booklet leaflets, allowing customers to simply flip and navigate through additional material. Protection and Transportation For the information communicated via packaging to be of use, patients and medical professionals must receive medicines in a complete and undamaged state. Packaging 88 INTERNATIONAL PHARMACEUTICAL INDUSTRY

therefore plays a vital role in the protection and transportation of medicines, ensuring that they are efficiently and safely delivered from the manufacturer through the entire supply chain. Simple factors, such as shape and structure, can help immensely when stacking and packing large amounts of content that need to be shipped, for example. On a more sophisticated level, more intricate structural elements can be installed. For fragile medical instruments, such as vials, packaging may need to include ‘crumple zones’ that are shaped to the contents’ form, ensuring that they are protected and are not prone to move when in transit. Protection does not just refer to transportation, however; it extends to the full journey of the medicine. Even when the drugs have been successfully delivered to the patient, consumers must be able to store the drugs safely when at home, often for a significant amount of time. For example, manufacturers can

Alan Davies Global Design Studio Manager for Essentra, brings together creative packaging design with extensive global manufacturing capability to reduce complexity in the supply chain and deliver engaging customer solutions. With over 20 years of experience enhancing some of the world’s top consumer brands both through agencies and in-house, Alan’s most recent achievement prior to joining Essentra includes reinvigorating the UK’s no. 1 boxed chocolate brand. Alan leads design within Essentra from the creation process to insights with a focus on helping customer’s brands stand out and reducing complications at the point of manufacture. This pairs the best of design with the knowledge of how to manufacture efficiently, saving valuable time to market and simplifying the design to production process.

Summer 2017 Volume 9 Issue 2


THINK INSIDE THE BOX PACKAGING PATIENTS CAN FOLLOW 6

By clearly displaying information and creating designs that make the pack easy to use, our packaging solutions can aid patient adherence.

5

1. TAMPER EVIDENT / RESEAL CARTON CLEAR TAMPER INDICATION

4

2. INFOGRAPHICS SIMPLE AND CLEAR INSTRUCTIONS 3

3. TEMPERATURE INDICATORS MONITOR STORAGE CONDITIONS 4. CRUMPLE ZONE DESIGNED TO PROTECT CONTENT 5. ALERT CARD REMOVABLE INFORMATION CARD

2

6. INSTRUCTION BOOKLET EASY TO NAVIGATE

ESSENTIAL SOLUTIONS, DELIVERED DISCOVER MORE AT WWW.ESSENTRA.COM ©2017 Essentra

1


Packaging

Crunch Time: The Impact of Serialisation Requirements on Packaging Operations A Q&A with Allison Gilpin, Business Unit Manager, Global Serialisation, and Ray Hook, Manager Global Serialisation Services, PCI Pharma Services The November deadline for including unique product identifiers on prescription drugs is putting a strain on multiple parts of the industry, much of which is ill-prepared to meet the target. Here, we look to the experience of a company that is ahead of the curve for lessons on how to manage and ease the transition to serialisation.

More than three years have passed since the US federal government signed the Drug Supply Chain Security Act (DSCSA) into law. Yet, despite facing a series of upcoming deadlines, many companies have held off on adapting their supply chains to the incoming requirements. Now, with the November serialisation deadline looming, companies cannot afford to wait any longer. Companies trying to meet the deadline from a standing start today will face acute challenges. The transition to serialisation of products is logistically complicated during normal times. The coming months, in which an entire industry is seeking the equipment and expertise needed to serialise products, will not be normal times. Lead times are extending and competition for resources is intensifying just as companies need to move forward at full tilt. Faced with this situation, there is value in looking to companies that have taken a very strategic approach to DCSCA readiness and timely implementation for lessons in how to manage the implementation of serialisation. PCI Pharma Services has been serialising commercial products for five years for US, European, and emerging markets. Along the way, PCI has adopted AntaresVision as its enterprise serialisation system at 90 INTERNATIONAL PHARMACEUTICAL INDUSTRY

all its European and North American sites, and qualified Marchesini for additional equipment solutions. Q&A Introducing serialisation across one of the largest packaging operations in the industry has been a challenging, but ultimately highly beneficial experience, according to Allison Gilpin and Ray Hook, PCI Pharma Services. In this Q&A, they discuss the transition process, what they have learned along the way, and how companies that still have work to do to meet the deadline can prepare. When did you get started with serialisation and how has the transition gone? Hook: In the transition from our home-grown serialisation technologies to a scalable enterprise-level vendor solution, our first Antares-based serialisation line went live in 2014. It was a voyage of utter discovery. In the last three years we have gone from knowing the theory, to becoming an organisation containing expert practitioners in serialisation. Gilpin: It was a very big learning curve. There’s an incredible amount of information, knowledge and experience required. We take people into our team and, to a person, they are shocked by how much is involved in serialisation. No matter how

experienced they are as an engineer or how experienced they are as a project manager, this is a completely different world. Can you give a sense of the scale of the serialisation transition? Hook: Globally, PCI packages over 8000 items. Most of those items that become serialised will effectively go through an entire launch process in the transition. The customer has to make their artwork serialisation ready. They have to manage the inventory so non-serialised product goes out first. We have to go through a significant batch record and process change to move from non-serialised to serialised. Gilpin: It’s a huge amount of work and it’s not just an engineering effort. It touches many functional departments: marketing, purchasing, project management, quality, regulatory, operations, etc. We’re all engaging with serialisation. It’s a huge learning curve for packaging teams, line leads, supervisors, quality inspectors, and everyone else within the facilities. Everything they do normally needs to be re-evaluated and thought of differently. Effectively, where we had been making 100,000 units of the same thing in a batch, now we are making and tracking 100,000 unique items in that batch. Serialisation is a major paradigm shift for the pharmaceutical industry. Summer 2017 Volume 9 Issue 2


Packaging What will be the consequences of failing to meet the deadline? Hook: It will be illegal for non-serialised products to enter the supply chain on November 27th, 2017. Any product going into a distribution centre is open for FDA or federal government sanctions, which could include fines for non-compliance. The polls we’ve taken indicate at least 50% of businesses are not ready as of today. What options are available to companies that are behind on preparations?

PCI partnered with industry leader Antares Vision for its global serialisation technology, including its FlexSuiteTM technology for standalone serialisation processes to support clients with achieving advancing industry deadlines in the US and EU.

How prepared is the industry? Hook: A large proportion of the industry is not ready. Those people who have not started are suddenly waking up realising we’ve got to get going. Lots of people are starting to place orders for equipment. Their challenge will be that from starting to evaluate a solution to putting the first line live is a 12-month cycle. There are nine months left today. Manufacturers of serialisation equipment, even though they’ve scaled up their build capabilities, are seeing an increase in lead times. We’ve seen delivery lead times increase from typically five to six months, to now seven months or more for a single piece of equipment, just over the last four months. So as 2017 progresses, I can see that increasing to eight or even nine months. This is going to put late adopters in a tough position. Gilpin: The staffing side is also a complex challenge. It’s going to require a lot of resources, whether it’s outside vendors or stepping up groups internally, to get everything in place for November. Many of our clients are relying heavily on consultant and contract resources to support their knowledge gap, but demand for those resources is also increasing exponentially. www.ipimediaworld.com

Hook: Customers can bring uncoded packages to PCI and we’ll run them through our Flexsuite™. The Flexsuite™ is designed to receive cartons of a wide variety of sizes, from a matchbox to a shoebox. It serialises the carton, which is then aggregated to the case and onto the pallet. What is the purpose of aggregation? Hook: Operationally, at the end of a packing run, a critical step is to understand where 100% of the serial numbers have gone, both viable numbers as well as those that were scrapped or not used. So conceptually, if you’ve got a packaging run of say, 40,000 units, which is not atypical, then you have a responsibility to understand where every one of those 40,000 numbers has gone. If a few are missing, we would need

Serialisation requirements vary by country and region, including the US DSCSA, the EU FMD, and emerging market countries such as China, Brazil, Turkey, South Korea, Saudi Arabia and others.

to investigate and that happens immediately in the batch. With the advanced technologies involved, it is a very robust and controlled process to provide that assurance. Serialisation gives you that control and positive verification. By reading boxes at every stage of the packing hierarchy, we know which cases are correctly built and can discount them as being the cause of the missing numbers. This process, known as aggregation, allows us to focus on the areas of the packaging suite that may have caused the issue. When we’re aggregating, we close a line down in five to ten minutes. Whereas not aggregating, it can take over an hour. That’s lost production time. Gilpin: The other significant benefit from aggregation is in the broader supply chain. With aggregation, you know specifically what is on each pallet, what is in each case, etc., due to the electronic verification and parent-child data pairing. This benefits the manufacturer, the wholesaler, and the downstream trading partners. Without the benefit of the electronic aggregation, the supply chain participants are left to “infer” what is contained on a pallet or a shipping case, which has been proven to be extremely problematic. Are there any operational benefits of serialisation?

Product aggregation yields substantive benefits for both the product supply chain traceability and adding positive operational process controls in packaging operations.

Hook: Yes, there are multiple benefits. Primarily, serialisation provides control and positive verification. For example, when serialising, if a creased label gets put onto a case so you can’t read the barcode and the case is rejected, the contents of the case become available for INTERNATIONAL PHARMACEUTICAL INDUSTRY 91


Packaging repacking, whereas previously anything that came off the line was rejected and repacked. The rejection and repacking process destroyed cartons and some leaflets. As such, serialisation reduces waste and saves time. Serialisation also supports automation. At the front end of the line, software has replaced manual entry of lot numbers and expiry dates. This has increased quality standards while cutting resource use. Similar benefits are realised by deploying cameras at the back end. There’s no need to weigh a case to check it contains 24 packs. The camera keeps count and the system labels accordingly. How are post-packaging modifications for sampling, damage, and rework handled?

30% impact on productivity. We can agree with that from our earliest lines. But now, with the experience we have, we’re really not seeing a great downturn in the productivity of a line. In some instances we are seeing the new equipment and processes are improving control and efficiency.

features such as photo-reactive elements to packaging so they can verify its authenticity by exposing it to light of a particular wavelength. People may alsoadd microcode or intentional design defects that a counterfeiter may overlook when copying product packaging and leaflets.

How do the incoming US requirements differ from those adopted in the European Union?

Gilpin: This is necessary because serialisation alone cannot stop counterfeiting. A multifaceted approach is required. Layered technologies and a rotational approach to their strategy, paired with effective serialisation, significantly increases their chances to mitigate counterfeiting and diversion activity.

Hook: The US uses a true track-andtrace system. Products are verified at each step in the supply chain. This will enable the US to address counterfeiting and help FDA eliminate bad actors from the supply chain.

Hook: Our Antares platform supports post-production interference with serialised material after packaging for situations like sampling, damage, or rework. If a customer asks for 10 additional samples after a batch has been completed and closed, we can go back and open a pallet, take 10 units out of a case, reseal the case with a new partial case label, and reseal the pallet with a new quantity using the Antares system while amending the aggregation data set. This can all be done in the warehouse, rather than needing to create some special operation. The same system handles damaged products and ensures pallet-level and aggregation hierarchy data we send to customers is accurate, not a theoretical figure based on production output.

Gilpin: In Europe with the Falsified Medicines Directive (FMD), the process is very different. The manufacturer tells a European government the serial numbers they’re entering. They don’t tell a distribution centre at all. The next normal verification step is when a pharmacist is about to hand a pack to a patient. Other than some special auditing, which is relatively low-level, there are no checks throughout the supply chain in Europe. Instead, Europe is mandating the use of tamper-evident technology on serialised packaging. These technologies, which destroy packs that are opened illegally, substitute for the step-by-step verification of the US approach. Most people either love the US model and dislike the European model, or vice-versa. Yet both are valid ways of managing supply chains.

What effect has serialisation had on overall equipment effectiveness and productivity?

What other approaches are companies using to prevent counterfeiting?

Hook: There is a lot of evidence that early implementation of serialisation had a negative 20% or

Hook: Layering of anti-counterfeiting technology is popular, particularly in Europe. Companies are adding

92 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Allison Gilpin Business Unit Manager, Global Serialisation, PCI Pharma Services Allison Gilpin is responsible for leading programme management across PCI’s Global Serialisation initiative, working with clients to assure success in achieving US, EU, and evolving emerging market requirements. Gilpin features an extensive background in project and commercial business unit management for PCI’s commercial packaging operations, having supported a multitude of emerging pharma, mid-tier and large multinational pharmaceutical clients.

Ray Hook Manager, Global Serialisation Services, PCI Pharma Services Ray Hook is responsible for leading technical evaluation and implementation of serialisation technologies across PCI’s global supply network. Hook features a diverse background and technical expertise in machine automation and vision inspection, including founding his own vision inspection company prior to joining PCI.

Summer 2017 Volume 9 Issue 2


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SMi proudly present their 6th annual conference…

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PDA Europe Conference, Exhibition

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19-20 September 2017 Cologne | Germany

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Advancements in drug development and biotechnology are transforming the way primary packaging and delivery systems are viewed during development and throughout the product lifecycle. Keep ahead of new challenges brought about by these new developments by attending the 2017 PDA Container Closure, Devices and Delivery Systems: Compatibility and Material Safety Workshop, Oct. 2-3, in Washington, DC. At this Workshop, you will find solutions for issues related to material compatibility and safety for container closure for devices and delivery systems. Industry and regulatory experts will explore such topics as strategies for biocompatibility testing, holistic safety and quality assessment, particle challenges associated with delivery systems and devices and compatibility of delivery systems with biologics. Quality considerations for combination products and devices will also be discussed.

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Abzena AirBridgeCargo Airlines Bioclinica Butterworth Laboratories Limited Cancer Vaccines / SMI Capsugel Cobra Biologics Container Closure, Devices and Delivery Systems / PDA Denny Bros Ltd EcoCool GmbH Emphasys Envigo Essentra Eurofins BioPharma Product Testing ExpreS2ion Biotechnologies Gaplast GmbH HGF Huber Kältemaschinenbau AG International Pharma Regulatory Summit 2017 Matcon Micro Automation Mikron Group Muller GmbH Natoli Engineering Company Inc Nemera Northern Health Science Alliance Orphan Drugs and Rare Diseases / SMI Packaging Coordinators, Inc Pharmaceutical Freeze Drying Technology / PDA Pharmaworld.tv Powder Systems Limited QuickSTAT Research Quality Association Sartorius Stedim Biotech Valsteam West Pharmaceuticals Wickham Laboratories Ltd

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

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