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Volume 10 Issue 2

Peer Reviewed

Strategies Adopted by Branded Drug Manufacturers Against Para IV Filers Patient Safety & Elemental Impurities ICH Q3D AI & the Transformation of Life Sciences What does the Future Hold? Data Integrity and Preservation in Pharmaceutical Manufacturing Technology’s Role in Safeguarding Compliance Throughout a Drug’s Entire Life Cycle

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Contents 06 Editor’s Letter REGULATORY & MARKETPLACE 08 Keeping Track of Traceability – Preparing for the EU Medical Device Regulation DIRECTORS: Martin Wright Mark A. Barker BOOK MANAGER: Anthony Stewart anthony@ipimedia.com BUSINESS DEVELOPMENT: Alessia Giangreco alessia@ipimedia.com EDITORIAL: Orla Brennan orla@pharmapubs.com DESIGN DIRECTOR: Jana Sukenikova www.fanahshapeless.com FINANCE DEPARTMENT: Martin Wright martin@ipimedia.com RESEARCH & CIRCULATION: Virginia Toteva virginia@pharmapubs.com

Under the FDA (Food & Drug Administration) rule in the USA, manufacturers have been required to implement UDI (unique device identification) on all medical product packaging since September 2014. European manufacturers of medical devices will now face even tougher regulations to ensure their products are safe to use under new EU laws that are scheduled to come into effect from May 26, 2020. With this legislation coming into effect, Volker Watzke from Domino explains that manufacturers now have a responsibility to invest in a coding solution that allows them to apply traceability codes onto products as well as packaging. 12 Regulatory Trends and Developments in the Pharmaceutical Industry in 2018 In the 2017 fiscal year, the FDA issued 114 warning letters to pharmaceutical manufacturers contravening Current Good Manufacturing practices (cGMPs). This followed a trend of continual increase in warning letters, with 102 issued in FY2016 and 42 issued in FY2015. Though this rise suggests that pharmaceutical companies are slacking in the field of compliance, it is more likely to be a reflection of increased scrutiny within the FDA and of evolving areas of focus. In this article, Jennifer Lopez from Maetrics explores why this is the case, and looks at lessons learnt from this increased scrutiny.

COVER IMAGE: iStockphoto ©

18 Navigating Risk Management Plans (RMPs) in the Evolving Regulatory Landscape

PUBLISHED BY: Pharma Publications Unit B202.2, The Biscuit Factory Tower Bridge Business Complex 100 Clements Road, London SE16 4DG

Pharmacovigilance (PV) is a vital part of healthcare and for monitoring the benefit-risk profile of medicinal products. The purpose of the European Medicines Agency’s (EMA’s) risk management plan (RMP) is to “document the risk management system considered necessary to identify, characterise and minimise the important risks of a medicinal product” and thus to help sponsors plan their PV and risk minimisation strategy. This article, by Dr Prashant Dhanavade from Sciformix, explores the continuously changing regulations and procedures in PV worldwide.

Tel: +44 (0)20 7237 2036 Fax: +44 (0)01 480 247 5316 Email: info@ipimedia.com www.ipimediaworld.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 Autumn 2018. 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. 2018 PHARMA PUBLICATIONS / Volume 10 issue 2 – Summer – 2018

24 Strategies Adopted by Branded Drug Manufacturers against Para IV Filers This article by Trishna Chetry, T.M. Pramod Kumar, M.P. Venkatesh and Balamuralidhara V. from JSS College highlights the complex and critical regulatory strategies adopted by branded drug manufacturers against ParagraphIV filers in the past. The Hatch-Waxman Act 1984, also known as the Drug Price Competition and Patent Term Restoration Act, grants generic manufacturers the ability to challenge a patent without risking enormous damages from any possible infringement. The idea behind this incentive was to encourage generic firms to invalidate and challenge bad patents. As an outcome, patent infringement and a 30-month FDA stay period became a common scenario. DRUG DISCOVERY, DEVELOPMENT & DELIVERY 36 Trends in Drug Development – In Denmark and Globally The entire process from discovering and developing a potential drug candidate to its delivery into the human body

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Contents requires comprehensive knowledge about the root cause of the disease at molecular, cellular and genetic levels, and can be a costly and long-term process. Nevertheless, Danish biotech and pharma companies are still among the best in Europe when it comes to drug development and innovation. However, Dr Rasmus Beedholm-Ebsen at Invest in Denmark argues it is important to look into new methods in order to discover and develop new drugs, and to have an innovative approach when it comes to drug delivery.

Delivering about five litres of blood at an average of 75 contractions per minute, it is required to perform without interruption. Considering the high performance demands, failings can occur beyond normal wear and tear in the heart’s electrical system, the valves, and the muscle itself. Of all complications leading to heart disease, ischemia – the insufficient supply of oxygen caused by restricted blood supply to the cardiac muscle – is the most prevalent. Dr Roman Schenk of Recardio explores the possible solutions to this issue.

40 Model Systems for Studying the Human Gut Microbiome

58 Proposed Therapeutic Strategies for Cancer Using New Methods and Novel Approaches

A variety of in vivo, in silico, in vitro, and ex vivo model systems are available to researchers for studying the human intestinal microbiome, its functionalities and complex interactions with the host. Different models serve different purposes, all of them having their relevance as well as limitations and interdependencies. This article by Alexander Maue and Randi Lundberg from Taconic provides an overview of the most popular model system concepts, how they are being employed in gut microbiome research, and how they are complementary to each other.

In the history of cancer treatment, the main idea was initially to have one approach, using one method or treatment agent. After this concept, the approach became a bit more multilevel and then the treatment was considered under the concept of surgery, radiation or chemotherapy. Unfortunately, despite this change in the concept of the treatment, the clinical outcome is still poor since the overall survival or response rate hasn't changed dramatically. This article by Ioannis Papasotiriou from RGCC will try to propose possible options that may be added to the present concept or become standalone alternatives to cancer treatment based on cancer physiology and the latest developments in molecular oncology, as well as in molecular and cellular biology.

44 Brown Adipose Tissue as a Therapeutic Model for Obesity Treatment Obesity is a major concern for governments worldwide. In the UK alone, it is estimated that the direct costs of obesity to the National Health Service total £6 billion ($8.5 billion), with prevalence standing at an astonishing 27% in 2015. In the USA, the rate for adults is higher still, totalling 36.5%. For these reasons, obesity has been labelled ‘a national emergency’ by Jeremy Hunt, the UK’s health secretary and an ‘epidemic crisis’ by the US Surgeon General David Satcher (in 2001). Shahzad Ali from Plasticell navigates the causes and a possible solution to this critical issue. 46 HBP Biomarkers & Assay Development within Laboratory Practice “Sepsis is the most preventable cause of death”, and every hour it is not diagnosed will increase the probability it will kill the patient by 7%, so recognising the early signs and symptoms is therefore crucial. Because HBP (heparin binding protein), also known as cationic antimicrobial protein of 37kDa (CAP37) and azurocidin, directly contributes to the maintenance and progression of inflammation, Christine Leiper from Onorach explains that it is a potential diagnostic marker for the assessment of patients at risk of sepsis and should be studied further in large-scale clinical studies. 50 iPSC Models to Improve Efficiency of Drug Discovery and Development Stem cells attract a great deal of attention due to their developmental potential and lineage-independent characteristics. Adult stem cells, otherwise known as inducible pluripotent stem cells (“iPSCs”), are particularly favourable as research tools because they are derived from somatic cells such as blood, skin, or muscle. In this article, Angela Huang from Tempo Bioscience demonstrates that appropriate applications of iPSCs and their disease models will improve the efficiency of drug discovery and development in the coming years. 54 Novel Drug-based Strategies for Cardiac Regeneration Following Myocardial Infarction The human heart is one of nature’s engineering marvels, considering the requirement specifications for this fist-sized hollow organ that only weighs 250–300 grams. 2 INTERNATIONAL PHARMACEUTICAL INDUSTRY

64 Simplifying NMR for Fluorine-containing Samples Currently, more than 200 marketed medicines, and approximately one-third of the most successful – so called ‘blockbuster’ – drugs contain fluorine atoms in their structure. Fluorine-containing compounds span a wide variety of therapeutic classes: anti-cancer drugs, antifungal agents and NSAIDs (non-steroidal anti-inflammatory drugs), for example. Fluorine is also now commonly found in illicit and illegal drugs, including synthetic cannabinoids and psychedelic phenethylamines. Michael H. Frey and Ron Crouch from JEOL USA explain how we can use NMR to distinguish readily between these legitimate and illegitimate substances. CLINICAL AND MEDICAL RESEARCH 68 Patient Safety & Elemental Impurities ICH Q3D From 1 January 2018, the European Pharmacopeia (EP) and the United States Pharmacopeia (USP) have replaced the old methods for testing of heavy metals (USP <231> and Ph.Eur. 2.4.8) in raw materials with a new harmonised guideline “ICH Q3D”. Drug product manufacturers are responsible for providing a risk-based assessment of the elemental impurities, justifying that the contents for each of the 24 elements are below the exposure limit as described in ICH Q3D. Rie Romme Rasmussen from Eurofins explains that the elemental impurity level and variability must be established by validated analytical methods specific for each matrix to avoid biased results. 72 Understanding the Challenges in Designing and Executing Clinical Trials for Screening Tests Clinical trials for screening tests of a drug candidate take place at the very early clinical development, i.e. Phase I clinical study. The aim of such studies is to assess drug candidate safety, its actual fate in human body after administration (PK/PD data, metabolite identification, mechanism of elimination and excretion, etc.), its tolerance threshold (dose escalating) and its adverse effects. All of those make Phase I clinical trials crucial to the drug development process; Isabelle Decorte from Synerlab Summer 2018 Volume 10 Issue 2


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Contents proposes that designing and executing such clinical studies needs much preparation and planning. 74 Digital Devices in Clinical Trials Most pharmaceutical companies are investigating how digital devices can be utilised in clinical trials to improve the data foundation, and potentially assist in securing a faster time to market and improving patient retention. One common challenge stands out: how do you create a setup robust enough to allow you to include the output data as evidence? This article by Rune Bergendorff from NNIT discusses the common challenges faced and, based on network consultations with a group of pharmaceutical companies, it seeks to identify a viable path forward. TECHNOLOGY 78 AI and the Transformation of Life Sciences: What Does the Future Hold? From accelerating scientific breakthrough and spotting previously elusive patterns in unwieldy global data masses, to enabling greater drug personalisation, AI and machine learning could help change the role and business models of life sciences in future, as part of a broader transformation of the health value chain. Siniša Belina of AMPLEXOR Life Sciences explores some of the potential opportunities, and considers how companies might start to prepare for what lies ahead. LOGISTICS & SUPPLY CHAIN MANAGEMENT 82 Clinical Operations and Supply Chain Management: Sharing Perspectives to Maximise Patient Benefits Predicting patient enrolment in clinical trials is challenging. While early enrolment forecasts are often evolving, they are required by clinical supply groups to establish drug demand. The link between enrolment forecast and drug waste can be a source of frustration between clinical operations and clinical supply groups. How can supply planners create accurate drug forecasts from uncertain enrolment forecasts? In this article, Louise Oliver and Luke Moyer from the Almac Group contend that synergy is the key to optimising supply and maximising patient benefits. 86 GS1 Standards: Making Pharmacy Fit for the Future As our healthcare system faces increasing pressure to improve safety and efficiency, and to be a world leader in delivering care, for pharmacy this translates into the challenge of keeping medicines safe, using them more cost-effectively and keeping up to date with the latest legislation and technology. Counterfeit drugs are a global problem, and medicines spend is one of the biggest costs to the NHS. Legislation such as the Falsified Medicines Directive will make our pharmacies safer and central initiatives such as the Global Digital Exemplar programme are pushing Trusts to stay ahead of the game in their use of data and technology – Glen Hodgson from GS1 suggests that GS1 standards are key to both. MANUFACTURING 90 The Excipient Challenge Excipients are defined as any component(s) of a dosage form other than the drug substance. They are added for the purposes of enhancing production, aiding patient acceptability, improving stability and/or controlling release. 4 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Moreover, they play an important role in enhancing the processability and bioavailability of drugs by modifying their solubility and/or permeability, which is important information when selecting excipients for any new formulation. This article by Dr Carolina Diaz Quijano from OMYA explores the potential of minerals such as functionalised calcium carbonate, and what kind of formulations it will make possible in the near future. 94 What Pharma Producers Need to Know About Changing Regulations on Cleanroom Films and Anti-static Additives With new USP <661.1> regulations on plastic packaging materials for pharmaceuticals set to take effect in May 2020, and following this, USP <665> (formerly known as USP <661.3>) for plastics used in the drug manufacturing process bringing new requirements, it is decision time for processors and pharmaceutical users of anti-static polyethylene and polypropylene films. In his article, Steve Duckworth from Clariant provides an overview of these changes and how to be sure to protect the value of in-process APIs and finished drug products. 98 Data Integrity and Preservation in Pharmaceutical Manufacturing: Technology’s Role in Safeguarding Compliance Throughout a Drug’s Entire Life Cycle The life sciences’ relationship with technology has come a long way since Deloitte’s 2015 global life sciences outlook describing it as ‘operating in an era of significant transformation.’ Since the report was published, most in the industry have re-evaluated traditional methods of operations, put to bed (or at least put a plan in place to deal with) ineffective, costly, and disjointed systems and practices, and are embracing the positive change innovative technology can bring. This article by Mark Stevens of Formpipe Life Science suggests embracing this technological revolution to get the most out of the pharmaceutical manufacturing process. PACKAGING 102 The Falsified Medicines Directive – Are You Ready? The Falsified Medicines Directive 2011/62/EU, which is due for adoption in February 2019, will require pharmaceutical companies to apply serialisation codes to every applicable pack (OTC and some minor exemptions). As a consequence, artwork changes will be required, which all too often are treated as a rushed afterthought. The impending legislation will affect all prescription medicines for the European market. In this article, Gill Wright from Westrock MPs advises the first step to comply with this legislation is to get your artwork amended and approved. 104 Prefillable Vials for Dual Sourcing Trends toward sophisticated, innovative medications and increasingly individualised medicine are increasing the quality demands on the primary packaging being used and are also creating a new division of labour between the pharmaceutical industry and packaging manufacturers. Quality-optimised ready-to-fill products enable the pharmaceutical industry to focus on its core areas of expertise and free up capacity by eliminating the washing and sterilisation of packaging. Maximilian Vogl of Gerresheimer explores how prefillable vials enable companies to comply with the relevant ISO standards and pharmacopoeias, whilst also making it possible to process a large number of primary packaging types with minimal conversion required. Summer 2018 Volume 10 Issue 2


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Editor's Letter It has been an intense start to the summer: the Anglo Nordic Life Science Conference took place in May in London, and was a great success; last week I was representing Cobra Biologics at the Swedish political week “almedalen” on the island Gotland in the Baltic sea, where 40,000 individuals attended over the seven days and there was a great presence from the life science sector, including companies like AstraZeneca, Bristol-Myers Squibb and Novartis, to name but a few. The overriding take-home message in all the events I have recently attended is that there is great innovative research going on with amazing clinical results, but it’s getting the international life science sector to unite and work together instead of working in silos. This is where we hope that our magazine gives you the most Th i s i s s u e o f I P I features an abundance of highly topical issues such as the Falsified Medicines Directive, changing regulations on clean-room films and anti-static additives, Artificial Intelligence and the use of technology in the life sciences, as well as the latest trends in drug development, and the evolving regulatory landscape, to name a few. The uncertainty in every industry brought on by the UK’s exit from the European Union in terms of the future of trade, pricing, and marketing (not to mention the influence of President Trump on pharma giants such as Novartis and Pfizer) has left pharmaceutical companies lost in a barrage of red tape. It’s now our job to lift you, our reader, from this fog of confusion, and assist

up-to-date thoughts and information. Maybe we can take some learning from global organisations like the World Health Organisation or the World Bank?

Sciences explores some of the potential opportunities and considers how companies might start to prepare for what lies ahead.

In this edition, we hear from Invest in Denmark. The Danes are amongst the happiest people on the planet and have been ranked as having the third best higher education in the world. Dr Rasmus Beedholm-Ebsen at Invest in Denmark gives us insights into trends in drug development in Denmark and globally, arguing that it is important to investigate new methods in order to discover and develop new drugs, and to have an innovative approach when it comes to drug delivery.

According to the World Health Organization (WHO), there are 1.9 million cancer deaths each year, making cancer the second biggest cause of death in Europe. Loannis Papasotiriou from RGCC gives an update on the proposed therapeutic strategies for cancer using new methods and novel approaches.

The buzzword for 2018 is certainly Artificial Intelligence, and how it’s going to transform all our lives. It could boost average profitability rates by 38% and lead to an economic increase of US $14TN by 2035. Siniša Belina of AMPLEXOR Life

Looking ahead to the autumn, we look forward to seeing you at the Nordic Life Science days in Stockholm between 10 and 12 September, Bio Europe in Copenhagen on 5 to 7 November, and the Genesis Conference on 13 December.

Lucy Robertshaw Director, Lucy J.Robertshow Consulting

you in navigating the countless new laws that are affecting the pharmaceutical industry in every aspect. From packaging to medical devices, manufacturing to technology, clinical research to marketing. In his article “Navigating Risk Management Plans (RMPs) in the Evolving Regulatory Landscape”, Dr. Prashant Dhanavade from Sciformix details that the purpose of the European Medicines Agency’s (EMA’s) risk management plan (RMP) is to “document the risk management system considered necessary to identify, characterise and minimise the important risks of a medicinal product” and thus to help sponsors plan their PV and risk minimisation strategy. Similarly, in packaging, Gill Wright, Cirrus’ Design & Development Director, gives an overview of how to prepare for the Falsified Medicines Directive in her article “The Falsified Medicines Directive - are you ready?” explaining: “The impending

legislation will affect all prescription medicines for the European market. The first step to comply with this legislation is to get your artwork amended and approved.” In Manufacturing, an article by Steve Duckworth from Clariant - “What Pharma Producers Need to Know About Changing Regulations on Clean-Room Films and Anti-Static Additives” proposes the use of “new ‘next generation ‘amine/ amide-free’ concentrates” that “address the future regulatory concerns of current systems and with a reasonable cost/ performance.” In summary, with us as your guide, you can successfully stay up to date with the latest developments in pharmaceutical regulations and legislation, automatically giving you a secret advantage – you’ll never be caught short! Orla Brennan Editorial Assistant, IPI

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

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

Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group

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

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

Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting

Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group

Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai)

Francis Crawley. Executive Director of the Good Clinical Practice Alliance – Europe (GCPA) and a World Health Organization (WHO) Expert in ethics

Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

Stefan Astrom, Founder and CEO of Astrom Research International HB

Maha Al-Farhan, Chair of the GCC Chapter of the ACRP

Steve Heath, Head of EMEA - Medidata Solutions, Inc

Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

T S Jaishankar, Managing Director, QUEST Life Sciences

Georg Mathis Founder and Managing Director, Appletree AG Heinrich Klech, Professor of Medicine, CEO 6 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2018 Volume 10 Issue 2


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Regulatory & Marketplace

Keeping Track of Traceability – Preparing for the EU Medical Device Regulation The term ‘medical device’ is broad and covers a wide range of items. It is referred to most commonly as an apparatus or a piece of equipment that is used to treat or diagnose a condition that comes into direct contact with the patient. Whether it is a simple pair of contact lenses or a more sophisticated device such as a pacemaker, the frequency with which we encounter medical devices in our day-to-day lives is surprisingly high and the key role they play in our wellbeing remains undeniable.

It is because of this role that regulations surrounding medical devices tend to be placed under more stringent scrutiny. Under the FDA (Food & Drug Administration) rule in the USA, manufacturers have been required to implement UDI (unique device identification) on all medical product packaging since September 2014. Following this and in light of the recently adopted EU Medical Device Regulation 2017/745, European manufacturers of medical devices will face even tougher regulations to ensure their products are safe to use under new EU laws that are scheduled to come into effect from May 26, 2020 onwards. The new regulation will also see the introduction of a new unique device identification system. This means that for traceability purposes, medical devices sold in the 28 member states of the EU as well as Iceland,

Liechtenstein, Norway and Switzerland will need to include a UDI code. The details of the UDI will need to be recorded in an EU database known as EUDAMED. With this legislation coming into effect, manufacturers now have a responsibility to invest in a coding solution that allows them to apply traceability codes onto products as well as packaging. Breakdown of Medical Product Classes • Class III: implantable pacemakers, pulse generators, HIV diagnostic tests, automated external defibrillators, endosseous implants and contact lenses for extended wear. • Class II a/b: acupuncture needles, daily wear contact lenses, powered wheelchairs, infusion pumps, surgical drapes and implantable radiofrequency transponder systems for patient identification and health information. • Class I: elastic bandages, examination gloves, and hand-held surgical instruments. For the classification of all medical devices refer to Annex VIII and Annex XVI included within the EU MDR. As a global leader of high-quality coding and marking solutions, Domino Printing Sciences is well placed to help these manufacturers meet the emerging requirements. The following white paper aims to identify the coding applications encountered most often in the medical industry and highlight the ways in which different coding and marking technologies are equipped to tackle them.

Industry Background Based on manufacturer prices, the European medical technology market is worth €110 billion and is estimated to make up 28% of the world market, making it the second largest in this sector after the USA. There are approximately 25,000 medical technology companies in Europe, with over 575,000 registered employees. Market research reveals that small and medium-sized companies (SMEs) make up almost 95% of the EU industry and that the majority of them employ less than 50 people per company. European Market Overview • Western Europe represents approximately 28% of the global medical device market. • In Europe, Germany represents 30% of the market, followed by France (15%) and the UK (13%). • In Western Europe, the current compounded annual growth rate for the medical sector is 3.7%; in Northern Europe a 5.1% compounded annual growth rate is forecast in the next five years. Source: MedTech Europe and IBISWorld

The current rules relating to the safety and performance of medical devices in the EU date back to the 1990s. However, the substantial scientific and technological advances in the medical sector that have taken place since their implementation have prompted the EU Commission to update the rules. The view is to improve the safety and performance of medical devices for EU citizens, while also creating the conditions to effectively modernise the sector and further consolidate the European Union’s role as a global leader. How Does the EU Regulation Affect Coding and Marking? With the new EU regulations coming into play, medical device manufacturers have a legal requirement to ensure that a UDI-DI number is assigned and registered in EUDAMED for every single item they produce by the May 2020

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Summer 2018 Volume 10 Issue 2


Regulatory & Marketplace

deadline. The May 2021 deadline marks the beginning of mandatory UDI coding onto medical devices, starting with Class III devices. Failure to comply with the legislation will have repercussions. Manufacturers will no longer be able to supply their products to every EU member state. Fee payers and healthcare providers will not accept devices without UDI codes that are up to the required standard. As a result, manufacturers now face a responsibility to familiarise themselves with the exact requirements of the legislation and ensure they have a coding and marking solution in place that can meet their needs, ahead of the stipulated deadline. However, to understand these requirements, a comprehensive audit and evaluation of the technologies available on the market is needed.

The Role of Coding and Marking in the Medical Sector The technology to assign, apply and verify identification codes to a wide range of products is an invaluable asset. The benefits are varied and apply to numerous industries such as www.ipimediaworld.com

the medical sector, where UDI is the accepted method for identifying and tracing medical devices throughout their lifecycles, from production through to distribution and finally to consumer use. The implementation of product codes onto medical devices results in more efficient recall procedures, the reduction of medical errors, and increased inventory visibility and supply chain security. The unique codes applied to each item during the manufacturing stages will provide the supply chain management system with key information, such as what the product is, where and when it was produced, its current location and how it got there. In the event a recall is necessary due to a product being faulty, the code is crucial to unlocking the so-called ‘chain of custody’, allowing the item in question to be traced back to its origin.

As is the case with other industries, counterfeit products can harm a medical brand in many ways, from affecting business revenues, to destroying consumers’ faith in the brand through poor-quality imitations. More importantly, counterfeit products

can endanger consumers’ health. Illicit trade can be even more detrimental, as it goes beyond simple counterfeiting to encompass equally damaging activities such as product diversion, where perfectly genuine products are deflected from intended channels into ones unauthorised by the manufacturer. With this in mind, item-level identification proves to be effective in helping to distinguish legitimate products from the counterfeit ones, while also helping governments to stem the erosion of revenues and jobs caused by illicit trade. Coding and Marking Technologies for the Medical Sector Depending on the medical device and the coding surfaces involved, there are several different technologies that can be deployed for the delivery of UDIs in this sector. Direct Part Marking The most prominent technology for direct part marking (DPM) on to medical devices is laser. While DPM is more commonly known as an industrial manufacturing application, it is most appropriate for medical device identification.

The presence of reprocessing devices throughout the supply chain can cause product items to be separated from their original packaging, which is why a permanent mark needs to be applied to the medical device. This way, a UDI code is readily available through the device distribution and use, even in the absence of packaging or labels. Medical devices such as pacemakers or surgical instruments are the kind of products that would require a permanent mark, as the UDI is designed to last as long as the device itself. With code durability being the key priority, a fibre laser marker is the preferred solution provided the required contrast can be achieved. A solid-state laser system can permanently mark a variety of materials with the utmost precision, producing unlimited lines of texts, graphics or even 2D data matrix codes, resulting in crisp, sharp codes that will not deteriorate over time. INTERNATIONAL PHARMACEUTICAL INDUSTRY 9


Regulatory & Marketplace Primary Packaging In contrast to DPM, a variety of coding and marking technologies as well as laser can be used for applying UDI codes onto primary packaging. Primary packaging is defined, in this instance, as the first layer of packaging which protects the medical device products from any damages. The technologies most commonly used for UDI coding onto primary packaging include thermal inkjet (TIJ), thermal transfer overprinting (TTO), drop-on-demand (DoD) piezo inkjet and print & apply labelling machinery (PALM). TTO is the preferred choice for coding onto flexible, web-based packaging materials. These materials and packaging applications include flexible laminated films to create pouches, sachets and bags or to lid rigid trays and apply labels to the surface of other primary packs, as well as coding directly onto speciality flexible materials, such as medical paper or TyvekÂŽ. TTO systems have the capability to print high-resolution (300 DPI) human- and machine-readable codes to satisfy the UDI requirement and can also print graphics, logos and other variable text fields over large areas. This additional functionality can be used to decorate and customise packaging according to the unique content and gives the medical device manufacturer the future option of saving operating costs. This is done by reducing the number of packaging material stock keeping units (SKUs) and reducing the downtime incurred by changing the packaging SKU during packaging job change-overs.

Specialising in printing highresolution codes at high speed, TIJ proves to be an ideal solution for all cartons and certain foils. These systems use solvent- and water-based inks to print complex and durable codes at a fast repeat rate, while still delivering the required legibility to meet the regulations for UDI coding. The ability to easily integrate a TIJ print head into multilane applications also make this system suitable for wider web coding applications. Employing multiple print heads to deliver individual codes across the substrateâ&#x20AC;&#x2122;s surface from a single controller gives significant cost and productivity benefits. DoD piezo inkjet is a high-resolution, non-contact solution most suited, in the medical device sector, to blister or web printing applications. The non-contact printing solution has very few moving parts, which minimises manual intervention and reduces downtime. DoD piezo inkjet systems also offer the capability of printing high-quality UDI codes with a native resolution of 600 DPI. Secondary and Tertiary Packaging Where larger label information needs to be printed and applied onto cases, or a label is the only option due to the substrate or the shape of a product, PALM proves to be an effective alternative to TIJ and TTO. PALM can also be deployed for secondary and tertiary packaging applications. As well as the other technologies, PALM enables high-resolution application of the required UDI and GS1 codes (used to to encode information such as product numbers, serial numbers and batch numbers) and offers multiple applicator options which includes corner wrapping of cases.

The aggregation of UDI codes onto tertiary packaging is not required under the EU Medical Device Regulation. However, some of the larger manufacturers are looking more closely at the opportunity for aggregation to gain better visibility of medical device products. Conclusion With the deadline now set in place to comply with the mandatory requirements of the EU regulations relating to medical devices, manufacturers have been given a timeframe to ensure they have all the affected areas of their business covered, including product identification. As outlined throughout this report, there are multiple aspects to take into consideration in order to select the coding and marking system that is best suited for oneâ&#x20AC;&#x2122;s business, such as substrates and materials, production volume, data management, etc. More importantly, manufacturers need to manage their timeframes as effectively as possible and act now. Sufficient time needs to be allowed to test solutions and potentially make the necessary adjustments to manage the new coding requirements. By taking action ahead of the deadline and partnering with a reliable supplier and partner that can provide the guidance and industry knowledge required, compliance can be successfully achieved.

Volker Watzke Volker Watzke is EU Medical Devices Sector Development Manager for Domino Printing Sciences. He has worked for Domino since 2010, both in Germany and the UK, in sales focussed roles. 4 years prior to moving into his current position, Volker began working in the Life Sciences sector as the German Strategic Sales Manager for the end-user market. Email: volker.watzke@domino-uk.com

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Summer 2018 Volume 10 Issue 2


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Regulatory & Marketplace

Regulatory Trends and Developments in the Pharmaceutical Industry in 2018 In the 2017 fiscal year, the FDA issued 114 warning letters to pharmaceutical manufacturers contravening Current Good Manufacturing Practices (cGMPs). This followed a trend of continual increase in warning letters, with 102 issued in FY2016 and 42 issued in FY2015.1 Though this rise suggests that pharmaceutical companies are slacking in the field of compliance, it is more likely to be a reflection of increased scrutiny within the FDA and of evolving areas of focus. Indeed, at Maetrics, we have observed that pharmaceutical companies overall have a solid understanding of regulatory requirements and typically have more mature quality systems in place than the medical device industry, for instance. However, this is not to say that the pharmaceutical companies can rest on their laurels. A closer analysis of FDA warning letters helps to shed light on some of the areas that businesses in the sector should be paying close attention to this year.

FDA Warning Letters: What to Look Out For From the total warning letters issued to pharmaceutical manufacturers, the number of warning letters issued to drug product manufacturing sites specifically doubled from 23 in 2016 to 46 in 2017, with US companies receiving the highest number of letters, followed by India and China. Five warnings were issued to drug product manufacturing sites within the European Union.2 The number of FDA warning letters issued in the EU may fall in the coming year; as of 31 October 2017, the FDA has recognised eight European drug regulatory authorities (Austria, Croatia, France, Italy, Malta, Spain, Sweden and the United Kingdom) as capable of conducting inspections of manufacturing facilities that meet FDA requirements, as part of the Mutual Recognition Agreement between the US and the European Union.3 This measure will improve efficiency and harmonisation in global pharmaceutical regulation, eliminating 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

double inspections and freeing up resources within the FDA for products of greater concern. The FDA is already improving efficiency levels as the amount of time between inspections and the issuance of a warning letter decreased across all FDA-regulated industries, from 11.9 months in FY2016 to 10.1 months in FY2017.4 This decreases to eight months for countries outside the US. Of the 114 warning letters issued in 2017, 45 of these targeted compounding pharmacies and outsourcing facilities, indicating an FDA clampdown on failures within these facilities. In general, the FDA defines compounding as a practice in which a licensed pharmacist or physician, or, in the case of an outsourcing facility, a person under the supervision of a licensed pharmacist, combines, mixes, or alters ingredients of a drug to create a medication tailored to the needs of an individual patient.5 Compounded drugs are not FDA-approved. The 2012 outbreak of fungal meningitis, where a pharmacy shipped contam i n at e d c o m p o u n d e d d r u g s throughout the country and caused over 60 deaths, is one of the cases contributing to the FDA’s increased scrutiny of compounding pharmacies. Businesses should expect this scrutiny to continue into 2018 as the FDA laid out their Compounding Policy Priorities Plan6 in January, so pharmacies should expect consequences if they do not carry out robust safety checks. The Priorities Plan also outlines the need to combat the practice of certain companies operating as pharmacies to evade FDA scrutiny, and sell drugs without approval. Excluding compounding pharmacies and outsourcing facilities, 20 warning letters were issued to US firms while 49 were issued to organisations outside of the US. Of the latter, India and China received the most with 14 and 17 respectively, followed by Europe with eight. This highlights issues related to the supply chain as India

and China are prominent suppliers of raw materials and outsourcing services. There is, therefore, a need for greater standardisation so that suppliers and sub-contractors perform to the same expectations across the board. During the period 2013–2018, China, India, and Europe accounted for almost 80 per cent of drug GMP warning letters issued outside the US over the five-year period.7 A significant concern for countries based outside of the US is that warning letters may be accompanied by import alerts, preventing them from distributing their products within the US. In the future, pharmaceutical companies can perhaps expect systems similar to the Medical Device Single Audit Program (MDSAP) which allows medical device manufacturers to achieve compliance with regulations in five different countries through a single audit. Supply Chain Vigilance It is not surprising that warning letters in 2017 also had a focus on contracted activities. In one warning letter to Sage Products Inc., the FDA berates the company for failing to ensure that their contractor is compliant with industry regulations, stating, ‘Contractors are extensions of the manufacturer’.8 Businesses cannot absolve themselves of compliance responsibilities when it comes to their partners, especially as this attitude may prove damaging to their business and more importantly, patient safety. Indeed, in the case of Sage, their contractor manufactured oral solution drugs using the same equipment for manufacturing toxic industrial-grade car washes and waxes. FDA guidance for the industry is that: “The pharmaceutical company is ultimately responsible to ensure processes are in place to assure the control of outsourced activities and quality of purchased materials.”9 As there are many elements to keep track of under the umbrella of quality and compliance, supplier audits can be a struggle for pharmaceutical companies, especially Summer 2018 Volume 10 Issue 2


Automated assembly and production systems for medical devices such as contact lenses, autoinjectors, insulin pens, syringes and many more Optical testing systems for contact lenses and medical devices e.g. optical defects Quality management and validation services in medical device production including GMP documentation MA micro automation GmbH | OpelstraĂ&#x;e 1 | 68789 St. Leon-Rot | Germany MA micro automation Pte. Ltd. | 128 Tuas South Avenue 3 | #03-02 | Singapore 637370

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 13


Regulatory & Marketplace if they are required to make site visits. When resources are lacking to carry out audits, one solution they opt for is to decrease the level of scrutiny, increasing the likelihood of non-conformances being overlooked. Apart from resources, other obstacles to successfully managing the supply chain are: complex multi-tiered supply chains; non-existent or inadequate IT systems; and limited experience. Moreover, a lack of visibility carries high risks for organisations not only in terms of compliance, but also when it comes to assessing and reacting to disruptions. A recent report found that lack of coordination, inventory management, order management, and temperature control are all in the top 10 of global health pharmaceutical supply chain challenges. Companies should have processes in place for regularly monitoring and reviewing their suppliers, as well as investing in technology where necessary to provide greater visibility and real-time data which means that all essential information is always a touch of a button away. Increased supply chain visibility is essential for combatting cargo theft. As individual ingredients or the final product itself are transported across regions or countries, the risk of theft or tampering is high. Without robust security and tracking measures, it may be impossible to identify the stage of the supply chain where security is breached. Not only is this costly to address if and when a breach comes to light, there is a clear risk to patient safety. Though pharmaceutical cargo theft dropped in 2017, suggesting that countermeasures are proving effective, even small-scale thefts prove to be extremely profitable for thieves due to the high value of the products. Furthermore, pilferage within the pharmaceutical sector is 49% more frequent than across all products, as it is also a method of advanced intelligence gathering for criminals, and therefore a long-term danger for businesses and patients.10 A related area of increasing focus is data integrity, in particular data gathered during drug development, in the testing and manufacturing phases, for instance. Data integrity issues were cited in 65% of all warning 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

letters, including those issued to compounding pharmacies.11 Taking a look at 483 forms issued in FY2017, the FDA identify the following data-related problems, among others: failures to record complete test data; failure to maintain data so that it can be reviewed annually; lack of drug expiration date supported by appropriate stability data; backup data not assured through hard copies or alternate systems; failure to verify data produced from a computer system.12 It is certainly positive that paper and legacy systems are being replaced with more efficient digital programs but companies should bear in mind that automation does not eliminate the need for checks and controls. If systems and processes are themselves not compliant, this will inhibit companiesâ&#x20AC;&#x2122; ability to detect problems on a larger scale. Future Pharmaceutical Trends New technology and innovations give rise to new regulatory requirements. Combination products are developing rapidly and the segment is projected to reach $115 billion in global sales by the end of 2019.13 According to 21 CFR 3.2(e), combination products are composed of two or more regulated components, meaning any combination of drugs, devices of biologics, that are physically, chemically, or otherwise combined or mixed and produced as a single entity.14 This means that companies must ensure that all components are compliant with the pertinent regulations. The 21 CFR Part 4 was published in 2013 to provide cGMPs for combination products, but as further advancements are made in this field, the regulatory landscape may become increasingly complex, necessitating greater awareness and expertise among all stakeholders. In the EU, combination products will now be regulated under the new Medical Device Regulation (MDR) as well as Directive 2001/83/EC on the Community code relating to medicinal products for human use. For medicinal products that integrate a medical device part, manufacturers must therefore ensure that the device part complies with the new MDR before the deadline in 2020. After this deadline, CE marking received under previous regulations will no longer be valid.15 Manufacturers seeing certification

under the Medical Device Single Audit Program (MDSAP) should note that there is some divergence when it comes to combination products. In Australia, combination products are subject to inspections by the Therapeutic Goods Administration (TGA), though effective MDSAP audit reports may reduce the frequency of inspections, and contribute to decision-making for issuing and renewing certificates. In the US, the FDA does not consider MDSAP audits of combination product manufacturers as an alternative to FDA inspections. However, in the remaining three participating countries â&#x20AC;&#x201C; Brazil, Canada and Japan â&#x20AC;&#x201C; the MDSAP audit covers their respective requirements and is therefore a valid alternative for confirming compliance of combination products.16 Other new developments related to drug product manufacturing include homeopathic drugs and stem cell treatments. In December 2017, the FDA announced a new, risk-based enforcement approach to homeopathic drug products to address harmful ingredients in homeopathic medication and a lack of compliance with cGMPs.17 In a similar vein, the hype around stem cell research means that unscrupulous clinics have tried to administer therapies without obtaining FDA approval. Due to the high risks to patient safety associated with stem cell therapy, organisations can expect particular scrutiny as research develops in the coming years. As these treatments are in the experimental stage, regulations vary from country to country and will most likely be subject to change over time to ensure optimal safety. Concluding Remarks In our experience, the bar is always being lifted in the pharmaceutical industry and this leads to higher expectations and rapid progress. Though innovation is ultimately beneficial for patient safety, compliance should not fall by the wayside as the long-term costs of a lax approach to regulation can prove to be disastrous. We have noticed that compliance often drops to the bottom of priority lists when company circumstances change, such as in the event of mergers and acquisitions, or financial pressures. Mergers complicate internal structures Summer 2018 Volume 10 Issue 2


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 www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 15


Regulatory & Marketplace as there is a pressure to quickly realise efficiencies by harmonising systems and processes within the new entity, many times without sufficient time and resources to delve into the processes of the newly acquired companies, especially in multinational companies. This means compliance failures and supply chain weaknesses can go overlooked until it is too late. On the other side of the coin, when companies are forced to downsize or are under financial pressure, quality is often sacrificed as it is perceived to be a cost centre that contributes to lower profits. This means that quality standards cannot be maintained. However, companies should consider the cost of quality versus the long-term costs of poor quality, such as long-term reputation damage which harms product sales. Pharmaceutical businesses will have to pay tenfold in the event of non-compliance; there is more money at stake when it comes to remediation and regaining a place in the market.

regulatory implications. There are multiple benefits in being proactive, as companies which prioritise quality and compliance are more likely to maintain a strong position in the market. Regulatory compliance can be complex and costly but those that plan in advance are able to seek the assistance and expertise they need, as well as begin a dialogue with relevant regulatory organisations to understand what is expected. Furthermore, organised businesses are well placed to occupy new ground when competitors are lagging behind. Staying abreast of regulatory changes therefore has benefits that extend far beyond compliance alone.

5.

REFERENCES

12.

1.

13.

2.

3.

Rapid progress and innovation also means that pharmaceutical companies are faced with the challenge of staying on top of new developments and their

4.

https://www.pharmaceuticalonline. com/doc/an-analysis-of-fda-fy-druggmp-warning-letters-0002 https://ungerconsulting.net/ wp-content/uploads/2017/12/ FINAL-FY-2017-FDA-Drug-WARNINGLETTER-DATA.pdf https://www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ ucm583057.htm http://www.thefdagroup.com/ thefdgroup-blog/fda-warning-letterenforcement-trends-of-2017

6.

7. 8. 9. 10. 11.

14. 15. 16. 17.

https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ PharmacyCompounding/ucm339764. htm https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ PharmacyCompounding/ucm592795. htm https://www.pharmaceuticalonline.com/doc an-analysis-of-fdafy-drug-gmp-warning-letters-0002 https://www.fda.gov/ICECI/ EnforcementActions/Warning Letters/2017/ucm568120.htm https://www.fda.gov/downloads/drugs/ guidances/ucm353925.pdf https://portaldagestaoderiscos.com/ wp-content/uploads/2018/02/2017_ annual_us.pdf http://www.thefdagroup.com/thefdgroup-blog/fda-warning-letterenforcement-trends-of-2017 https://www.fda.gov/ICECI/ Inspections/ucm589892.htm https://www.pharmpro.com/article/ 2017/02/4-things-you-need-knowabout-combinationdrug-compliance https://www.fda.gov/Combination Products/AboutCombinationProducts/ ucm118332.htm http://eur-lex.europa.eu/legal-content/ EN/TXT/PDF/?uri=CELEX:32017R0745 https://www.fda.gov/downloads/ MedicalDevices/International Programs/MDSAPPilot/UCM430563.pdf https://www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ ucm589243.htm

Jennifer Lopez Jennifer is a Director of Maetrics Solutions Delivery with experience in Pharmaceutical and Medical Device Industries. Prior to coming to Maetrics, she spent 17 years with a leading global pharmaceutical company. Jennifer has over  15 years in Quality and Regulatory Compliance roles with some of the leading Pharma and Medical Device companies. She serves Maetrics as the Audit Practice Leader and has experience leading large audit teams on global projects for some of their largest clients. She has proven skills in global remediation, CAPA, manufacturing startup, quality assurance and regulatory compliance. Email: media@maetrics.com

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Summer 2018 Volume 10 Issue 2


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 17


Regulatory & Marketplace

Navigating Risk Management Plans (RMPs) in the Evolving Regulatory Landscape Pharmacovigilance (PV) is a vital part of healthcare and for monitoring the benefit-risk profile of medicinal products. The purpose of the European Medicines Agency’s (EMA’s) risk management plan (RMP) is to “document the risk management system considered necessary to identify, characterise and minimise the important risks of a medicinal product” and thus to help sponsors plan their PV and risk minimisation strategy. The plan is based on the frequency and severity of the risks identified during product development (including a new indication for a previously approved product), and during the post-marketing setting.

Regulations and procedures in PV are continually evolving and changing worldwide. On 30 March 2017, the EMA published Revision 2 to the RMP template, requiring that all EU-RMP submissions post 31 Mar 2018 use the new template. Significant changes have been introduced in the revised template2, which has been used by some since its announcement and is the subject of much discussion in the industry. The complexity of the new RMP template has introduced significant challenges to preparing high-quality and compliant documents that meet all of the requirements. This article discusses the different challenges posed by the new RMP template, and how to navigate them successfully. Background The EU RMP consists of seven parts, including the product overview, safety specification, PV plan, plans for post-authorisation efficacy studies, risk minimisation measures, summary and annexes. It is a standalone scientific synopsis which includes relevant parts of the dossier and emphasises the important, clinically relevant facts. Certain aspects of the RMP, in particular the safety specification, are subdivided into modules so the 18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

content can be tailored to the type of the medicinal product (innovator products, generics, biosimilars, etc). This design helps in reusing modules across different safety documents which in turn improves consistency and prevents discrepancies.1

following an industry trend towards large, repetitive documents being streamlined to accompany submission documents.

If several medicinal products have the same active substance, the differences between indications, formulations and target population can be accommodated by dividing the relevant parts of the RMP into modules and/or sections. This structure also means that the RMPs can be simply updated. As the product matures, some RMP modules or sections may cease changing, for example, non-clinical studies and clinical trials. These RMP modules can be locked in place until new data needs to be added. This modular structure also simplifies the process for the RMPs of established products or biosimilars, as they do not require all the information, such as reference medicinal products.

Key Changes in the EU RMP Template The updated EU RMP template is

The revised template intends to achieve –

Better representation of safety concerns – identification, presentation and focus areas Removal of duplication within the RMP and across other submission documents Additional guidance on the expected changes during the lifecycle of the product Updated requirements for different types of initial MA applications to create risk-proportionate RMPs More succinct document

Other additions include a public summary for lay people that will form a part of the European Public Assessment Report (EPAR) and a section for information on plans for post-authorisation efficacy studies. The key changes for each part are presented in Table 1, below:

Part

Key Changes

Part I: Product Overview

No significant differences.

Part II: Safety Specification

Module SI: Epidemiology of the indication (S) and target population (S) • Only data relevant for identification of the safety concerns required. • Brief summary of epidemiology, including an interpretive, high level overview of the information. • May not be applicable for generics, fixed combination medicinal products, and biosimilars which do not contain a new active substance. • Risk proportionality principle to be followed. • Differences in specification with the “originator” product to be justified for generic products. Module SII: Non-clinical part of the safety specification • Data requirements for clinical and non-clinical sections have changed. More details are to be provided. • Detailed patient exposure data is required and must be stratified by demographics, special populations and regions, wherever possible. Important to note this data may not be available for mature products as it was not required previously.

Summer 2018 Volume 10 Issue 2


Regulatory & Marketplace •

Part III: Pharmacovigilance Plan

Part IV: Plans for Postauthorisation Efficacy Studies

Part V: Risk Minimisation Measures

• •

• •

Module SIII-IV: Clinical trials • More details are required with regard to duration of exposure, age group – gender, dose, ethnic origin, etc. • Module SVI: Additional EU requirements for safety specification • Only potential for misuse for illegal purposes is retained. Module SVII: Identified and potential risks • Several sub-modules have been added. • Risk-proportionate approach and detailed justifications are required for inclusion as well as exclusion of risks from the categories of ‘important’ identified or potential risks. • Risk-benefit impact assessment is required for individual risks. Detailed description of PV activities/studies intended to identify and/or further characterise safety concerns. Studies measuring the effectiveness of risk minimisation measures where such studies are required. Detailed instructions and guidance have been added on inclusion of various annexes pertaining to post-authorisation safety studies (PASS). A list of post-authorisation efficacy studies (PAES) imposed depending upon specific obligations to be included. Examples of such specific requirements are provided in the guidance. If no such studies are required, RMP Part IV may be left empty. No significant changes. The revision clarifies initial marketing authorisation applications for generic, hybrid medicinal products and fixed combination products with no new active substance, noting that if the medicinal product does not have additional risk minimisation activities, sections V.1 – V.3 may not be applicable and a statement regarding alignment with reference medicinal product is sufficient. The new template explains routine and additional risk minimisation activities in greater detail.

Part VI: Summary of the RMP

A separate RMP Part VI should be provided for each product in the RMP. As it is a stand-alone document, any references to other parts of eCTD dossier or other medicinal products’ published RMP summaries should not be included.

Part VII: Annexes

The number of annexes has been reduced from 12 to 8.

Lifecycle Management of RMPs Benefit-risk assessment for all marketed drugs is an ongoing activity and needs to continue throughout the lifecycle of the product. A new or revised RMP may need to be submitted to the EMA at various points during a product’s lifecycle. An update is expected to be submitted when: • •

There is a change in the list of the safety concerns There is a new or significant change in the existing additional PV or risk minimisation activities.

This would include a change in study objectives, population, due date www.ipimediaworld.com

of final results, due date for protocol submission for an imposed study, addition of a new safety concern in the key messages of the educational materials, with the procedure triggering those changes. The RMP update can be submitted either as part of a procedure driven by another main change defining the procedure classification (e.g. extension of indication, new formulation, etc.) or as a stand-alone variation exclusively, including the RMP.  Irrespective of whether the RMP update is consequential to another change or a stand-alone update, the RMP document follows the electronics common technical document (eCTD)

lifecycle management and should be provided in Module 1.8.1 of the eCTD structure. Revision 2 of the guidance on format of the risk-management plan in the EU should be used for all products, including generics. Best Practices for Developing RMPs The new template includes additional expectations in many parts and modules, along with several new sections. The overall objective is to create a risk-proportionate and concise document which should not include duplication. Therefore, based on either the need to develop a new RMP or to create/update a regionspecific RMP, an effective strategy needs to be developed; collation and review of all the available data in the form of previous RMPs, aggregate reports, reference safety information (RSI) including core & regional labels, and regulatory commitments. By reviewing the existing data, applicants will gain a better understanding of the additional data required and the sources that should be explored. This is particularly important for generics or biosimilars, which may not have substantial clinical data as compared to the reference medicinal product. This could be due to exemptions from certain requirements on toxicology and clinical studies. In order to maintain consistency, data from the reference medicinal product has to be referred to for creating many sections of the RMPs for generics or biosimilars. Labels of reference medicinal product (RFP) available from regulatory websites, the European public assessment reports (EPARs) and the summary provided by the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) can be very useful starting points. Epidemiology Data Epidemiological databases like the GLOBOCAN and SEER Programme of the National Cancer Institute, United States provide data on major types of cancers. Publicly available databases such as US FDA (Food and Drug Administration) AERS (Adverse Event Reporting System), the Drug Analysis INTERNATIONAL PHARMACEUTICAL INDUSTRY 19


Regulatory & Marketplace Prints (DAP) available from The Medicines and Healthcare products Regulatory Agency (MHRA) of the United Kingdom, EudraVigilance and the World Health Organisation (WHO) ADR database provide a number of reports and insights into the types of reactions that have been reported for drugs. However, they do not provide exposure, nor are they useful for determining background rates. Effective Use of Published Literature Literature should be screened using widely recognised reference databases (e.g. Medline, PubMed, Embase Excerpta Medica). It is important to check authenticity of all reference literatures along with their latest updates, so that the most recent and relevant information can be extracted. Examples of some commonly used websites/online sources include: â&#x20AC;˘

â&#x20AC;˘

Medical textbooks, information on human diseases: Merck Manual, Medscape. Clinical guidelines: The National Institute for Health and Care Excellence (NICE) guidelines (UK); The National Comprehensive Cancer Network (NCCN) guidelines (US).

While developing a search strategy, filters should be applied with due consideration to the specific purpose of the literature search. When using literature as a major source for identification and characterisation of risks, the selection should focus on articles that provide the most recent data with the maximum strength of evidence. For example, if clinical trial data are being used to cite the frequency of an identified/potential risk, articles involving meta-analysis or systematic reviews in the indications will gain precedence over those concerning individual clinical trials. Monitoring of Regulatory Websites Marketing authorisation holders (MAHs) are required to take into account monitoring requirements and recommendations by health authorities (HA). This information from HA websites is crucial for discussion in the RMP and specific requirements 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to be addressed for designing risk minimisation measures. Examples for the EMA include cumulative list of signals evaluated by PRAC, list of products under additional monitoring, EPAR and CMDh list of safety concerns and outcomes of PSUSA procedures. Identification of Risks The new RMP template provides detailed guidance for selection of important risks for inclusion in the RMP. For innovators, this activity is comparatively easier due to availability of adequate non-clinical and clinical data. For generic products and biosimilars, extensive literature search may be required to find relevant information for characterisation of safety concerns. Product information, and public assessment reports of the reference product, and in the EU, the EPAR and CMDh list may be used as reference material. While the overall approach should be to align the reference and the generic products, it is possible that the safety concerns for a generic product may not exactly match those of the reference product. For products marketed/intended for marketing in different countries, it is not unusual for safety concerns to differ. A local regulatory authority may request for certain additional safety concerns to be addressed or, what is considered an important potential risk by the regulator in one region may be considered an important identified risk by the regulator in another region. Use of footnotes to document regional differences in safety concerns, separate tables for each region, or including information indicating the varying status of each of the risks can help in representing such discrepancies and ensuring regional compliance. In addition, the MAH may also indicate the companyâ&#x20AC;&#x2122;s core position on the categorisation of various risks. Characterisation of Risks For assessment of benefit-risk impact for individual risks, two components are essential in determining the impact on an individual patient. These include impact on health and impact on quality of life. Regarding public health, one should assess the overall impact

of that risk at the population level, such as incidence rate in exposed population, course of the disease, and the consequences (including consideration of seriousness, preventability, and reversibility). Quantitative measures, such as the ratio of number needed to treat (NNT) to number needed to harm (NNH), relative risk or risk ratio (RR) and odds ratio (OR), are also useful in assessing the public health impact. However, a careful interpretation of these measures is required. For example, an RR of 2 can be a difference between a 10% rate and a 20% rate of occurrence of an adverse event (AE), or between a 1% and 2% rate of occurrence. Thus, both absolute and relative risk should be considered for determining public health impact. Routine risk minimisation activities are those which apply to every medicinal product. These relate to the product labelling, packaging and the legal status of the product. The majority of safety concerns are addressed by routine risk minimisation measures. Additional risk minimisation activities are introduced for certain important risks for which routine risk minimisation is considered insufficient. In determining if additional risk minimisation activities are needed, safety concerns should be prioritised in terms of impact on public health, treatment and preventability. Focus should be on selecting the most appropriate measure for the most important and preventable risk. Additional PV activities, such as pre-clinical, clinical, epidemiological or non-interventional studies, are not considered routine. When any doubt exists about whether, or which, additional PV activities are needed, competent authorities may be consulted. Summary The EMA has published a second revision of the RMP template aligned with Guideline on GVP Module V Revision 2, meaning that all EU RMPs submitted to the EMA on or after March 31, 2018 must be submitted using the updated EMA template. This updated EU RMP template is designed to streamline the documentation to accompany submission documents. Summer 2018 Volume 10 Issue 2


DRIVING QUALITY AND INTEGRITY IN SCIENTIFIC RESEARCH AND DEVELOPMENT As a not-for-profit association we have around 2,300 members of which 44% are based outside of the United Kingdom and located in 58 countries worldwide, with many of our members working in an international environment and to international standards. We continue to meet the needs of our members by: • Promoting quality standards in scientific research and development • Facilitating knowledge sharing through events, publications and networking • Liaising with regulatory agencies in the development and interpretation of regulations and guidance • Offering professional development opportunities • Working in partnership/cooperation with other organisations. Our membership caters for professionals including managers, scientists, auditors, inspectors and practitioners concerned with the quality and compliance of research and development. Our members focus on the safety and efficacy of pharmaceuticals, biologicals, medical devices, agrochemicals and chemicals in man, animals and the environment. More information on all of our first class services and products can be viewed on our website.

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Regulatory & Marketplace This is a continuously evolving landscape and it will take time for applicants to get used to using the new template. Updating older RMPs to the new RMP template is not a simple task and demands a good understanding of drug safety and regulatory expectations. Companies need to ensure they have the relevant knowledge and expertise in place (whether it be in-house or from a speciality service provider) for implementing these new requirements. For more information about how Sciformix can assist with risk management plans, please visit: https:// www.sciformix.com/our-expertise/ safety-risk-management/. REFERENCES 1.

EMA. Risk-management plans (Internet) http://www.ema.europa.eu/ema/index. jsp?curl=pages/regulation/document_ listing/document_listing_000360.jsp [Accessed 15/05/2018] 2. EMA, 2017. Guidance on the format of the risk management plan (RMP) in the EU â&#x20AC;&#x201C; in integrated format (Internet) http://www.ema.europa. eu/docs/en_GB/document_library/ Regulatory_and_procedural_ guideline/2017/03/WC500224771.pdf [Accessed 15/05/2018]

Dr. Prashant Dhanavade Dr. Prashant Dhanavade is Subject Matter Expert at Sciformix Corporation, with over 10 years of experience in Drug Safety and Risk Management. His area of expertise spans across end-to-end drug safety activities including Individual Case Safety Reports, Aggregate Safety reports, Signal and Risk Management. He has worked with multiple global innovator and generic pharmaceutical companies for supporting safety activities to products in various life-cycle stages. An orthopaedic surgeon by background who has successfully led and mentored global delivery teams. Email: prashant.dhanavade@sciformix.com

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Summer 2018 Volume 10 Issue 2


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Regulatory & Marketplace

Strategies Adopted by Branded Drug Manufacturers against Para IV Filers This article highlights the complex and critical regulatory strategies adopted by branded drug manufacturers against Paragraph-IV filers in the past. The Hatch-Waxman Act 1984, also known as the Drug Price Competition and Patent Term Restoration Act, grants generic manufacturers the ability to challenge a patent without risking enormous damages from any possible infringement. Generic product entry into the market allows the public to have access to drugs which are equivalent to branded drugs at a lower cost. Prices fall dramatically, after the 180 days exclusivity period when generic firms enter the market with their bioequivalent drug. The approval process of generics revolves around submission of an ANDA. FDA approval of ANDA depends on the ability of generic firms to demonstrate their product safety and effectiveness. Primarily, the ANDA applicant has to establish that the generic drug is bioequivalent to the reference listed drug (RLD). Inventors of new drugs were given additional protection by the Hatch-Waxman Act in terms of lengthening patent terms. In exchange, Hatch-Waxman made the entry of generic drug products into the pharmaceutical market easier. A generic drug product could enter the market either by challenging weak patents or by waiting until the patent expires. In order to encourage generic manufacturers, Hatch-Waxman offered a 180-day exclusivity incentive to the generic challenger so as to challenge and identify weak patents listed in the orange book. Generic exclusivity of 180 days is granted to the first filer of ANDA, as Paragraph IV with the FDA. Within this exclusivity period of 180 days, other generic drugs cannot enter the market. The idea behind this incentive was to encourage generic firms to invalidate and challenge bad patents. When multiple ANDAs are filed on the same day, 180-day exclusivity is shared between these multiple filers. As an outcome, patent infringement and a 30-month FDA stay period became a common scenario, and the 180-day exclusivity period eventually led to an increase in the number of Paragraph IV filings.

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Hatch-Waxman Act â&#x20AC;&#x153;The Drug Price Competition and Patent Term Restoration Actâ&#x20AC;?, also known as the Hatch-Waxman Act, was enacted in the year 1984. The Hatch-Waxman Act of 1984 amended the Federal Food, Drug, and Cosmetic Act and Patent laws. The main objective of the Hatch-Waxman Act was "To provide a balance between the interests of branded drug manufacturer, generic drug manufacturer and consumers" by: a) Reducing the cost associated with the approval of a generic drug. b) Allowing early experimental use. c) The time lost during the regulatory approval formality from the patent term being compensated to the branded drug manufacturers. d) Motivating generic drug manufacturers. FDA's requirements for generic drugs are:1 a) The generic product should have the same active ingredients, dosage form, and same labels as the innovator product. b) Generic drug manufacturers must show that "the generic version of the drug delivers the same amount of active ingredients into a patient's bloodstream in the same amount of time as the innovator drug product" which means that generic drug is bioequivalent to the innovator drug. c) The generic drug's chemistry, manufacturing steps, and quality control measures must be fully documented by the generic drug manufacturer. d) Firms must provide surety to the FDA that the raw materials and finished generic product meet specifications of the US Pharmacopoeia. e) Generic drugs will remain potent and unchanged until the expiration date on the label. This should be demonstrated by the applicant. f) There must be compliance with Good Manufacturing Practice,

and firms should provide FDA all relevant information pertaining to the facilities used during manufacture, process, test, package, and labelling of the drug. New Drug Exclusivity New drug applicants are provided with certain market exclusivities according to the Hatch-Waxman Act. 1) Non-patent Exclusivities The Hatch-Waxman Act allows new drug applicants to obtain certain non-patent exclusivities, including: a) Orphan Drug Exclusivity Orphan drug exclusivity is the "exclusivity which is granted to drug manufacturers for drugs that are used to treat a rare disease or condition that affects less than 2 lakhs people in the US or when it is unlikely that US sales of the drug will recoup its development costs". This exclusivity period is seven years.2 b) New Chemical Entity (NCE) Exclusivity "When a pharmaceutical manufacturer introduces a drug that contains an active moiety that has not been approved by FDA in a new drug application (NDA)[, it] can gain NCE exclusivity in United States". During the NCE exclusivity period of five years, FDA would not accept an abbreviated new drug application (ANDA) for a generic that is based on the same active moiety, regardless of whether the generic drug is for the indication, either the same as or different from the innovator drug, or for any new indication. However, during the five-year NCE exclusivity period, FDA can accept and approve a new drug application (NDA) for a drug product that is based on the same active moiety that relies upon the clinical trials data conducted by the second NDA applicant.2 c) New Clinical Study Exclusivity This exclusivity, sometimes called Summer 2018 Volume 10 Issue 2


5 THINGS TO CONSIDER

WHEN MANUFACTURING CONNECTED DRUG DELIVERY DEVICES The estimated number of connected drug delivery devices continues to increase and the impact of this trend could be significant, explains Phillips-Medisize

While digital connectivity or connected health can improve the coordination and delivery of patient care, original equipment managers need to keep these five things in mind when creating connected drug delivery devices: 1 2 3 4 5

Development strategy and design consideration Situation analysis and patient compliance Connectivity ecosystem Wireless subsystem Security of device and information

As the Internet of Things continues to become an integral part of people’s lives, the opportunity to use it within drug delivery device applications remains promising. The manufacturers and device designers must identify, investigate and overcome these challenges so that the implementation of wireless and other related smart technologies can be achieved. When done successfully, connected systems enable the patient and caregivers to have a 360° view of both the patient and the disease – not only to manage adherence, but to improve results by understanding the effect of the regimen.

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 25


Regulatory & Marketplace data exclusivity, prohibits the FDA from approving a generic drug application for the new dosage form or novel use for a period of three years after the first NDA approval. Further new clinical study exclusivity prevents FDA from approving an ANDA for the protected modification supported by the clinical trial. During the new clinical study exclusivity, FDA can accept an ANDA application and facilitate the review process. However, FDA may not provide approval of the competitor’s application until the period of exclusivity is over.3 d) Paediatric Exclusivity "In order to promote paediatric drug development and testing, an act was enacted by the congress in the year 2002. Developing useful information about safety and efficacy of their products in children results in six months of additional exclusivity to drug manufacturers" according to "Best Pharmaceuticals for Children Act". "Paediatric exclusivity attaches only to products that already has another form of marketing exclusivity and cannot stand on its own". Therefore, a need for carrying out such studies in [a] paediatric population would help a sponsor by extending its patent, NCE exclusivity, clinical investigation exclusivity, or orphan drug exclusivity by six months.4 2) Patent Exclusivity "Branded drug companies obtain patent protection for their approved drugs so that they have a period of exclusivity; this period of exclusivity prevents unlicensed third parties from selling, using, making or importing the patented invention."4 Discussion: Challenging Patent Exclusivity According to the Drug Price Competition and Patent Term Restoration Act, certain procedures are provided to generic drug companies for challenging a reference listed drug product (RLD). Patent Certification According to FDA “there are four types of certifications; a generic drug company submitting either an ANDA or a section 505(b) (2) application 26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

must make one of the following four certifications as to each patent listed in the orange book for an RLD”: •

• •

Paragraph I certification: When there is no relevant patent listed in the orange book. Paragraph II certification: When the listed patent has expired. Paragraph III certification: When the listed patent will expire on a particular date. Paragraph IV certification: When the listed patent is invalid or will not be infringed by the generic drug for which permission/ approval is being sought.5

A generic drug company may also make a section VIII statement, which means that the listed patent does not claim a use for which the applicant is seeking approval. Both a Paragraph IV certification and a section VIII statement can be made by a generic company, for example, the patent covers both the product and a method of use.3 Paragraph IV Certification When a generic drug company intends to engage in the commercial manufacture, sale or use of the generic drug before the expiry of RLD’s exclusivity, a Paragraph IV certification needs to be filed by that particular generic company. A generic drug applicant making a Paragraph IV certification must provide a notice letter to the NDA holder and the patentee (if different from the NDA holder), setting out a detailed statement of its basis for believing that the listed patents are invalid or not infringed. The Paragraph IV filer must provide the notice letter to the NDA holder within 20 days after the FDA accepts the ANDA for filing. The certification requirement imposes a duty of care on a generic drug company. The patent holder may bring a patent infringement suit within 45 days of receiving such notification. An ANDA certified under Paragraphs I or II is approved immediately if the application meets all the regulatory and scientific requirements. An ANDA certified under Paragraph III must, even after meeting pertinent regulatory and scientific requirements, wait for approval until the drug’s listed patent expires. If a patent infringement charge against the ANDA applicant has been

brought by the patent owner in the allocated 45 days’ time, then the FDA must suspend approval of the ANDA until: a) The listed drug’s patent is declared as either invalid or not infringed by the court; b) The listed patent of the drug expires; or c) The date that is 30 months (subject to modification by the court) from the date the owner of the listed drug’s patent received notice of the filing of a Paragraph IV certification. The FDA is prohibited from approving the drug in question for 30 months or until such time that the patent is found to be invalid or not infringed, once the brand name company indicates intent to bring a patent infringement suit against the generic company as a result of the paragraph IV filing. If the court holds that the patent is invalid or would not be infringed prior to the expiration of 30 months, then the FDA will approve the ANDA when that decision occurs. Conversely, the FDA will not approve the ANDA until the patent expires, if the court holds that the listed patent is valid and would be infringed by the generic product proposed in the ANDA prior to the expiration of 30 months. The first generic applicant to file a Paragraph IV certification with the FDA is awarded 180 days’ market exclusivity according to the Hatch-Waxman Act, as a reward for challenging the patent associated with an approved pharmaceutical. This provision was intended to encourage generic applicants to challenge a listed patent for an approved drug product. The 180-day market exclusivity period ordinarily began on the earlier of two dates: a) The day when the drug enters the commercial market; or b) The day a court gives a decision that the patent is invalid or not infringed.3 Paragraph-IV Filing Incentives When a generic company prevails in the lawsuit after being a first Paragraph IV filer for a particular drug product, that first filer is granted 180 days’ market exclusivity. 180 days’ market exclusivity is of great significance for a generic Summer 2018 Volume 10 Issue 2


Regulatory & Marketplace company as, during this period of 180 days’ exclusivity, the only generic version available in the market will be of the first filer with approved ANDA. So, the generic player can price its drug product slightly below the innovator's version for the first six months and make good profits in this exclusivity period and maintain its price before other generics enter the market after the exclusivity period, and erode the price and profit from that particular drug product. If a generic firm challenges a so-called blockbuster or megabrand drug with a Paragraph IV certification, then the profit during these 180 days can be enormous for the first filer. The example discussed below shows how this works and why a generic company would opt in for a Paragraph IV challenge process.6 Lilly's megabrand Prozac® (fluoxetine) was identified by a generic company, Barr Laboratories, as a drug product with a weak patent that could be challenged. Since Prozac had a large market potential, Barr filed an ANDA with a Paragraph IV certification in

1996, where Barr claimed that a generic version of Prozac will not infringe Lilly's listed patents. After litigation which continued for almost five years, the Court of Appeals in August 2000 ruled a decision in favour of Barr. The compound patent and a paediatric exclusivity for Prozac expired in August 2001. The generic form of the 20mg strength of fluoxetine was launched by Barr, and this 20mg strength fluoxetine in the first two months took over 65% of the Prozac market share after it was launched by Barr. However, by the end of the six-month exclusivity period of Barr's, Prozac had lost 82% of its prescriptions to the generic firm and was left with only 16% of the Prozac/ fluoxetine market. This incentive of 180 days’ exclusivity provided by the Hatch-Waxman Act enabled Barr to successfully challenge the fluoxetine patent and reap the economic benefits during the exclusivity period. After the launch of Barr's generic version of Prozac, within eleven months the sales of Barr's generic fluoxetine reached

$367.5M, which accounted for 31% of the company's total product sales. The net effect of Hatch-Waxman on generic drug development has been explicit, and the effect has been beneficial for consumers. An increase in ANDA applications and Paragraph IV challenges has been observed as a result of this incentive, especially since 1998. With the Hatch-Waxman Act’s introduction, virtually all top-selling drugs, especially blockbuster drugs, face generic competition; only 35% of the branded dugs had generics available in the market prior to the introduction of Hatch-Waxman. Today generic drugs account for more than 70% of prescriptions, whereas pre– Hatch-Waxman generic prescriptions numbered less than 15%. Along with generic penetration, generic drugs are priced approximately 60% or less than innovator drug products. The average length of patent extension under the Hatch-Waxman Act is three years. It can take between five and seven years from initial product selection to market (including Paragraph IV litigation) for a generic drug product.6

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Regulatory & Marketplace 30-month Stay Period In patent litigations where the generic company files a Paragraph IV-certified ANDA in an attempt to manufacture and market a drug product which is bioequivalent to the innovator drug product, much of the litigation focus and drama revolves around the so-called “30-month stay period”.7 Under the HW Act, "once the brand name company indicates intent to bring a patent infringement suit against the generic company as a result of the Paragraph IV filing, the FDA will not grant the generic company final approval of its product for 30 months.” If the court holds that the patent is invalid or would not be infringed prior to the expiration of 30 months, then the FDA will approve the ANDA when that decision occurs. Conversely, the FDA will not approve the ANDA until the patent expires, if the court holds the patent is not invalid and would be infringed by the product proposed in the ANDA prior to the expiration of 30 months. Basically, the 30-month stay period is designed by the FDA to provide the FDA with sufficient time to review the generic company’s ANDA and provide the court enough time to resolve the branded pharmaceutical company’s patent issues. Court is granted complete authority by the HW Act, which states that a court may either lengthen or shorten the 30-month stay period if either party involved in the litigation failed to reasonably cooperate in expediting the litigation process. The generic company must invoke the statute to try to shorten the stay period and would generally like to enter the market sooner than the 30-month FDA stay period. An ANDA submission for a drug product application containing a Paragraph IV certification may be sued for patent infringement. If the NDA holder or patent owner files a patent infringement suit against the ANDA applicant within 45 days of the receipt of notice, final approval to the ANDA cannot be given by the FDA for at least 30 months from the date of that notice. Under the FDA’s traditional interpretation of the HW Amendments, multiple 30-month stays have been possible. As a result, there have been a number of instances in which delays 28 INTERNATIONAL PHARMACEUTICAL INDUSTRY

in ANDA approval have exceeded 30 months. Strategies Adopted by Branded Drug Manufacturers7 Branded drug manufacturer has adopted three main strategies to fend off generic pressures: a) Delisting patents from the orange book, b) Layering patents over a drug, and c) Authorising generics. a) Delisting Patents The FDA gives branded drug manufacturers near complete control over patent listing in the orange book. The act mandates the FDA to add patent information for drugs still under patent protection in its orange book. However, the statutory language is vague regarding what patents shall be included in the orange book. The FDA promulgated guidelines governing the type of patents the drug owner should submit to the orange book, but it lacks punishment provisions for violations.2 Though the FDA did later issue tighter regulations on patent listing in 2003, it still refuses to create either an administrative process or an office to oversee the listing practice. As a consequence, a branded drug manufacturer can request the FDA to remove patents from the orange book if the branded drug manufacturer deems that the patents were listed improperly in the first place; or a branded drug manufacturer can add new patents to the orange book if it has reason to believe the patents are relevant to the drug. These FDA regulations created a loophole in the Hatch-Waxman framework. The Act encourages generic makers to challenge the patents of brand drugs by filing Paragraph IV certifications alleging the patents are invalid or non-infringed. However, if there are no patents in the orange book for the brand drug on which Paragraph IV certifications may be filed, the generic maker is not entitled to the exclusivity. In other words, the awards of the Act do not reach brand drugs that have no patents on which Paragraph IV certifications can be filed. To exploit the loophole, the branded drug manufacturer adopts the strategy of delisting patents from the orange

book and purposely making the drug fall into the loophole, therefore denying generic makers the biggest incentive under the Act: marketing exclusivity. Case Study 1 Merck pioneered this strategy in its Zocor battle with Ranbaxy, an Indian generic maker. Zocor was Merck’s biggest drug with annual sales of $5.2 billion in 2004.8 There were initially three patents listed in the orange book for the hyper cholesterol drug: active ingredient patent 4,444,784 (‘784 patent), reissued patent RE36,481 (‘481 patent), and reissued patent RE36,520 (‘520 patent). The latter two patents both claim compounds related to Zocor and their use in treating high cholesterol, but neither patents claim Zocor itself or its use. In December 2000, Ranbaxy filed an abbreviated new drug application (ANDA) to market generic versions of Zocor, with Paragraph III certification on the ‘784 patent (promise to wait until patent expiration date on June 23, 2006) and Paragraph IV certifications on both the ‘481 patent and ‘520 patent (alleging both patents invalid or non-infringed by its generic drug). Surprising to many, in 2003, Merck requested the FDA to delist the ‘481 and ‘520 patents from the orange book. The FDA accepted Merck’s reason that these two patents were improperly listed in the first place and subsequently delisted them. Ranbaxy was left with no patents on which to base their Paragraph IV certifications, resulting in the loss of the 180-day exclusivity under the Act. Accordingly, the FDA then denied Ranbaxy’s right to the exclusivity.9 To revive its exclusivity right, in 2005 Ranbaxy filed a citizen petition to the FDA asking it to relist the two patents. The FDA denied the petition. Ranbaxy next filed a lawsuit in the district court of the District of Columbia to force the FDA to relist the patents. Though the FDA’s ruling does have textual support in the Act, the court put great emphasis on the legislative intent and found the FDA violated the intent. The court concluded that the FDA improperly denied Ranbaxy’s citizen petitions.10 The DC Circuit agreed that the delisting policy of the FDA diminishes Summer 2018 Volume 10 Issue 2


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Regulatory & Marketplace the incentive for a manufacturer of generic drugs to challenge a patent listed in the orange book.11 Denying Ranbaxy marketing exclusivity by delisting Merck’s patents was inconsistent with the purpose of the Act. FDA subsequently relisted the two patents in the orange book and complied with the court's decision and gave Ranbaxy back the marketing exclusivity. Case Study 2 In another patent delisting battle on Johnson and Johnson’s Risperdal, the DC Circuit sided with pharma. In August 2001, generic maker Teva filed an ANDA with certifications on both patents listed with Risperdal in the orange book: patent 4,804,663 (‘663 patent) and patent 5,158,952 (‘952 patent). Here, the main patent, the ‘663 patent, covers Risperdal’s active ingredient and expired in December 2007. The secondary patent, the ‘952 patent, claims tablet formulation of the drug and expires in 2009. Teva chose to challenge the weak formulation patent (Paragraph IV certification on the ‘952 patent), but would delay generics until the expiration of the main patent (Paragraph III certification on the ‘663 patent). In October 2001, the FDA informed Teva that the ‘952 patent has been delisted from its orange book at the request of Johnson and Johnson.12 The FDA denied Teva’s citizen petition on relisting ‘952 patent, which was promptly challenged in the courts. A generic maker obtains a vested right to marketing exclusivity only after a valid Paragraph IV certification has been submitted.13 If a patent has been delisted from the orange book before the Paragraph IV certification is submitted, there can be no valid certification, and the generic maker’s right to a period of marketing exclusivity does not vest. The ‘952 patent was delisted months before Teva attempted to submit a Paragraph IV certification. The patent delisting made Teva’s subsequent Paragraph IV certification invalid, which gave Teva no vested rights to marketing exclusivity. Since Teva’s exclusivity right never vested, the court held that there were no conflicts with congressional intent. 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Views on patent delisting: Intended purpose of patent delisting by branded drug manufacturers is to deny generic makers the marketing exclusivity. However, once an ANDA has been filed and Paragraph IV certification submitted, generic makers should have the right to 180 marketing exclusivity and in such cases, the FDA should reject the branded drug manufacturer’s request to delist a patent. This strategy of patent delisting to hurt generic makers by denying them 180 days marketing exclusivity hurts branded drug manufacturers too; firstly by delisting the patent, the branded drug manufacturer concedes that the delisted patent does not cover the drug and deprive itself of protection. Secondly, a patent delisting strategy gives the branded drug manufacturer bad publicity. Current scenario: Patent cannot be delisted once an ANDA has been filed. b) Layering Patents The branded drug manufacturer often receives both a principal patent and multiple secondary patents for the same drug. During a typical process of drug development, a branded drug manufacturer first discovers the compound which would later become the active ingredient of the drug. After numerous experiments in the laboratories and lengthy clinical trials, the branded drug manufacturer identifies more features of the compound. In addition, the branded drug manufacturer has to determine the best ways to formulate, make, and use the drug before the FDA could approve it. The branded drug manufacturer obtains the principal patent that covers the compound early in the drug development process. Years later, the branded drug manufacturer may obtain secondary patents on the new features of the compound or other aspects of the final product once they are discovered. Secondary patents can also provide protection over the drug when the inventions are truly innovative and substantially related to the drug. Secondary patents extend the protection on the drugs after the principal patent expires. Many secondary patents provide no legal protection. Many secondary patents aimed at layering over drugs in the orange book do not survive the generic maker’s

challenges in courts. These patents are often found either not valid because anticipated/obvious in light of prior art, or non-infringed because the generic makers have designed their products around the patents. So the layering patents give no protection over the drug. There are five types of secondary patents commonly used by branded drug manufacturers in a patent layering strategy: i) formulation patents; ii) metabolite patents; iii) polymorph patents; iv) process patents; v) use patents. I. Patents on Drug Formulation The formulation patents cover the inactive ingredients, which are used to improve the appearance, bioavailability, stability, and/or palatability of the drugs. The common inactive ingredients are divided into categories of coatings, artificial sweeteners, preservatives, colouring agents, fillers such as sugars, lactose, starch, and salts. Throughout the history of modern medicine, the pharmaceutical industry has developed very mature technologies in formulating drugs. The rich prior art makes formulation patents very vulnerable in the face of obviousness challenges. Even if the formulation patent is valid, the generic maker can easily design around it. According to the Act, the generic maker can substitute the formulation inactive ingredients in the brand drug as long as the replacing formulation is not “unsafe for use under the conditions prescribed, recommended, or suggested in the labelling proposed for the generic drug.” Because of this loose statutory language, the drug formulation is readily changeable and replaceable. II. Patents on Metabolites Drugs undergo metabolism, which breaks down the active ingredient into intermediates called metabolites. Though the metabolites do not exist in the drug, the branded drug manufacturer still lists patents on metabolites in the orange book to layer over the drug, such as metabolite patents for two drugs, BuSpar and Prilosec. Because the generic drugs do not contain the metabolites, the courts found that generic makers did not infringe the two metabolite patents. In a later example of a metabolite patent Summer 2018 Volume 10 Issue 2


Regulatory & Marketplace on the popular allergy drug Claritin, the Federal Circuit went even further to declare the metabolite patent invalid as “inherently anticipated” by the patent on the active ingredient. III. Patents on Polymorphs When the active ingredient has different crystal/chiral forms, the branded drug manufacturer will patent the new form once it is discovered. These are referred to as polymorph patents. Once again, the Federal Circuit has not treated these polymorph patents favourably. If the patent claims a new crystal form different from the one used in the drug, the generic drug containing the old crystal form does not infringe the patent. A more recent decision by the Federal Circuit put even more restrictions on the polymorph patents. If the claimed form exists in the drug as part of a mixture with other forms, then the polymorph patent is obvious in light of the drug itself. IV. Patents on Processes Besides patenting the drugs, the branded drug manufacturer also obtains process patents on making or using the drugs. The Federal Circuit has invalidated these patents on several occasions. For example, the court found that the drug Prilosec’s 6,013,281 patent claiming the process of producing the coating of the drug was inherently anticipated by the patent on coating itself. Other examples are patents 5,641,803 and 5,670,537, directed to a process of three-hour administration of the drug Taxol to treat cancer patients. Both patents were found invalid as anticipated by prior art. V. Patent on the Use of Drugs The last category of common secondary patents is those claiming a new use for a drug. The branded drug manufacturer constantly tries to expand the market for its drug by finding new uses in additional diseases. But if generic makers market the drug for the old uses only, the patent on the new uses is not direct infringement.14 Otherwise, the branded drug manufacturer “merely by regularly filing a new patents application claiming a narrow method of use would be able to maintain its exclusivity.” The branded drug manufacturer could then bar the entry of generics from the market altogether. www.ipimediaworld.com

The branded drug manufacturer’s near complete control over patent listing in the orange book also created another loophole in the Hatch-Waxman framework, allowing patent layering. Though the Act encourages generic markers to challenge the patents of brand drugs by filing Paragraph IV certifications, it also gives the branded drug manufacturer the opportunity of fully adjudicating the patents by staying the approval of ANDA for thirty months if the branded drug manufacturer engages prompt defence of the patents in courts. If the branded drug manufacturer could bring multiple infringing lawsuits on multiple patents covering the same drug, the Act gives multiple stays (one for each lawsuit). To exploit the loophole, the branded drug manufacturer adopted the strategy of layering later-issued patents over the drug in the orange book, which forces generic makers to submit a new Paragraph IV certification for each newly-listed patent. The new certification is the basis for a new infringement lawsuit on the new patent, which leads to another automatic thirtymonth stay of the ANDA approval. These multiple stays can significantly delay the introduction of generic drugs into the market, and extend the monopoly for the brand drug. Patents such as metabolite patents and process patents have only dismal relevance to the drug itself; therefore it is inappropriate to include them in the orange book. If these patents are allowed in the orange book, the branded drug manufacturer can extend the monopoly drastically by finding new, non-essential aspects of the drugs when the old patents are close to expiration. These new patents will keep the generic drugs out of the market for an extended period. Case Study 3 A most noticeable example is that of drug Paxil; the active ingredient of Paxil was discovered by Glaxo in the early seventies and in 1974 Glaxo filed a patent for this active ingredient (patent 4,000,196). More features of this active ingredient were discovered by Glaxo during the developmental phase. A secondary patent was filed on the hemihydrate form of the drug in 1986 by Glaxo (4,721,723). Four more secondary patents: patents 5,872,132

and 5,900,423 on new crystal forms in 1996 and 1997 respectively; patent 6,080,759 on a process of making the drug in 1997; and patent 6,113,944 on a tablet formulation in 1998, were filed later. Even though the principal patent of Paxil expired in 1992, the secondary patents effectively extend the monopoly of Paxil into 2018. Glaxo was able to obtain five stays for a total of sixty-five months for its popular antidepressant drug, Paxil. When the ANDA was filed in 1998 by generic maker Apotex, there were two patents listed in the orange principal patent on the active ingredient, patent 4,000,196, which expired in 1992; patent 4,721,723 that covers the hemihydrate form of the drug until 2006 (formulation patent). Apotex’s ANDA contains Paragraph IV certification challenging the formulation patent, on which Glaxo promptly brought a lawsuit alleging infringement. This triggered the first thirty-month stay.15 In 1999, Glaxo obtained two more patents, 5,872,132 and 5,900,423, that cover new crystal forms of Paxil (polymorph patents). Both patents were subsequently listed in the orange book with Paxil. Apotex was forced to file additional Paragraph IV certifications on these two patents. In August 1999, Glaxo brought two more infringement suits against Apotex, which triggered two more thirtymonth stays, fourteen months into the first stay. In June 2000, Glaxo received two additional patents for Paxil. Patent 6,080,759 claims the process of making the drug (process patent) and patent 6,113,944 claims a tablet formulation (formulation patent). In two separate requests, Glaxo had FDA list these two patents in the orange book. Apotex filed two more Paragraph IV certifications, on which Glaxo filed two more infringement lawsuits. Each lawsuit gave Glaxo one more thirtymonth stay. Glaxo layered a total of nine patents in the orange book on Paxil after the ANDA was filed. Glaxo brought infringement suits for four of the nine patents and was able to get five separate, but overlapping stays spanning 65 months. This extension was thirty-five months more than the stay of thirty months intended by the Congress. Because the annual sales of Paxil during these stays was about $1 billion, this patent layering strategy generated about $3 billion in sales for Glaxo. INTERNATIONAL PHARMACEUTICAL INDUSTRY 31


Regulatory & Marketplace There were two factors making the patent layering strategy possible. One was that the FDA gave control over patent listing to the branded drug manufacturer, which allowed the branded drug manufacturer to layer questionable patents in the orange book. Many of these patents were either not valid, or had only a distant relationship with the drug. Another factor was that the Act did not limit the number of stays that could be granted for a single drug. Both the FDA and Congress took actions to close this loophole. To curb listing questionable patents in the orange book, the FDA issued a new regulation in 2003 specifying the types of patents that could be submitted. The regulation excludes patents that are generally not relevant to the underlying drug: “process patents, patents claiming packaging, patents claiming metabolites, and patents claiming intermediates.2 Congress passed the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (“MMA”), which limits the branded drug manufacturer to only one thirty-month stay per drug. The MMA also relieves generic makers of the obligations of certifying later listed patents after their ANDA was filed. This amendment eliminated the incentive for branded drug manufacturers to layer patents in the orange book, which likely would put an end to the strategy of patent layering. The FDA’s new regulations on listing patents in the orange book categorically ban some of the most abused secondary patents. This will have some effects on restricting patent layering. More importantly, Congress enacted the MMA which allows only one thirty-month stay for each drug. This new provision takes away the biggest incentive of patent layering: multiple stays. The MMA will have a big impact on stopping the patent layering practice by branded drug manufacturers. We are unlikely to see much of patent layering as a strategy to fight generics in the future. c) Authorising Generics "An authorised generic (AG) is a pharmaceutical product that is manufactured under a new drug application (NDA) by a branded drug manufacturer, but is relabelled and marketed under a generic product name. Authorised generics do not have 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to abide with provision of 180 market exclusivity granted by Hatch-Waxman Act to the first generic on the market". Authorised generics could thus undercut the rationale of 180 market exclusivity granted by the Hatch-Waxman Act to the first filer, and thus have the potential of threatening the generic pharmaceutical market.16 An authorised generic is marketed and distributed as a generic, either by a generic subsidiary of innovator company or through a third party, but manufactured by a brand company. In the early 1990s, authorised generics were first used as part of litigation settlements where the generic company, in exchange for the opportunity to market an authorised generic version of the brand product, would agree to forgo its patent challenge. Typically, during the 180-day exclusivity period, the innovator of the branded drug may license a third party to market a generic version of its own brand drug. Since the branded drug manufacturer authorises marketing of its own generic version, this generic version is called authorised generics (AG). The difference between AG and the branded drug is: the authorised generic is packaged under a generic label; marketing of AG does not require a separate approval from FDA and marketing legality of AG depends on the NDA submitted by the branded drug manufacturer for the brand drug to the FDA. AG represents a great threat to the generic manufacturer with 180 marketing exclusivity, as AG can compete directly with the generic version granted 180 days’ exclusivity even during the 180-day market exclusivity period. The generic maker would make significantly less profit when there are two generic versions of the brand drug, instead of one, during the exclusivity period. Introduction of an AG during such a period will worsen the scenario for the generic firm. Case Study 4 Generic maker Apotex had the right of 180-day exclusivity for generic Paxil. Apotex initially expected the generic drug to generate sales between $530 million to $575 million during the exclusivity period. However, because the owner of Paxil introduced an AG, Apotex only had sales of approximately $150 million to $200 million.17 The reduction of profit was due to both loss of about half of the generic market and selling at a lower price during the exclusivity

period; because the generic makers receive the bulk of their profits during the exclusivity period, they feel a great threat from the AG. But an AG allows a branded drug manufacturer to recoup some of the loss that will occur during the exclusivity period. An AG competes with the generic version from the first ANDA applicant and recoups nearly half of sales in a generic drug market. Because the monopoly of the brand drug is lost anyway when the exclusivity period starts, the strategy of authorising generics to make up the loss after monopoly is over is a natural defence for a branded drug manufacturer. Case Study 5 When Pfizer and Proctor & Gamble introduced their respective AGs into the market during the 180-day exclusivity period, the generic makers Teva and Mylan launched vigorous challenges to the legality of AGs. The generic makers argued that Congress had a clear intent in the Hatch-Waxman Act to “grant the first ANDA filer complete exclusivity in the generic market for 180 days.”18 They charged that exclusivity shared with an AG was not exclusivity. The AG violated the Act because, the generic maker contended, it was contrary to the legislative intent. The two generic makers submitted citizen petitions separately to ask the FDA to “prohibit the marketing and distribution of authorised generic versions of brand name products until after the expiration” of the exclusivity period. The FDA denied both petitions in a single letter, concluding that the statute “does not contemplate or countenance delaying the marketing of authorised generics.”19 The FDA found no authority under the statutes to regulate when a branded drug manufacturer could introduce, or license a third party to introduce, an authorised generic version of its brand drug into the market. On review of the FDA’s ruling, both the Fourth Circuit and the DC Circuit agreed that the FDA simply did not have “the power to prohibit the marketing of authorised generics during the 180-day exclusivity period.”20 First, there was no textual support of alleged authority from the statutes. The courts found no support from the original FDCA that prohibits NDA holders from introducing a brand generic drug in the market during the ANDA’s exclusivity period.21 Summer 2018 Volume 10 Issue 2


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 33


Regulatory & Marketplace Secondly, the court did not agree with the generic makers. The generic makers argued that the legislative intent behind the Hatch-Waxman Act was creating “the 180-day exclusivity period to encourage generic companies to file Paragraph IV challenges to brand drug patents.” Since an AG would “reduce the revenues” for the ANDA applicant, the practice was against the legislature intent. The court found this argument unconvincing. A branded drug manufacturer is free to license generic versions of its pioneer drugs at any time. In conclusion; the courts agreed that “the statute does not grant the FDA the power to prohibit the marketing of authorised generics during the 180-day exclusivity period.” Agency’s Requirement for Authorised Generics According to the FDA, authorised generics can be brought to the marketplace in a number of ways, but the three most commonly identified ways are: •

With private label marketing and distribution companies, brand companies can establish agreements whereby they give authority to market and distribute authorised generic products. As a result of such an agreement, there are generally two generics competing in the marketplace during the exclusivity period. Establishing subsidiaries to market authorised generics: branded drug manufacturers can establish subsidiaries of their own brands to market AGs. In the past, several companies have launched authorised generics by establishing subsidiaries, but this approach has been abandoned nowadays for other options. This kind of approach results in two generic firms competing in the marketplace during the exclusivity period. Branded drug manufacturers can establish agreements with generic drug manufacturers (oftentimes a result of a patent challenge settlement).

NDA holders in annual reports must submit certain information concerning 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

authorised generics to the FDA. The FDC Act was amended by the Food and Drug Administration Amendments Act (FDAAA) § 920 and a new section (§ 505(t)) “Database for Authorized Generic Drugs” was created, this new amendment requires "FDA to compile and publish a complete list of all authorised generic drugs identified in annual reports and submitted to the FDA" since January 1, 1999.22 The final rule of the authorised generics amends 21 CFR § 314.3(b) regulation of the FDA; this new amendment includes the following definition of an “authorised generic drug” which is identical to that mentioned in the FDC Act §505(t): "Authorised generic drug means a listed drug, that has been approved under section 505(c) of the act and is marketed, sold, or distributed directly or indirectly to retail class of trade with labelling, packaging (other than repackaging as the listed drug in blister packs, unit doses, or similar packaging for use in institutions), product code, labeller code, trade name, or trademark that differs from that of the listed drug". The FDA’s post-marketing reporting requirement was amended by the final rule to add 21 CFR § 314.81(b)(2)(ii)(b) to require NDA holders to include in their annual reports information detailing: a) The date of authorised generic entry into the market; b) The date each authorised generic ceased being distributed; and c) The corresponding brand name drug. "FDA considers each dosage form and/or strength to be a different authorised generic drug that should be separately listed in an annual report. Moreover, the first annual report submitted after implementation of this regulation must provide information regarding any authorised generic drug that was marketed during the

time period covered by an annual report submitted after January 1, 1999.”2 Conclusion The Hatch-Waxman Act provides first Paragraph IV filer with 180 marketing exclusivity; various strategies have been used in the past against Paragraph IV filers to deprive them of this exclusivity period. A strategy employed recently by branded drug manufacturers was authorised generics (AG). Even though the FDA and FTC have allowed marketing of authorised product, issues related to authorised generics are still being assessed. REFERENCES 1.

2.

3.

4.

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6.

7.

8. 9.

Greater Access to Generic Drugs [Internet]. Fda.gov. Available at: https:// www.fda.gov/Drugs/ResourcesForYou/ ucm134448.htm CFR - Code of Federal Regulations Title 21 [Internet]. Accessdata.fda.gov. Available at: https://www.accessdata. fda.gov/scripts/cdrh/cfdocs/cfCFR/ CFRSearch.cfm?fr=314.108 [Internet]. Available at: https:// www.thepharmaletter.com/article/ new-drug-application-impact-onpatent-and-exclusivity An assessment of the effect of authorized generics on consumer prices. Authorized Generics and Consumer Prices [Internet]. Available at: https://sites.google.com/site/ combesite/hollisliang.pdf U.S. Code § 355 - New drugs [Internet]. LII / Legal Information Institute. Available at: https://www.law.cornell. edu/uscode/text/21/355 ParagraphFour.com [Internet]. Paragraphfour.com. Available at: http://www.paragraphfour.com/ explained.html [Internet]. Available at: http://www. cardozoaelj.com/wp-content/ uploads/Journal%20Issues/Volume% 2025/Issue%202/Pechersky.pdf Maggon K. Best-selling human medicines 2002-2004. Drug Discovery Today. 2005;10(11):739-742. [Internet]. Available at: http:// www.fda.gov/ohrms/dockets/ dockets/05p0008/05p-0008pdn0001-vol2.pdf

Latest AG Approved23 Proprietary Name

Dosage Form

Strength

NDA Applicant Name

Entered Market On

CLOZARIL

Tablets

25 & 100 mg

Heritage Life Sciences (USA), Inc.

September 2017

DUTOPROL

Tablets

100/12.5 mg

Concordia Pharmaceuticals Inc.

August 2017

Summer 2018 Volume 10 Issue 2


Regulatory & Marketplace 10. [Internet]. Available at: http:// www.fdalawblog.net/NEXIUM%20 -%20Ranbaxy%20TRO%20Brief.pdf 11. [Internet]. Available at: http://www. fdalawblog.net/files/losartancomplaint.pdf 12. Barkoff A. Orange Book Blog: Teva Seeks Relisting of J&J's Risperdal Patent and Asserts Right to 180-Day Exclusivity [Internet]. Orangebookblog. com. 2008. Available at: http://www. orangebookblog.com/2008/01/ teva-seeks-reli.html 13. Ranbaxy Laboratories Limited, et al., Appellees v. Michael O. Leavitt, Secretary of Health and Human Services, et al., Appellants, 469 F.3d 120 (D.C. Cir. 2006) [Internet]. Justia Law. Available at: https://law.justia. com/cases/federal/appellate-courts/ F3/469/120/622319/ 14. FindLaw's United States Federal Circuit case and opinions. [Internet].Findlaw. Available at: http://caselaw.findlaw. com/us-federal-circuit/1593837.html 15. [Internet]. Repository.jmls.edu. 2017. Available at: https://repository.jmls.edu/cgi/ viewcontent.cgi?referer= https://www.google.co.in/&https redir=1&article=1103&context=ripl 16. [Internet]. Available at: https:// www.fenwick.com/Fenwick Documents/Authorized_Generics.pdf 17. GSK-AUTHORIZED GENERIC PAXIL SLASHES APOTEX'S SALES [Internet]. Fdanews.com. Available at: https://

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www.fdanews.com/articles/64615gsk-authorized-generic-paxilslashes-apotex-s-sales?v=preview United States Court of Appeals D. 410 F3d 51 Teva Pharmaceutical Industries Ltd Teva Pharmaceuticals UsaInc v. M Crawford [Internet]. Openjurist.org. Available at: https://www.justice.gov/ atr/file/900991/download [Internet]. Available at: https://www. fda.gov/ohrms/dockets/dailys/04/ july04/070704/04p-0075-pdn0001.pdf [Internet].Available at: https://www. everycrsreport.com/files/20130117_ RL33605_befaebe4ec06d39b f32c7f68a6907286ef0b3537.pdf United States Court of Appeals D. 410 F3d 51 Teva Pharmaceutical Industries Ltd Teva Pharma-ceuticals UsaInc v. M Crawford [Internet]. Openjurist.org. Available at: https:// www.justice.gov/atr/file/900991/ download FDA Law Blog: FDA Finalizes Authorized Generics Reporting Rule; Electronic Submissions Will be Permitted and Eventually Required [Internet]. Fdalawblog.net. Available at: http://www.fdalawblog.net/2009/07/ fda-finalizes-authorized-genericsreporting-rule-electronic-submissionswill-be-permitted-and-eventu/ FDA Listing of Authorized Generics [Internet]. Fda.gov. Available at:https:/ /www.fda.gov/AboutFDA/Centers Offices/fficeofMedicalProductsand Tobacco/CDER/ucm126391.htm

Trishna Chetry Trishna Chetry is pursuing Masters in Regulatory Affairs, Department of Pharmaceutics, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India. Email: trish.chetry@gmail.com

T.M. Pramod Kumar T.M. Pramod Kumar is the Principal & Professorin JSS College of Pharmacy, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India. Email: pramodkumar@jssuni.edu.in

M.P. Venkatesh M.P. Venkatesh is an Assistant Professor in Department of Pharmaceutics in JSS College of Pharmacy, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India. Email: venkateshmpv@jssuni.edu.in

Balamuralidhara V. Balamuralidhara V. is an Assistant Professor in Department of Pharmaceutics in JSS College of Pharmacy, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India. Email: baligowda@gmail.com

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 35


Drug Discovery, Development & Delivery

Trends in Drug Development â&#x20AC;&#x201C; In Denmark and Globally The entire process from discovering and developing a potential drug candidate to its delivery into the human body requires comprehensive knowledge about the root cause of the disease at molecular, cellular and genetic levels. It is also necessary to identify the target with which a potential new drug might be able to interact, validation of the target, discovery of the potential drug that can interact with the desired target, and testing of its safety and efficacy in humans. This is an intricate, costly and long-term process. Nevertheless, Danish biotech and pharma companies are still among the best in Europe when it comes to drug development and innovation. However, it is important to look into new methods in order to discover and develop new drugs, and to have an innovative approach when it comes to drug delivery. New methods include such things as small-angle scattering for discovering new potential drugs, immunotherapy for curing cancer more efficiently, and nano-drugs for precise and controlled delivery of the drugs.

Neutron-scattering Facilities and X-ray Synchrotrons for Use in the Development of New Medicine Almost any medicine works because a medical molecule interacts with a molecule in the body that is either directly or indirectly related to the disease. With the technique of small-angle scattering, it is possible to examine the interaction between molecules under natural conditions, which is important in order to develop new medicine. When treating diseases with medicine, the purpose is to attack the disease all the way down to the molecular level. This can, for instance, be obtained by correcting a deficit of a particular molecule or protein, like when Novo Nordisk develops insulin to be given to diabetics. Furthermore, it could also be affected by turning up or down the function of a molecule activity. Other diseases are related to the fact that certain molecules in 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the body do not behave as intended. This is the case for a wide range of neurodegenerative diseases such as Parkinson's and Alzheimer's disease, which are serious diseases that result in lost brain function, and which are associated with accumulation of proteins in the brain. The active substance in the medicine can be either a protein or a small molecule like acetylsalicylic acid, which together with codeine is the active substance in painkillers. In addition to the actual effect of the drug, the specific drug delivery in the body is also an important factor in how effective the drug is. In order to understand both the diseases and the treatment, it is important to be able to examine the structure of the molecules and proteins involved, at a very small scale. The technique of crystallography has until now been essential to understanding the structure and function of proteins. Here, the atomic structure of a protein can be determined from diffraction patterns of x-ray or neutron radiation. However, it requires that the proteins are crystallised, which means that the proteins are placed in a well-organised grid, closely surrounded by neighbour proteins. This is quite far from the physiological conditions in the body, where the protein is functioning normally. It is, therefore, further important to get additional information about how the protein and the other relevant components of a drug formulation behave in a solution, at physiological temperature and pH-value. This is possible by using the technique called small-angle scattering. Small-angle scattering gives structural information on a scale from 1 to about 500 nanometers, on all types of samples. The big advantage is that it is possible to see how biological and medical molecules interact and shape complexes under more realistic

conditions outside the crystals. It provides a more representative picture of how these processes take place in the body and is a unique opportunity to follow processes under development. Neurodegenerative Diseases on a Molecular Scale Denmark is among the leading countries in the research field of CNS-related diseases, including neurodegenerative diseases. This is a natural consequence of both a strategic focus on research and development in this area in Denmark, and of Denmark being at the forefront in the use of the small-angle scattering method, as well as within crystallographic methods. Neurodegenerative diseases are associated with the formation of long fibres of protein, in a modified, inactive form. The pharmaceutical industry is very interested in investigating similar fibres, in order to prevent them from being formed in protein and peptidebased drugs, during preparation of the drugs. It is difficult to study the structural development of the fibres, since there is a continuous wealth of different coexisting forms of fibres in the process and because the relative distribution of these forms just develops over time. However, small-angle scattering has proved to be a very suitable tool to get the relevant information about these fibres and their formations. Danish researchers have investigated the formation of the specific fibre named alpha-synuclein protein, related to neurodegenerative disease1. The Danish research team have shown that lipid model systems, which imitate cell walls, are destabilised and destroyed by the proteins, which are formed early in the process. Furthermore, during the process, an aggregate consisting of both protein and lipid is formed, which may be an important factor in explanation of the cellular degradation which is observed in neurodegenerative diseases. This knowledge ensures Summer 2018 Volume 10 Issue 2


Drug Discovery, Development & Delivery that the Danish researchers are now one step closer to understanding the disease on a molecular scale, which is the prerequisite for developing a drug for treatment of neurodegenerative diseases.

the last couple of years, which means that it will soon be possible to treat a very large group of cancer patients, with a variety of different cancerous diseases, far more efficiently by using immunotherapy.

From Niche to Mainstream During the last ten years, the small-scale scattering method has moved from being a niche method, used only by specialists, to being a method used by a wider range of researchers and developers, to get essential information about medical molecules and diseaserelated molecular structures. The method is one of the most sought techniques at the international neutron-scattering facilities, and on the X-ray synchrotrons. It has been a rapidly growing technology over the last ten years and is a central part of the instrument portfolio in most international facilities. Denmark is one of the leading countries in research and use of the small-scale scattering method. First, this is since Denmark has pioneered the small-scale scattering method and has built up strong skills in using the method. This also means that Denmark now has several researchers who have mastered the use of the small-scale scattering method for the development of new medicine. Second, Denmark is geographically well-placed in relation to some of the most excellent and well-known neutron-scattering facilities and X-ray synchrotrons in Europe2.

Currently, new forms of immunotherapies are rapidly being adopted for different cancerous diseases. The new treatment indicates that the overall survival of many different cancerous diseases will be improved significantly and more patients, even with metastasis, could become completely diseasefree. Immunotherapy is expected to bring changes in cancer treatments over the next few years.

One of these facilities is the European Spallation Source (ESS). This new facility will be around 30 times brighter than todayâ&#x20AC;&#x2122;s leading facilities, enabling new opportunities for researchers in the field of life sciences. The ESS is one of the largest science and technology infrastructure projects currently constructed. The ESS facility is being built in Lund, Sweden, while the ESS Data Management and Software Centre will be located in Copenhagen, Denmark. In addition to the neutron-scattering facility in Lund, there is also a state-of-the-art X-ray synchrotron. Furthermore, there is another new X-ray synchrotron in Hamburg, Germany, as well as an electron microscope facility in Aarhus, Denmark (Figure 1). www.ipimediaworld.com

New Opportunities â&#x20AC;&#x201C; New Treatments Sometimes it is necessary to examine novel methods, in order to develop new drugs and treatments. Immunotherapy is an example of such a new way of treatment, currently focused on cancer treatment, where the treatment is directed toward the immune system and not directly against the cancer cells. Many types of immunotherapy, such as cytokines, cancer vaccines, cellular immunotherapies and antibodies, have been tested in clinical trials over the past few decades. Cancer immunotherapy activates the immune system to fight the cancer, which can result in significantly improved treatments. Immune Therapy is Central in the Future of Cancer Treatment Cancer treatment is a global issue that has great awareness among the general population, healthcare professionals, patient associations and politicians. The progress currently taking place in the treatment of cancer is mainly occurring within immunotherapy. This development has accelerated over

A Conceptual Break with Classic Cancer Treatment Immunotherapy represents a completely new way of thinking cancer treatment, where the focus of treatment is primarily on the immune system and not directly, on the cancer cells (Figure 2). The principle is based on recent knowledge of the immunological mechanisms of action. The treatment intends to manipulate the immunological equilibrium for the purpose of eliminating the cancer cells. Hence, cancer-immunotherapy acts by activating the immune system to fight the cancer, which can result in significantly improved cancer treatment. The breakthrough in the immunotherapy is innovating the treatment of cancer and has made a major contribution to this research area, both in Denmark and internationally. Not only are new immune-regulatory and cellular therapies in development, but many new combinations are in the discovery phase.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 37


Drug Discovery, Development & Delivery One of these new discoveries is currently ongoing in a public-private partnership, with a Danish spin-out company and a Danish University hospital. They are developing a cancer vaccine aimed at programmed death-ligand 1 (PD-L1) and the enzyme indoleamine 2,3-dioxygenase (IDO), which are both known to be cancer-related immune suppressors. IDO peptide vaccination has demonstrated promising clinical effect, consolidating after chemotherapy, in patients with lung cancer. Vaccination with PD-L1 is currently being tested in patients with myelomatosis3. In general, peptide vaccines appear to be non-toxic, making them attractive candidates for combination with other immunotherapies, as they potentially increase the anti-tumour effect without causing further side-effects. Nano-medicine Targeted Drug Delivery It is not only essential to look at the development of new drugs; it is also crucial to focus on new and accurate drug delivery methods. The term nano-medicine has emerged as an independent concept in recent years. Nano-medicine is based on two trends in science: The rapidly growing understanding of which molecular mechanisms underlie human diseases and the development of new advanced techniques for synthesis of biomaterials, in regard to biology. As the name indicates, these are drugs which are designed on nanoscale, i.e. a scale of about one billionth of a metre. This is actually a larger scale than the one in which normal chemical processes take place and where traditional drugs often work. Unlike traditional drugs, nano-medicine can therefore contain advanced features, which can be expressed at precise planned times and locations in the body. …And it is Not Even Expensive… It would be natural to think that nano-medicine would very expensive to produce, because of the complexity. However, the fact is that the scientists have understood how to utilise a method known from nature as molecular self-assembly, where simple substances come together by themselves and form well-defined complex structures, without human intervention. One of the current focus areas of nano-medicine is drug delivery. 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Nano-medicine Used as Drug Delivery An example of a very promising method of using nano-medicine for drug delivery is the development of nano-capsules containing drugs. At Aarhus University in Denmark, a team of researchers has developed a capsule of a sugar called chitosan in which genetic medicine is built4. The advantage of this method is that the medicine and the sugar assemble themselves in nanoparticles. The sugar capsule protects the fragile biomolecules from degradation, and furthermore, lures the cells to absorb the sugar capsules. Then the sugar capsules are degraded and release the drug inside the cells. By connecting certain chemical groups to the sugar capsule, it can be ensured that they only stick to the diseased cells. This is a very effective, as well as inexpensive, method for accurate delivery of the intended drug. A New Look at Old Medicine Denmark has a long history of accurate and comprehensive medical database-keeping. These databases are among the most sophisticated in the world, providing researchers with a rich source of medical and genetic information. The majority of the databases are available to researchers at little or no cost once their research projects have been approved. This is also the reason why Denmark is one of the countries in the world with the best data in regard to assessing the relationship between different types of medicines and diseases, especially cancer. This is because Denmark has registered patients' cancer data since 1942 and has registered their drug consumption since 19955. In order to generate accurate research results, it must be possible to follow people for a very long time, and such data is available in Denmark. This gives the Danish researchers and their collaborators a unique opportunity to investigate the relationships between different types of medicines and cancers. These data are the foundation that makes Denmark a world leader in the field of register-based research. Conclusion Discovering and developing better drugs, and designing innovative delivery methods or improving current

ones is of absolute importance. However, drug improvements will only be effective if the methods are developed in companion with safe drug-delivery methods. Thus, the drugs need to be directed through specific areas of the body, such as the stomach with low pH, without destroying the medication. The field of drug discovery, development and delivery plays a significant and critical role in social healthcare and therefore there is a dire need to continually advance this field, in order to provide better medication to the patients and increase their survival rate. REFERENCE 1. Lobbens, E. S. et al. Mechanistic study of the inhibitory activity of Geum urbanum extract against α-Synuclein fibrillation. Proteins and Proteomics, 9, 1160-1169 (2017) 2. Beedholm-Ebsen, R. Regional Focus: Denmark. EBR. 2, 104-107 (2015) 3. Andersen, M. H. The Balance Players of the Adaptive Immune System. Cancer Res. 6, 1379-1382 (2018) 4. Manuguerra, I. et al. Construction of a Polyhedral DNA 12-Arm Junction for Self-Assembly of Wireframe DNA Lattices. ACS Nano. 9, 9041–9047 (2017) 5. Beedholm-Ebsen, R. Denmark; small and personalised. IPI. 1, 8-11 (2017)

Dr Rasmus Beedholm-Ebsen Dr Rasmus Beedholm-Ebsen is Senior Advisor within Life Science, at Invest in Denmark, under the Ministry of Foreign Affairs of Denmark. Dr Beedholm-Ebsen received his PhD in Medicine at Aarhus University, Denmark, and worked at the Department of Medical Biochemistry at Aarhus University before joining Invest in Denmark. Recently, Dr Beedholm-Ebsen received a degree in Certificate in Business Administration, and holds a Bachelor of Commerce degree. Dr BeedholmEbsen also holds a Masters degree in Molecular Biology, and is Scientific Expert Reviewer for the European Commission. Email: rasbee@um.dk

Summer 2018 Volume 10 Issue 2


Drug Delivery Devices Innovative developments Customized solutions GMP contract manufacturing

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Drug Discovery, Development & Delivery

Model Systems for Studying the Human Gut Microbiome A variety of in vivo, in silico, in vitro, and ex vivo model systems are available to researchers for studying the human intestinal microbiome, its functionalities and complex interactions with the host. Different models serve different purposes, all of them having their relevance as well as limitations and interdependencies. This article provides an overview of the most popular model system concepts, how they are being employed in gut microbiome research, and how they are complementary to each other.

In Silico Modelling

The extreme complexity of our inner microbial ecosystem, the gut microbiome, challenges researchers’ abilities to map and understand what specific role organisms in the community have and how they interact with the other community members. Computational, or in silico, methods can aid in identifying the metabolic functions and the cross-talk happening between community members and potentially even with the host. Based on the wealth of sequencing and functional profiling data available from organisms identified in the human microbiome, researchers use computational simulations to identify roles and molecular pathways of the microorganisms in the community. Informed by gene expression experiments, it is even possible to use in silico methods to model how the community responds to changes in the environment. Different mathematical techniques are employed for modelling different aspects of the microbiome, spanning from models able to predict ecological population dynamics and spatial structure to models based on genome-scale metabolic networks. Genome-scale metabolic network models are based on collections of metabolic functions derived from the genome of each organism in the network. That enables very detailed analysis of complex cellular processes in the context of a complex community, which can be difficult to get from other 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

model systems. Going forward, it is the hope that computational methods can be utilised to identify in silico biomarkers for predicting disease-associated changes in the human microbiome. Furthermore, the computer models may be applied in the field of personalised medicine by the construction of personalised metabolic models. Despite the potential for discovery and hypothesis generation for subsequent testing in the wet lab models, in silico experiments are still relatively underutilised by the scientific community. In silico methods modelling complex communities with a large amount of data associated with each organism in the community require considerable computational power, which can be a limiting resource. More importantly, designing and executing computer simulations requires interdisciplinary skills from microbiology, biology and computer technology, which can be a heavy lift to accomplish. Additionally, not all microbial genes have been sequenced; of those with sequences available, less than half have been annotated to a specific function, making in silico methods highly dependent on currently available databases and existing knowledge of the microbiome. Hence, it is continuously necessary to inform the computational approaches with experimental data obtained from other model systems, e.g. animal models.1,2 In Vitro and Ex Vivo Models Literally meaning “in the glass”, in vitro experimentation refers to the study of cell lines, microorganisms or molecules outside of the living context they stem from, e.g. in petri dishes, test tubes, microplates, flasks or the like. Ex vivo studies are defined by the removal of tissues or cells from a living organism to enable the greatest similarity to the conditions in the live host, yet happening “out of the living” and thus considered an in vitro method. In vitro bioreactor models of the human gut microbiome are used to mimic microbial processes and physical conditions in the gastrointestinal tract.

Such model systems typically consist of different compartments connected in series, with each compartment harbouring human bacteria specific to an intestinal section, i.e. the stomach, or small or large intestine. Enzymatic processes relevant to each intestinal section happen in each compartment. In some systems a mucus layer can be added so the microbiota can adhere to the “gut surface,” which is useful for understanding which bacteria are important for shaping the intestinal barrier and mucus layer. Some systems integrate dynamic conditions such as peristaltic movements and absorption of water and nutrients. These “gut-ina-bottle” models are very good for investigating how food, dietary compounds and drugs metabolise, but lack the immunological and other physiological cross-talk with the host. Because of the large physical setup, it is a notable constraint that in vitro bioreactor systems do not allow for several biological study replicates to be run in parallel under comparable conditions. The microfluidics-based system is another type of model often referred to as “gut-on-a-chip”. In tiny chambers, human and microbial cells can be co-cultured and separated by membranes to mimic the host-microbiome interface. Various technologies exist and they are constantly being refined, adding more details and conditions to the system to make the model as representative as possible of the real-life situation. For instance, investigations are underway to add immune cell populations to a “gut-on-a-chip” to open up avenues of analysing adaptive and innate immune responses to the microbiome.3 The key limitation of microfluidics-based model systems is that only one organ is simulated and effects on other tissues and organs cannot be measured. While there are development initiatives underway to expand the systems by integrating more organs in the model, the technology is still in its infancy and cannot substitute for animal models. Functions throughout Summer 2018 Volume 10 Issue 2


Drug Discovery, Development & Delivery the entire body are influenced by the host-microbe interaction happening in the gut, including brain development and behaviour. Such systemic effects are still impossible to fully study in microfluidics devices, but these models can serve as very valuable tools for narrowing down compounds before going into animal studies. Ex vivo models involve removal of living and functional tissue or organs for cultivation in an artificial environment outside the host organism. Three-dimensional cell culture models, so-called organoids, are particularly interesting in human gastrointestinal and microbiome research and have seen rapid progress in recent years. Organoids mimic morphological and functional features of the donor original tissue. The three-dimensional aspect is usually obtained by creating scaffolds of various natural or synthetic materials, e.g. collagen or polymers. The organoids can be derived from human embryonic and induced pluripotent stem cells or in some cases even from tissue biopsies. The cells grow, differentiate and organise in an architectural structure relatively comparable to the in vivo situation. The added complexity of organoids compared to more simplistic in vitro methods provides the opportunity to more accurately study concepts like epithelial barrier dynamics, differentiation and proliferation of cells and immune cell crosstalk. Bacteria, such as probiotics, or microbial communities can be added to the system and enables understanding of the molecular processes happening in the host-microbiome interface. The top application area of gastrointestinal organoids is within infectious disease, but the models are also viable for studying inflammation, cancer and the involvement of the microbiome in intestinal development. Additionally, organoids may represent a tractable starting point for the creation of “synthetic” or bioengineered organs for future transplantation into humans, an area known as regenerative medicine. Efforts for refining and expanding on the utilities of organoid models are constantly ongoing, for example by the integration of neurons to model pathways in the enteric nervous system. Nevertheless, outside of the relative high expenses related to the maintenance of organoid models, the key limitation is the lack of a systemic nervous system, www.ipimediaworld.com

vascular, lymphatic and full immune system. The micro-anatomy, i.e. how the cells organise and form structures, can also differ from that of the in vivo situation. All in vitro/ex vivo models have in common that they cannot link the microbiome composition to the host phenotype and processes in organs other than the gut. Additionally, these models are biased towards the microorganisms that are able to survive and grow under in vitro conditions, which is currently estimated to be around 20-80% of the human microbiome under standard cultivation conditions.1,4,5 In Vivo Models In vivo models, i.e. animal models, are the only model systems capturing the essence and complexity of a whole organism and the only model able to link the microbiome to phenotype. Behavioural studies are inherently only possible to do in live animals, but also systemic and local physiological processes, such as immune activation orchestrated by many different cell and tissue types, can only fully be studied in whole, living organisms. After all, a functioning body is more than merely the sum of its parts. Animal model organisms range from invertebrates such as worms and insects, to fish, birds and mammals. For microbiome research, the most popular models include mice and rats, zebrafish and fruit flies. Common to these models is the relative ease with which they can be created and maintained as germ-free, i.e. sterile. Germ-free animals harbour no microor macroorganisms, meaning they are completely free from bacteria, viruses and parasites. Pigs are also highly relevant as translational microbiome models for humans and can also be generated as germ-free, but with much less ease than rodents, zebrafish and fruit flies. Access to germ-free animals is extremely valuable to researchers engaged in understanding basic mechanistic aspects of the hostmicrobiome interface, as well as for drug screening and testing. Mice represent the most widely used animal model in biomedical research across disciplines, as well as the most characterised. As such, germ-free mice hold a unique position when it comes to studying the microbiome in a well-known and

practical model organism. Germ-free mice can be colonised with individual, defined bacterial strains (a reductionist approach) or with microbial communities (a holistic approach), e.g. derived from human faecal samples. Both the reductionist and holistic approaches are used for mechanistic and proof-of-concept studies, whereas the holistic approach also has another important application: the creation of laboratory mice with controlled microbiota of interest. Laboratory rodents display pronounced microbiome variability between different commercial vendors and animal facilities, a fact that has been linked repeatedly to poor reproducibility of studies if performed without consideration to this variability. This is because the microbiota composition of rodents has a significant influence on the phenotype of a wide range of disease models, leading to trouble when trying to replicate experiments across laboratories and across mice from different sources. In some cases, one microbiome may be advantageous for the phenotype of one type of disease model (for example, within infectious disease), but the opposite in another model (for example, within autoimmune and metabolic disease). Hence, there seems to be an identified need for animal models harbouring microbiomes of relevance to different research applications.6,7 One reliable way to achieve this would be to colonise germ-free mice with the microbiome of interest and use these mice as the starting point for a breeding colony. If the mice are housed under controlled and protected conditions, the microbiome remains stable over time.8–10 Such an approach would provide researchers with a steady source to repeatedly obtain mouse cohorts from – for drug candidate testing, for example – without the risk of running into issues with reproducibility due to microbiome variability. As for any model system, the biggest limitation of using rodents for microbiome research is how well they mimic humans. For instance, the host-microbe interaction is heavily based on activation of the host immune system and there are certainly known differences between the murine and human immune systems. Additionally, or maybe because of this, colonising germ-free mice with human microbiota INTERNATIONAL PHARMACEUTICAL INDUSTRY 41


Drug Discovery, Development & Delivery

does not induce full immune system development in the mouse – a critical limitation to be aware of. To better understand the underlying mechanism behind this phenomenon, in vitro cell cultures of human gut epithelial cells or intestinal organoids could be employed.11 Zebrafish serve as a very interesting alternative to rodents for gut microbiome research, with a steady increase in their use over the past decade. They are easy to maintain as germ-free, especially in their early life before requiring to be supplied with feed. Zebrafish are unique in that they are transparent until adulthood. Hence, colonisation with microbes can be visualised directly or organogenesis can be monitored. The gastrointestinal tract of zebrafish has many anatomical and physiological traits that make them relevant as models for humans, but they are nevertheless more different than rodents are to us. For instance, zebrafish lack organised lymphoid structures which, in contrast, are highly conserved between mice/rats and humans. Fruit flies constitute an even simpler model, and one with surprisingly many possible applications. The inherent gut microbiome of fruit flies is very simple, with only 2–20 different bacteria found naturally in the fly gut. The flies can be maintained as germ-free and colonised with specific microbes. By dietary interventions, it is possible to study how different microbes metabolise food and potentially shape innate immunity. Behavioural observations can be done to see how different microbes affect the fly’s feeding behaviour. The short generation time, low cost, easy maintenance and possibility to do various interventions make fruit flies tractable, yet relatively underutilised models. A significant limitation is their lack of adaptive immunity and the fact 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

that only aerobic bacteria can colonise the gut. This is in stark contrast to the mouse and human gut microbiome, which are both dominated by anaerobic species.1,11,12 In silico, in vitro, ex vivo and in vivo models all have their interdependencies and pros and cons when it comes to studying the human gut microbiome. Optimal advancement of microbiome research to enable discovery of microbiome-based therapeutics requires scientists to collaborate across disciplines. Every time an experiment is designed, the choice of model system should thoroughly be scrutinised with consideration to what would be most informative and translationally relevant.

9.

Collins, J., Auchtung, J. M., Schaefer, L., Eaton, K. A. & Britton, R. A. Humanized microbiota mice as a model of recurrent Clostridium difficile disease. Microbiome 3, 35 (2015). 10. Lundberg, R., Bahl, M. I., Licht, T. R., Toft, M. F. & Hansen, A. K. Microbiota composition of simultaneously colonized mice housed under either a gnotobiotic isolator or individually ventilated cage regime. Sci. Rep. 7, 42245 (2017). 11. Douglas, A. E. Which experimental systems should we use for human microbiome science? PLOS Biol. 16, e2005245 (2018). 12. Newton, I., Sheehan, K., Lee, F., Horton, M. & Hicks, R. Invertebrate systems for hypothesis-driven microbiome research. Microbiome Science and Medicine 1, (2013).

REFERENCES 1.

Fritz, J. V, Desai, M. S., Shah, P., Schneider, J. G. & Wilmes, P. From meta-omics to causality: experimental models for human microbiome research. Microbiome 1, 14 (2013). 2. Magnúsdóttir, S. & Thiele, I. Modeling metabolism of the human gut microbiome. Curr. Opin. Biotechnol. 51, 90–96 (2018). 3. Eain, M. M. G. et al. Engineering Solutions for Representative Models of the Gastrointestinal Human-Microbe Interface. Engineering 3, 60–65 (2017). 4. Roeselers, G., Ponomarenko, M., Lukovac, S. & Wortelboer, H. M. Ex vivo systems to study host–microbiota interactions in the gastrointestinal tract. Best Pract. Res. Clin. Gastroenterol. 27, 101–113 (2013). 5. Hill, D. R. & Spence, J. R. Gastrointestinal Organoids: Understanding the Molecular Basis of the Host–Microbe Interface. Cell. Mol. Gastroenterol. Hepatol. 3, 138–149 (2017). 6. Hansen, A. K., Hansen, C. H. F., Krych, L. & Nielsen, D. S. Impact of the gut microbiota on rodent models of human disease. World J. Gastroenterol. 20, 17727–36 (2014). 7. Bleich, A. & Hansen, A. K. Time to include the gut microbiota in the hygienic standardisation of laboratory rodents. Comp. Immunol. Microbiol. Infect. Dis. 35, 81–92 (2012). 8. Alpert, C., Sczesny, S., Gruhl, B. & Blaut, M. Long-term stability of the human gut microbiota in two different rat strains. Curr. Issues Mol. Biol. 10, 17–24 (2008).

Alexander Maue Alexander Maue is Director of Microbiome Products & Services at Taconic Biosciences, a fully-licensed, global leader in genetically engineered rodent models and services with an advanced portfolio of microbiome products and services. Prior to working at Taconic, he was the Head of the Campylobacter Immunology Laboratory at the Naval Medical Research Center in Silver Spring, MD. Trained as an immunologist, his research focus was on enteric diseases and the development of vaccines and therapies to prevent illness. Email: alexander.maue@taconic.com

Randi Lundberg Randi Lundberg is Field Applications Scientist at Taconic Biosciences, a fully-licensed, global leader in genetically engineered rodent models and services with an advanced portfolio of microbiome products and services. A veterinarian and PhD in in vivo pharmacology from University of Copenhagen, Denmark, Randi specialises in the study of the microbiome in animal models. Prior to joining Taconic, Randi served as laboratory animal veterinarian in the pharmaceutical industry.

Summer 2018 Volume 10 Issue 2


ExpreS2ion Biotechnologies is world leading within recombinant protein expression in Drosophila Schneider-2 insect cells using ExpreS2 ExpreS2 is a virus-free S2 cell expression platform for R&D in diagnostics, vaccines, and therapeutics, basically Challenging Proteins Made Easy

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ExpreS2ion Biotechnologies ApS · Agern Allé 1 · DK-2970 Horsholm · Denmark www.ipimediaworld.com INTERNATIONAL PHARMACEUTICAL INDUSTRY 43 Tel (+45) 42 56 68 69 · info@expreS2ionbio.com · www.expreS2ionbio.com


Drug Discovery, Development & Delivery

Brown Adipose Tissue as a Therapeutic Model for Obesity Treatment Obesity is a major concern for governments worldwide. In the UK alone, it is estimated that the direct costs of obesity to the National Health Service totals £6 billion ($8.5 billion), with prevalence standing at an astonishing 27% in 2015. In the USA, the rate for adults is higher still, totalling 36.5%. For these reasons, obesity has been labelled ‘‘a national emergency’’ by Jeremy Hunt, the UK’s health secretary and an ‘‘epidemic crisis’’ by the US Surgeon General David Satcher (in 2001). This crisis is not isolated to North America and Western Europe, with rates rising rapidly in China and India to match high rates across Middle Eastern countries.

Obesity is traditionally characterised as an energetic imbalance where caloric intake outweighs energy expenditure (resulting in a BMI above 30). This is mainly due to the rise in sugar and dietary fat consumption in combination with an increasingly sedentary lifestyle. Obesity is a risk factor for a host of chronic conditions such as cardiovascular disease, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) as well as osteoarthritis and some forms of cancer. In addition to its metabolic nature, recent research has begun to

44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

suggest that obesity is in fact a form of chronic low-grade inflammation. As visceral fat depots become excessively large, the surrounding areas tend to become characterised by secretion of pro-inflammatory cytokines (such as TNF-α) as well as proliferation and infiltration of inflammatory immune cell types such as M1 macrophages, Th1 and cytotoxic lymphocytes over anti-inflammatory types such as Treg tolerance lymphocytes, M2 macrophages and eosinophils. The primary means of targeting obesity by governments has been to use fiscal policy tools and regulation to affect spending and consumption decisions. Examples include increased food labelling, sugar taxes and investment in obesity education, particularly amongst low-income families, who tend to be most at risk. However, these methods are limited in their efficacy, partially due to the proliferation of cheap foods with high sugar and fat content. Pharmaceutical methods to target obesity have tended to use sympathomimetic β-adrenergic agonists to promote lipolysis, fatty acid oxidation and insulin activity. However, these have been severely limited due to non-specific, off-target effects (particularly on cardiovascular pathways) as well as loss of efficacy

with chronic use. The other method of targeting obesity has centred around bariatric surgery, by either decreasing the stomach size or rerouting the small intestine. Whilst this has shown some promise in terms of efficacy, limitations do remain, including healthcare system resource constraints, difficulty in performing invasive surgery on obese patients, and resulting nutritional deficiencies. For these reasons, the use of brown adipose tissue (BAT) as a therapeutic tool for obesity has become increasingly attractive in recent years. Whilst white adipose tissue (WAT) is characterised by its ability to store lipids, BAT is able to oxidise lipids and burn fat via a uniquely expressed mitochondrial membrane protein known as UCP1. This protein acts by bypassing the ATP synthase mechanism of proton transport across the mitochondrial membrane (which produces chemical energy in the form of ATP) to allow protons to ‘‘leak’’ across the membrane through UCP1, generating heat energy in the process. The activation of UCP1 in mammals primarily occurs upon cold activation. Briefly, cold stimulation of the sympathetic nervous system causes the release of adrenergic agonist

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Drug Discovery, Development & Delivery noradrenaline, which activates β-3 adrenergic receptors on the BAT surface. Through a signalling cascade including peroxisome proliferatoractivated receptor gamma (PPAR-γ), cAMP and PGC-1α, UCP1 is eventually activated and heat generated to counteract cold sensation. This is an important means of heat generation in small mammals undergoing hibernation, as well as infant humans unable to generate heat through shivering response. However, masses of BAT decrease dramatically in adult humans, eventually becoming restricted to small deposits mainly in the neck region. Indeed, the existence of BAT in humans was only confirmed in 2009 using FDG-PET scans. In addition to what is known as classical or canonical BAT (which has a distinctive developmental lineage from WAT), there exists a third type of adipose tissue, which has a variety of names including beige or BRITE cells, which are brown-like adipocytes (characterised by high mitochondrial content and thermogenic potential) within WAT depots that follow a similar developmental lineage to WAT. Whilst BAT is rare in adults, higher ratios in BAT volume compared to WAT have been associated with lower rates of obesity and type 2 diabetes due to its increased insulin sensitivity and energy expenditure capability. This has made BAT a highly attractive therapeutic target for obesity. There are overall four approaches to using BAT to target metabolic disorders such as obesity. One is cold activation, which is limited by practical means as it requires extended periods of cold exposure with limited clothing coverage. Another is the pharmaceutical approach. This aims to activate classical BAT or beige reserves by targeting β-3 adrenergic receptors similarly to the sympathomimetics previously mentioned. A third option is to differentiate stem cells or WAT into BAT or beige adipocytes ex vivo and transplant the tissue as a cell therapy. A fourth option is to consume foods able to either recruit and activate BAT or trans-differentiate WAT into beige, brown-like adipocytes. Future pharmaceutical approaches may also aim to use BAT to target obesity and type 2 diabetes in such a way. www.ipimediaworld.com

Finding new compounds able t o a c t i vat e BAT w i t h o u t t h e disadvantages associated with sympathomimetics has been hampered by the limited availability of human BAT in vitro for screening purposes. However, Plasticell was able to use its proprietary bead-based combinatorial screening platform Combicult to develop protocols able to differentiate stem cells into human BAT in vitro. This allowed Plasticell to form a partnership with Pierre Fabre laboratories in France to develop a screening platform able to identify novel compounds derived from plant extracts able to recruit and activate human BAT.

Dr Shahzad Ali Dr Shahzad Ali leads the metabolics programme at Plasticell, developing new therapies based on plant-derived natural extracts that are able to increase recruitment and activation of brown adipose tissue in order to combat type 2 diabetes and obesity. He received his MEng and PhD from the Department of Biochemical Engineering at University College London. Email: contact@plasticell.co.uk

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Drug Discovery, Development & Delivery HBP Biomarkers and Assay Development within Laboratory Practice

“Sepsis is the most preventable cause of death”1, and every hour it is not diagnosed will increase the probability it will kill the patient by 7%, so recognising the early signs and symptoms is therefore crucial. Severe sepsis is the leading cause of death in the non-coronary ICU with mortality rates between 30% and 50%.

According to Dr Adam Linder2, "Approximately one in five patients with sepsis who are admitted to hospital are at risk of developing severe sepsis within the first 24 hours”. Sepsis is also the biggest killer of children under five worldwide. Konrad Reinhart1 notes that every year 6 million babies from third world countries and 100,000 of their mothers will die from sepsis. As sepsis often affects the elderly (usually when they have some other condition) it is perhaps less talked about, but it also affects children. With such susceptible groups as these, anything which raises awareness amongst medical staff of the signs, symptoms and dangers of sepsis can only be a good thing. In sepsis, the immune system overreacts to an infection, causing a cascade of events to occur within the body such as leakage from blood vessels causing a drop in blood pressure. Over time, this leads to kidney, heart and brain damage. It is no wonder that sepsis is the most common cause of death for intensive care patients, who are already vulnerable. Sepsis is a potential killer and its dangers need far more promotion. Due to patients presenting with similar clinical signs and symptoms, many patients in hospital are put on antibiotics and a large proportion of those are on antibiotics unnecessarily. This results in certain patients being misdiagnosed. Either they're diagnosed with having a 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

non-infectious condition when they actually have an infectious condition, or vice versa. Existing laboratory tests can also be non-specific, which can lead to patients getting the wrong treatment or not getting treatment at the right time 2 . The actual progression of sepsis is rapid, so decision-making is crucial in treating it when it is suspected. Currently, hospitals monitor the patient’s vital signs, but this in itself is not enough for a definitive diagnosis. Rashid Bashir, at the Carle Illinois College of Medicine, has undertaken work focussing on an alternative means of quickly identifying patients in the early to peak phases of sepsis by measuring biomarkers in the blood that point to elevated immune system responses. The Illinois group found that combining biomarker data with electronic medical record data yielded the greatest predictive power. However, they also found that biomarkers alone carried more predictive power than data from electronic medical records alone. In fact, one biomarker measurement from a single sample of blood yielded the same results as monitoring vital signs for an additional 16 hours – time that is crucial for treatment in sepsis 3,4. Sepsis is a medical emergency, and the sooner it is treated, the lower the mortality. If medical staff don’t act immediately, there is a high risk that the patient will not receive adequate treatment. Sepsis is the tenth most common cause of death in the world, and the most common cause of death among already weak patients in hospital intensive care units. A lack of a clear definition of what sepsis is, and a lack of a ‘gold standard’ diagnosis for sepsis are possible factors contributing to its low-profile status. Sepsis is the name of an infection that causes a series of reactions in the body, and the problem for both patients and doctors is that the early symptoms are difficult to distinguish from less

harmful infections such as a severe flu or gastritis. “Many biomarkers have been evaluated for use in sepsis. Most of the biomarkers had been tested clinically, primarily as prognostic markers in sepsis; relatively few have been used for diagnosis. None has sufficient specificity or sensitivity to be routinely employed in clinical practice. PCT and CRP have been most widely used, but even these have limited ability to distinguish sepsis from other inflammatory conditions or to predict outcome”14. I have chosen one specific biomarker to focus on, as it has shown very promising results from current and ongoing clinical trials in Europe. The biomarker is heparin binding protein, or HBP, and its assay development process. Heparin binding protein is a new marker which has been shown to be useful in identifying patients (on admission to the emergency department) who are at risk of developing severe sepsis with circulatory failure. According to Dr Linder1, he has found HBP a better biomarker for identifying sepsis. HPB is released by a certain type of white blood cell in amounts which correspond to the immune system's reaction: the greater the overreaction (and thus the risk of sepsis), the greater the amount of HBP in the blood of a patient. However, for HBP measurements to be used successfully in hospitals, it must be possible to perform the analysis quickly. Normally, laboratory analysis of HBP would take about six hours. As patients do not have six hours, laboratory scientists will now have to reduce analysis time to one hour to facilitate earlier treatment which, in some cases, may save patients’ lives. Heparin binding protein has been shown to be useful in identifying patients at risk of developing sepsis with circulatory failure. An increase in plasma heparin binding protein levels has been shown to precede the clinical Summer 2018 Volume 10 Issue 2


Drug Discovery, Development & Delivery development of circulatory failure by several hours in many patients. What is HBP? Heparin binding protein (HBP), also known as cationic antimicrobial protein of 37kDa (CAP37) and azurocidin, is a 37kDa glycoprotein synthesised in neutrophils6. Structurally, HBP belongs to the serine protease superfamily and although it has 45% sequence identity with human neutrophil elastase, it is inactive as a protease. HBP has several roles in the pathophysiology of bacterial infection, including antimicrobial activity and pro-inflammatory effects on white blood cells, as well as a key involvement in dysregulation of vascular function: Anti-bacterial effects HBP acts as an opsonin during infection by Gram-positive and Gram-negative bacteria and C. albicans by binding to the pathogens to enhance phagocytosis7. It has also been shown to bind to LPS and it is therefore possible that HBP may neutralise LPS during infection8. Inflammatory response At the site of infection, HBP is secreted from azurophil granules during phagocytosis, where it is responsible for the recruitment and activation of monocytes and other inflammatory mediators. It is also internalised by monocytes to prolong survival and enhance cytokine production9. Vascular leakage HBP is released from the secretory vesicles of activated neutrophils on contact with the endothelium. Once released, it induces a calciumdependent rearrangement of the endothelial cell cytoskeleton 10, resulting in cell contraction, which in turn increases permeability of the endothelium, a vital stage in the bacterial response to allow circulating white blood cells to reach the site of infection11. HBP thus directly contributes to the maintenance and progression of inflammation12 and has therefore been proposed as a potential diagnostic and prognostic marker for the assessment of sepsis risk in infected patients. www.ipimediaworld.com

Measurement of HBP in human plasma is done by automated immunoassays. The ELISA assay is an easy manual method for the determination of HBP in human plasma. Assay Development Process: Laboratories have different methods for their assay development so have described a general method for assay development. The steps and equipment may vary depending on the laboratory and their guidelines. The principles I mention below reflect current industry standard approaches. The assay development process comprises a phased strategy, with each phase having clearly defined goals and success criteria. Progression from one phase to the next is contingent on demonstrating that the predefined success criteria have been satisfied. All projects begin with a scope document and an ‘assay design specifications’ document, the latter of which sets out the required attributes and performance characteristics for the candidate assay to be considered to meet end-user/clinician needs. These performance characteristics include attributes like imprecision, detection limit, and dilution linearity. Additionally, the assay design specifications document will set out requirements such as maximum time-to-first result, maximum sample volume, predicate device, and how the assay should be standardised. Pre-development The first R&D process activities are termed ‘pre-development.’ Within this, the laboratory will investigate the basic feasibility of a candidate immunoassay. The laboratory then explores the fundamental elements of the immunoassay (solid phase components, antibodies and antibody pairs) in an effort to prove simple performance characteristics, e.g. dose response, discrimination between signal and noise, etc. Generally, the laboratory will begin with a simple microtitre plate assay and then, when functionality is demonstrated in that format, transport the assay on to the platform of choice. The predominant platform used by many laboratories is chemiluminescent microparticle

immunoassay, compatible with the kinds of analysers and instruments encountered in laboratories. Upon successful demonstration of the proof-of-concept for an immunoassay, a design review group (comprising key stakeholders from the senior management group, including R&D, regulatory affairs, operations, and quality assurance) meet to appraise the candidate assay versus the stated success criteria for the ‘pre-development’ phase. The design review group also assess against the assay design specifications document. At this point, it is not expected that the proof-of-concept assay will necessarily meet any of the design requirements, but it does give an impression of where potential development challenges may be encountered in downstream activities. Phase I Following ‘pre-development’, the proof-of-concept assay progresses in to Phase I of a pre-design control development process. The first phase is termed ‘assay prototype’, where the aim is to refine the proof-of-concept assay in respect of antibody tracer/ labels, solid phase coating techniques, antigens for calibrator materials, buffer and matrix formulations, instrument test protocol, and then begin some sample testing (often against a predicate device). This is also the time when an examination of the stability of the assay components starts. Phase I ends with a review of the work performed and assessment of the assay against success criteria. Phase II Phase II of the development process encompasses optimisation of the assay prototype and calibration/ standardisation. During the optimisation processes, the laboratory deploys a variety of statistical tools in a strategy of ‘robust design’. The aim is to challenge the critical elements of the assay to understand its performance. For example, at extremes of solid phase antibody coating concentration or buffer pH, a laboratory may decide to begin a failure mode effect analysis (FMEA) process to identify key process INTERNATIONAL PHARMACEUTICAL INDUSTRY 47


Drug Discovery, Development & Delivery variables and key raw materials. These exercises inform where the laboratory must focus their design efforts. Using a risk analysis style approach allows the laboratory to pay attention to the elements of the assay that have the greatest potential to be challenging in respect of performance. In terms of assay standardisation, a ‘calibration strategy’ is devised which sets out how to standardise the assay against an international reference preparation. The laboratory will control and monitor the standardisation over time, including the materials the laboratory use as part of that standardisation. The calibration strategy also demonstrates that assay standards are homogeneous, commutable with patient samples, and stable. Again, this phase is followed by a review of the assay performance versus success criteria. Pre-verification Once the first two phases of development are complete, the assay formulation is ‘near final’. That is, the laboratory does not expect to make any further drastic changes. The laboratory prepares pilot lots at larger scales and process the material into final packaging. The last phase of our development process is termed ‘pre-verification’. This is where the assay is put through testing intended to identically simulate design verification studies. The intention here is to iron out any final performance quirks to establish that the assay is ready to enter design control (thereafter, the assay is considered finalised and cannot be altered without formally processing changes through a quality system). Pre-verification is completed via a final review of the assay versus success criteria. At this point, it is expected that the assay will achieve all the design requirements set out in the assay design specifications document. Thereafter a series of stage-gate design reviews is conducted, which manage the assay through process validation, design verification, and design validation until the product reaches market. In conclusion; recognising early signs and symptoms of sepsis can save lives. The speed of diagnosis is 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

crucial as the progression of sepsis is swift and therefore a diagnostic test that proves the patient has sepsis is required to give results within one hour. Because HBP directly contributes to the maintenance and progression of inflammation, it is a potential diagnostic marker for the assessment of patients at risk of sepsis and should be studied further in large-scale clinical studies. REFERENCES 1. Reinhardt K, Fooling a silent killer, European Biotechnology 15: pp15-21, 2016 2. Linder A, HBP Biomarkers & Assay Development within Laboratory Practice. ISICEM Symposium February 2016 3. Taneja I et al., Combining biomarkers with EMR data to identify patients in different phases of sepsis, Sci Rep 7(1): 2017 4. Heinzelmann M et al., J Immunol: pp5530-36, 1998 5. Pierrakos C and Vincent JL, Sepsis biomarkers: A review, Crit Care, 14(1): R15, 2010 6. Bashir R, Biomarkers as predictive of sepsis as lengthy patient monitoring, Science Daily: September 2017 7. Tapper H et al., Heparin Binding Protein, Blood, 99: pp1785-93, 2002 8. Soehnlein OJ, Mol Med, 87(12): pp115784, 2009 9. Pereira H et al., Platelet-neutrophil interactions under thromboinflammatory conditions, J Clin Invest, 85: pp1468-76, 1990 10. Heinzelmann M et al., Heparin Binding Protein (CAP 37) is an Opsonin for Staphylococcus Aureus and increases Phagocytosis in Monocytes, J Immunol: 160, pp5530-6, 1998 11. Gautam N et al., Plugging the Leaks, Nature Medicine, 7(10): pp1123-27, 2001 12. Muller WA, Heparin Binding Protein, Vet Pathol, 50(1): 7-22: 2013 13. Linder A et al., Binding Potency of Heparin Immobilized on Activated

Charcoal for DNA Antibodies, Immun; 2(5): pp431-8, 2010 14. Linder A et al., An exciting candidate therapy for sepsis: Ulinastatin, a urinary protease inhibitor, Crit Care Med: 43(11), 2010

Christene Leiper Professor Christene Leiper attended Sydney University, RMIT Melbourne and Bond University in Australia and achieved Professor of Medicine and Life Sciences at Bond University Queensland in 2006. Christene also undertook research at Edinburgh University, Scotland as part of her PhD. Christene’s specialisation has been in nuclear medicine / medical imaging, as well as experience in a wide range of therapeutic areas. Christene’s extensive international experience encompasses many disciplines, including working for an international company as a medial liaison for stem cell research in London. Christene has also been a principal investigator for clinical trials, which enables her to operate across many disciplinary boundaries within clinical research in a coherent and productive manner. In 2007, Christene was appointed Director of Research at a Scottish CRO which, in turn, led her to start her own CRO, Onorach Ltd, in 2009. Since then Onorach has established a subsidiary in Riga, Latvia, known as Onorach Baltics, and a software company, Onorach Innovation. In early 2018 Onorach have added two new companies to their portfolio. Email: christene.leiper@onorach.com

Summer 2018 Volume 10 Issue 2


Introducing TLX PCM with Fibre-Flex Technology...

TLX PCM is the first cargo cover to incorporate Phase Change Material (PCM) into its structure. The smart technology allows the cover to self-regulate its performance according to the external conditions by freezing at 18oC and absorbing heat up until 25oC. Being able to encapsulate PCM within the physical structure of the cover gives a simple to use all in one product. This unique system delivers an easy to handle solution that’s ultra-lightweight, robust yet thin and flexible.

WHY USE PCM IN A CARGO COVER? Phase Change Materials are ideal for thermal energy storage as they are highly cost effective, stable and environmentally friendly. PCMs are ideal for cold chain transportation/storage of temperature controlled packaging containing food and pharmaceuticals. TLX PCM cargo covers give consistency in performance over a substantial number of cycles, helping to maintain a constant temperature through the release and absorption of energy. • Unique, non-leak PCM system

TLX PCM vs the same cover without PCM

• Strong, flexible, easy to handle • Waterproof • Ideal for pharmaceutical, chemical, perishable and healthcare shipments

40°C 35°C 30°C

8 mins

1hr 20mins

7hrs

25°C 20°C 15°C 10°C

TEMP °C

HOUR

1.00h

Without PCM Probe between box and cover

2.00h

3.00h

With PCM Probe between box and cover

4.00h

5.00h

6.00h

7.00h

8.00h

With PCM Probe inside box

*TEST CONDITIONS: Ambient temperature 40°C, 38°C simulated tarmac temperature and 20% mass of product.

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Drug Discovery, Development & Delivery iPSC Models to Improve Efficiency of Drug Discovery and Development Stem cells attract a great deal of attention due to their developmental potential and lineage-independent characteristics. Adult stem cells, otherwise known as inducible pluripotent stem cells (iPSCs), are particularly favourable as research tools because they are derived from somatic cells such as blood, skin, or muscle. iPSCs and their derivative cell types provide important resources for all drug discovery and preclinical development scientists. Appropriate applications of iPSCs and their disease models will improve the efficiency of drug discovery and development in the coming years.

Disease Models Using Human Donor-reprogrammed iPSCs and iPS-derivatives What are iPSCs? Adult stem cells, otherwise known as inducible pluripotent stem cells, are multipotent stem cells reprogrammed from donor's somatic cell types such as fibroblasts, PBMCs, adipocytes, bone marrow-derived stem cells, or myoblasts. iPSCs can be further differentiated into endoderms, ectoderms, and mesoderm lineages. These three lineages define the fates of many cell types such as neurons, glial cells, osteoblasts, pancreatic beta cells, hepatocytes, and cardiomyocytes. Traditionally, iPSC derivation is reprogrammed via episomal-, genetic vector-, or viral-based methods. Recent developments in the field have pointed to new methodologies that are integration-free, non-viral, feederfree, and non-genetic. The major benefit of these new technologies for reprogramming is the ability to generate large-scale iPSCs with high purity without causing chromosomal abnormalities such as rearrangements or insertions during reprogramming. Furthermore, another major benefit is that these reprogrammed iPSCs and iPS-derivative cell types may be adopted into a highly efficient 50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

GMP process for cell therapy manufacturing. What are the Advantages of Donor-derived iPSCs over Primary Cells and Cell Lines? Many applications in the biotech and pharmaceutical industry have traditionally relied on human primary cell types and immortalised cell lines. A major advantage of iPSCs is that they can be derived from a variety of donors – healthy donors, patients, and extended family members of patients. These donor-derived iPSCs serve as an indispensable resource for modelling disease phenotypes in-a-dish. Major advantages over primary cells are 1) diversity of donors, 2) availability of cell types, 3) scale of cells supplied, and 4) manufacturing consistencies. The diversity and limitations of donated primary tissues have often been presented as a time-consuming and rate-limiting factor, when scientists try to procure primary samples. Furthermore, donors’ primary cells usually come from only one or two donors at a time during the procurement process and, depending on the number of independent biorepositories needed for a procurement project, variabilities can be found between sample collections.

Given these challenges to acquire primary tissues and cells, immortalised cell lines are typically used as a primary source for preclinical screenings and non-animal-model studies in the industry. Although the immortalised cell lines present as a cost-effective cell source for the over-expression of targeted genes-of-interest in a study, they are often derived from immortalised tumorigenic cells of human or rodent origin. Furthermore, gene expression networks and profiles found in tumours do not reflect the same gene expressions found in terminally differentiated human cell types such as neurons, osteoblasts, kidney, liver, or oesophageal, to name a few. Another important hallmark of the immortalised cell lines is observed in their genetic or chromosomal instabilities which are representative of tumorigenic cells but not non-cancerous cells. Thus, the cell lines can become genetically unstable over time, and high passage number is an important contributing factor to aberrant gene expressions observed. Examples of how iPSC Models are Used to Expedite the Preclinical Drug Development Process: iPS-derived cell types (Figures 1 and 2) – Figure 1 shows that, derived from

Figure 1: Diagram of human iPSCs reprogrammed using donor’s skin sample. iPSCs can further differentiate into three lineages: endoderm, mesoderm, ectoderm. Summer 2018 Volume 10 Issue 2


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 51 Š Copyright 2017 PCI Pharma Services. All Rights Reserved


Drug Discovery, Development & Delivery somatic cells, iPSCs can be further reprogrammed into a variety of lineage-specific cell types such as neurons, melanocytes, hepatocytes, and microglia. Furthermore, iPSCs and iPS-derivatives can be cultured as spheroids and organoids. In the lab, cells are typically grown as a 2D monolayer, but many cell types can be adopted into 3D spheroid models to better represent their native tissue environments. Depending on the disease model, 3D spheroids can be further differentiated and engineered into organoids. Embrace, Rather than Fear, Human Genetics Unlike primary cells and immortalised cell lines, iPSCs from patients manifest their disease phenotypes (e.g., from mild to severe) and are genetically defined (i.e., “wildtype versus mutant allele” or single nucleotide polymorphism). An example is shown in Figure 3 from patients’ derived cell types.

clinical phenotype and drug candidate responses correlate in-a-dish. iPSC lines from patients' donated somatic cells (blood or skin) recapture aspects of their phenotype. Figure 3 shows that the iPS-derived cell types can reflect patients’ disease severity in-a-dish, from a healthy individual to Patient-1 to Patient-2. This variability may seem daunting to the researcher who is used to immortalised cell lines, where one consistent line is the expected norm. However, the variabilities can serve to represent drug candidate responses in a population of individual patients. The key is to gather the appropriate cohorts and to engineer their iPSC models, thereby generating a “patients in-a-dish” model in order to experimentally determine the effects of drug candidates (Figures 3 and 4). Positive Effects of Using Human Genetics Another advantage of using donorand patient-derived iPSCs is an

yielded novel drug targets. Figure 5 (left) shows a typical family kindred diagram where autosomal Mendelian inheritance is observed, and Figure 5 (right) illustrates that sporadic mutations are commonly found in small nuclear families.

Figure 4: Representative column graph demonstrating cellular phenotype differences between healthy donor, patient with mild phenotype, and patient with severe phenotype.

Figure 2: Images of human iPSCs differentiating into iPS-derived hepatocytes and iPS-derived neurons.

Figure 5: Left panel: An example of autosomal Mendelian inheritance. Filled circle/square = affected individual. Half-filled square/circle = probably affected individual. Circle-filled square/circles = unknown. Open square/circle = unaffected individual. Top right: An example of a nuclear family with a potentially affected individual with an unknown diagnosis. Circle-filled square/circles = unknown. Open square/circle = unaffected individual. Figure 3: Images of patients’ samples derived iPSCs and iPS-derived cell types. Representatives shown from healthy donor, patient with mild phenotype, and patient with severe phenotype.

iPSC Models Capture Donor's Genetic Background iPSCs generated from donors, patients, and family members preserve their genetic background information. Therefore, their cellular phenotypes are reflective and useful for drug mechanisms and target gene mechanism discoveries. Variations of the disease manifestations aid in drug candidate validation when patient’s 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

ability to identify novel drug targets that are clinically relevant. Mutations discovered from patients using genomic sequencing and mapping methods have yielded many potential drug targets. Examples from familial Alzheimer's, Parkinson's, and rare cancer patients have all reported genetic targets. Examples from rare or orphan disorders that have Mendelian inheritance traits have also

Bottom right: An example of a nuclear family with an affected individual. Open square/circle = unaffected individual. Filled circle/square = affected individual.

Challenges of Using Human Population Genetics Data In hereditary disorders, the challenge of "non-penetrance" – the donor inherited the mutation but does not manifest the disease phenotype – could create confusion and data mis-interpretations during collection and analysis. Another Summer 2018 Volume 10 Issue 2


Drug Discovery, Development & Delivery challenge is the question of "genetic bottleneck effects" that exist predominantly amongst homogenous populations and their prevalent disease phenotypes. Strong genetic associations within a homogeneous population would bias targets towards ancestral and founder's effect. A recently published study showed data from a Finnish population in a study of migraine genetics: DNA from patients suffering from migraine were sequenced and common genetic variants were identified. However, due to the population chosen for the study, the genetic variants identified were subjected to founder’s effect. Hence, collections comprised of representatives from a diverse population ARE preferred. Challenges of Using iPS Models Depending on the disease (familial or sporadic), more than one line per disease phenotype will be required. If all donors express mutations in the same gene(s), donor lines should be selected from the most severely affected patients according to their medical diagnosis and categorisations. If all donors possess mutations in independent genes, donor-derived iPSC lines should include as many patients as possible to be able to group their patient responses according to medical criteria such as tests already performed or responsiveness to already-existing medications.

Multiple Usages of iPSC Models in Discovery and Development Aside from engineering iPSC and iPS derivative models for evaluating drug candidates (small molecules, biologics, or gene therapy), iPSC models serve other useful functions. Biomarker Discovery A biomarker is a unique identifier of a patient population's disease characteristics. It can be defined as a chromosomal marker, a gene expression pattern, a genetic variant, a genomic structural feature (such as rearrangements or translocations), a cellular phenotype, an aberrant tissue pathology, or a bodily excretion product. iPSC and iPS-derivative models can assist with all of these biomarker identifications and validations. For example: Figure 4 shows a calcium wave deficiency identified using patients’ iPS-derived cells. Calcium wave is a hallmark of glial cell function and disruption of the calcium wave properties is documented in numerous neuroinflammatory diseases. Streamlined Procurement Traditionally, biobanks have been sought after for their collected donor samples such as bodily fluids (e.g., urine, blood, plasma), skin, or tumour biopsies. However, the challenge is to gather appropriate cohorts and their relevant tissue samples and cell

types for drug target validation. This is a critical step in the preclinical drug development process. Obtaining relevant cell types from the appropriate donors or patients validates whether traditional in vitro models applied during the discovery process truly reflect the disease state. Another challenge is to maintain proper consistency during procurement and processing, in order to minimise sample-to-sample variability observed during subsequent data collection and analysis. Using iPSC and iPS-derivative models simplifies procurement challenges in terms of streamlining standard operating procedures (SOPs). Reprogramming donors’ samples into iPSCs serves as a normalising step and can better guarantee consistency of cryopreserved iPSCs and iPS-derived cell types. In Closing At Tempo Bioscience we strongly believe in the advantages of using iPSC-based models for target validation, preclinical drug discovery and development, and biomarker discovery. Genetically relevant and multi-donor iPSC models validate screening, discovery, and preclinical development data. As a whole, the models serve as “pre-clinical trials” to evaluate promising drug candidates. When utilised appropriately, this new process can streamline pharmaceutical development.

Angela L. Huang Angela founded Tempo Bioscience, Inc in 2013. She developed, patented, and commercialized Tempo’s core technologies. Together with Tempo's team, the enabling technologies became available to scientists worldwide. Angela is listed as an inventor on numerous patents – issued and pending – worldwide and has published in journals such as Nature. She received her scientific training from University of California, Berkeley (undergraduate), University of California, San Diego (doctorate), and University of California, San Francisco (postdoctoral fellowship). Email: angela@tempobioscience.com

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Drug Discovery, Development & Delivery Novel Drug-based Strategies for Cardiac Regeneration Following Myocardial Infarction The human heart is one of nature’s engineering marvels, considering the requirement specifications for this fist-sized hollow organ that only weighs 250-300 grams. Delivering about five litres of blood at an average of 75 contractions per minute, it is required to perform without interruption. This translates into 2.5 billion contractions in a 70-year old person, resulting in approximately 2 to 3 billion joules of work in a lifetime, which is a huge amount (Muslumova, 2003). Considering the high performance demands, failings can occur beyond normal wear and tear in the heart’s electrical system, the valves, and the muscle itself. Of all complications leading to heart disease, ischemia – the insufficient supply of oxygen caused by restricted blood supply to the cardiac muscle – is the most prevalent.

Heart ischemia is the most common cause of death in most western countries. It results from atherosclerosis and manifests itself when there is a severe narrowing or closure of either the large coronary arteries and/or of coronary artery end branches. The narrowing or closure is predominantly caused by the covering of atheromatous plaques within the wall of the artery rupturing, in turn leading to an acute myocardial infarction (AMI). Patients presenting with severe chest pain are initially diagnosed for an AMI with an electrocardiogram and confirmed subsequently with a blood test to detect the presence of troponin, a contractile protein that is released only when myocardial necrosis occurs (Kumar, 2009). Morbidity and mortality from MI are significantly reduced when symptoms are recognised early and thus shorten the time to definitive treatment. The in-hospital mortality of patients following an acute myocardial infarct (AMI) in the US has fallen dramatically from 20% in the late 1980s to approximately 5–7% through the use of percutaneous coronary interventions (PCI) with 54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

stent placements (McManus, 2011). However, this initial gain in survival has led to an increase in longer-term complications such as chronic heart failure. These complications are a significant driver of late morbidity, reduced quality of life, mortality, and healthcare costs. The chronic complications that often follow a successful PCI procedure are related closely to the biologic events that take place in the heart muscle at the location of the infarct. The AMI that results in significant cardiomyocyte necrosis sets in motion a pathophysiology that has been characterized extensively in animal models. Within 30 min of ischemia, cardiomyocyte structural changes and edema develop, leading to progressive cell death from three hours. Acute contractile dysfunction occurs due to oxidative stress and calcium overload, which is reversible if flow is restored. Reperfusion itself causes a second wave of injury, by production of reactive oxygen species. Despite successful epicardial reperfusion, embolisation of thrombotic debris, plugging by inflammatory cells and release of vasoactive mediators from damaged endothelium leads to ongoing microvascular dysfunction in up to 50% of patients. Myocardial injury leads to activation of a stereotyped inflammatory cascade. Between days 3-5 following MI, there is a transition from inflammation to repair, with activation of fibroblasts and progressive scar deposition. However, the lost cardiomyocytes are not replaced. Over time there is compensatory activation of the renin-angiotensin and sympathetic nervous systems and pathological remodelling, with changes to the ventricular geometry, wall thinning, ischemic mitral regurgitation, and further cardiomyocyte loss (Frangogiannis, 2015). Current drug-based therapies including primarily diuretics, ACE inhibitors, and beta blockers do not have an effect on the process

of cardiomyocyte death and scar formation occurring alongside ventricular remodelling described a b o v e . C a rd i a c re g e n e rat i v e medicine is emerging as an attractive alternative with the potential to treat cardiovascular failure and its consequences, including the repair of tissue necrosis caused by myocardial ischemia. Since 2002, over 100 clinical studies have been performed using stem cell therapies for cardiac regeneration in AMI, ischemic and non-ischemic advanced HF, and refractory angina. According to a recent study by the transnational alliance for regenerative therapies in cardiovascular syndromes (TACTICS), as of 2016, 2732 patients in these studies or about half of all cardiac indication patients were treated for MI (Fernandez-Aviles, 2016). The stem cell therapy protocols typically consisted of harvesting non-cardiac stem cells from bone marrow, circulating blood, adipose tissue, and other sources. The cells were then processed minimally for concentration or purification and delivered to the damaged myocardium via endocardial injections. The clinical outcomes of the initial stem cell therapy approaches has been generally disappointing. A major barrier to the success of transplanted stem cells is poor retention and survival of the cells in the heart, which can be >10% as early as one hour after injection in most human and large animal studies (Levit, 2013). Various factors contribute to this phenomenon and include exposure of cells to ischemia and inflammation, mechanical washout of cells from incessantly beating myocardium, flushing by the coronary vasculature, and leakage of cells from the injection site. The overwhelming majority of cell displacement and death occurs within the first few days after delivery. The development of an effective regenerative therapy in the treatment of post-AMI is in part dependent on Summer 2018 Volume 10 Issue 2


Drug Discovery, Development & Delivery new strategies to enable pluripotent stem cells to engraft in infarcted tissue and exert therapeutic benefit through differentiation or through paracrine effects for longer periods. In animal models, Zaruba et al. demonstrated a new regenerative alternative that does not rely on the harvest, processing, and injection of stem cells to the myocardium (Zaruba, 2009). Using an in vivo pathway, engraftment and an improvement in cardiac output were possible by mobilising intrinsic bone marrow stem cells into circulating blood with G-CSF and then initiating stem cell migration and homing to cardiac sites of ischemia with dutogliptin, a small molecule inhibitor of dipeptidylpeptidase-IV (DPP4), the key enzyme responsible for degradation of stromal derived factor-1α (SDF-1α), which is the major chemokine responsible for mobilisation and migration of stem cells to areas of ischemic injury (Figure 1).

and c-kit positive cells) (Deindl, 2006). Despite demonstration of decreased apoptosis and improved arteriogenesis in the zone of infarct, G-CSF alone has been shown overall to be clinically ineffective (Engelmann, 2006; Brunner, 2008a; Brunner, 2008b; Abdel-Latif, 2008), possibly due to the lack of proper homing and migration of the mobilised cells to the area of injury. SDF-1a is an important chemokine for initiating stem cell migration and homing to cardiac sites of ischemia with consequent neovascularisation, activation of residual cardio-blasts, and anti-apoptotic pleiotropic effects (Penn, 2011). Therefore, the local preservation of SDF-1a represents a promising approach to treat acute MI. However, safety concerns and the need of invasive transplantation protocols limit strategies to augment SDF-1a gene expression or protein delivery to the ischemic myocardium (Kuliszewski, 2011). An alternative approach to increase SDF-1a concentration in the injured heart is inhibition of CD26/DPP4, which is responsible for cleavage and inactivation of SDF-1a. Early preclinical data demonstrated that DPP4 inhibition improves survival and myocardial function after infarction by increasing regenerative capacity, particularly when potentiated by concomitant administration of G-CSF (Zaruba, 2009). Clinically available gliptins (e.g., sitagliptin,

vildagliptin) and G-CSF have been shown to effectively mobilise CD34+/ CD45+ chemokine receptor (CXCR4)+ and CD34+CD45+c-kit+ stem cells into peripheral blood. Myocardial homing was also demonstrated to be significantly increased for gliptins of CD34+/CD45+/CXCR4+, CD34+/ CD45+/c-kit+, CD34+/CD45+/Sca1+, and lin-Scal+/c-kit+ cell populations (Theiss, 2013). When dutogliptin, a novel DPP4 inhibitor developed by RECARDIO, was combined with stem cell mobilisation with G-CSF, the combination treatment significantly improved survival and reduced infarct size in a murine model (Nix, 2016) (Figure 2). Considering the extensive clinical experience with G-CSF to mobilise stem cells and the well-defined safety profile of dutogliptin gained from its previous clinical evaluation as a drug candidate for Type 2 diabetes, progression to a clinical setting is proceeding rapidly. In 2017, for dosing of dutogliptin, a two-part Phase I study evaluating the safety, tolerability and pharmacokinetics (PK)/pharmacodynamics (PD) of parenterally administered dutogliptin was carried out in healthy volunteers. Dutogliptin was well tolerated at the maximum dose tested of 120mg. Sustained inhibition of plasma DPP4 was observed to last for 8–12 hours following a single 60 mg dose, therefore twice daily 60 mg dosing was selected as the active dose. In early 2018, a Phase II clinical study was

Figure 1: Stem Cell Mobilisation and Homing to Ischemic Cardiac Tissue

The clinical use of G-CSF to increase the release of bone marrow stem cells into the circulation is well known and generally accepted. G-CSF administration significantly increases blood cluster of differentiation (CD)45 leukocytes, including subtypes of CD34 positive cells: CD45+/CD34+, 13-fold,CD45+/CD34+/CD31+, 9-fold; CD45+/CD34+/Sca-1+, 6-fold; CD45+/CD34+/c-kit+, 31-fold. These CD34+ and CD31+ stem cells induce neovascularisation and G-CSF results in differentiation into endothelial cells and cardiomyocytes (Sca-1 www.ipimediaworld.com

Figure 2: Preclinical Proof of Concept: Survival Benefit of Dutogliptin plus G-CSF INTERNATIONAL PHARMACEUTICAL INDUSTRY 55


Drug Discovery, Development & Delivery approved by the FDA and European authorities and initiation is expected soon. The impending RECARDIO Phase II trial consists of an EU/US multicentre, randomised, double-blind, placebocontrolled study of 140 evaluable subjects. Besides the primary objectives of safety and tolerability of administration of dutogliptin in combination with G-CSF, left ventricular ejection fraction (LVEF), left ventricular end-systolic and end-diastolic volumes and other cardiomechanic outcomes will be determined based on blinded assessment of cardiac MRI by a core lab. The use of MRI is considered crucial to prevent the variability that is often observed in echocardiography. Lastly, secondary efficacy endpoints such as major adverse cardiac events and rehospitalisation will be explored to inform the design of a future pivotal trial. The drug-based cardiac regenerative therapy employing G-CSF and dutogliptin is practical and reproducible. First and foremost, it eliminates the complexities, risk, and expense of harvesting and manipulating stem cells by relying on in-vivo mechanisms and facilitating homing and engraftment of a patient’s own circulating stem cells to the site of cardiac ischemia. Moreover, due to its simplicity, this therapy can be applied in a much wider spectrum of healthcare facilities and opens up additional perspectives to use growth factors, chemokines, inhibitors, and other agents to elicit a regenerative response. Human clinical outcomes are expected in 2019.

4.

5.

6.

REFERENCES 1.

2.

3.

Abdel-Latif A, Bolli R, Zuba-Surma EK, Tleyjeh IM, Hornung CA and Dawn B. G-CSF Therapty for Cardiac Repair After Acute Myocardial Infarction: A Systematic Review and Meta-Analysis of Randomized Controlled Trial. Am Heart J. 2008;156 (2):216-26. Brunner S, Huber BC, Fischer R, Groebner M, Hacker M, David R et al. G-CSF treatment after myocardial infarction: Impact on bone marrowderived vs cardiac progenitor cells. Exp Hematol. 2008;36:695-702. Brunner S, Winogradow J, Huber BC, Zaruba MM, Fischer R, David R et al. Erythropoietin administration after myocardial infarction in mice

56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

7. 8.

9.

attenuates ischemic cardiomyopathy associated with enhanced homing of bone marrow-derived progenitor cells via the CXCR- 4/SDF-1 axis. FASEB J. 2008;23:1-11. Deindl E, Zaruba MM, Brunner S, Huber B, Mehl U, Assmann G et al. G-CSF administration after myocardial infarction in mice attenuates late ischemic cardiomyopathy by enhanced arteriogenesis. FASEB J. 2006;20:E2736. Engelmann MG, Theiss HD, HennigTheiss C, Huber A, Wintersperger BJ, Werle-Ruedinger AE et al. Autologous bone marrow stem cell mobilization induced by granulocyte colony- stimulating factor after subacute ST-segment elevation myocardial infarction undergoing late revascularization: final results from the G-CSF-STEMI (Granulocyte ColonyStimulating Factor ST-Segment Elevation Myocardial Infarction) trial. J Am Coll Cardiol. 2006;48:1712-1721. Fernandez-Aviles F, Sanz-Ruiz R, Climent AM, Badimon L, Bolli R, Charron D et al. Global position paper on cardiovascular regenerative medicine: Scientific statement of the transnational alliance for regenerative therapies in cardiovascular syndromes (TACTICS) international group for the comprehensive cardiovascular application of regenerative medicinal products. European Heart Journal (2017) 38, 2532–2546. Frangogiannis NG. Pathophysiology of Myocardial Infarction. Compr Physiol. 2015 Sep 20; 5(4):1841-75. Kuliszewski MA, Kobulnik J, Linder JR, Steward DJ and Leong-Poi H. Vascular Gene Transfer of SDF-1 Promotes Endothelial Progenitor Cell Engraftment and Enhances Angiogenesis in Ischemic Muscle. Mol Ther. 2011;19(5):895-902. Kumar A and Cannon CP. Acute Coronary Syndromes: Diagnosis and Management, Part I. Mayo Clin Proc.

2009;84(10):917-938. 10. Levit RD, Landazuri N, Phelps EA, Brown ME, García AJ, Davis ME, Joseph G, Long R, Safley SA, Suever JD, Lyle AN, Weber CJ and Taylor WR. Cellular Encapsulation Enhances Cardiac Repair. J Am Heart Assoc. 2013;2:e000367 doi: 10.1161/JAHA.113.000367 11. McManus DD, Gore J, Yarzebski J, Spencer F, Lessard D and Goldberg RJ. Recent Trends in the Incidence, Treatment, and Outcomes of Patients with ST and Non-ST-Segment Acute Myocardial Infarction. Am J Med. 2011 January ; 124(1): 40–47. 12. Muslumova I. The Power of the Human Heart. Hypertextbook: The Physics Factbook. https://hypertextbook. com/facts/2003/IradaMuslumova. shtml 13. Nix D and Schenk R. Impact of the Novel DPP-IV Inhibitor Dutogliptin in Combinatino with G-CSF on Survival Rates and Cardiac Remodelling after Acute Myocardial Infarction. Poster session presented at: Cardiovascular Research Foundation, TCT, Washington DC, 2016. 14. Penn MS, Pastore J, Miller T and Aras R. SDF-1 in myocardial repair. Gene Ther. 2012;19:583- 87. 15. Theiss HD, Gross L, Vallaster M, David R, Brunner S, Brenner C et al. Antidiabetic gliptins in combination with C-CSF enhances myocardial function and survival after acute myocardial infarction. Int. J of Cardio 2013;168:2259-69. 16. Zaruba MM, Theiss HD, Vallaster M, Mehl U, Brunner S, David R et al. Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction. Cell Stem Cell. 2009;4:31.

Dr. Roman Schenk Dr. Roman Schenk is founder, former CEO and since 2016 Executive Chairman of RECARDIO Inc. Dr. Roman Schenk is founder, former CEO and since 2016 Executive Chairman of RECARDIO Inc. Prior to founding RECARDIO he was founder and CEO of various start-up companies in life sciences. He is board member of various health care companies and international organizations. Before starting his entrepreunial career he held various european management positions in research, marketing and business development in the pharmaceutical industry. Email: info@recardio.eu

Summer 2018 Volume 10 Issue 2


Quality. Proven

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Drug Discovery, Development & Delivery

Proposed Therapeutic Strategies for Cancer Using New Methods and Novel Approaches In the history of cancer treatment, initially, the main idea was that the treatment would have one approach and use one method or treatment agent. After this concept, the approach became a bit more multilevel and then treatment was carried out under the concept of surgery, radiation or chemotherapy. Surgery was used for the excision of the primary tumour or the metastases (metastasectomy). Radiation was used for the local control of the disease and chemotherapy for the dissemination of the disease and the systemic control of the disease. Unfortunately, despite the change of treatment concept, the clinical outcome is still poor since the overall survival or response rate hasn't changed dramatically. A possible cause of this failure is ignorance of the physiology of the disease itself and the lack of consideration of the diseaseâ&#x20AC;&#x2122;s heterogeneity. This article will try to propose possible options that may be added to the present concept or become standalone alternatives to the cancer treatment based on cancer physiology and the latest developments in molecular oncology, as well as in molecular and cellular biology.

Cancer Physiology It is well known and established that carcinogenesis is a process that lasts for long periods and when the cancer phenotype is established, the abnormal cancerous cells are characterised by their genetic and epigenetic instability1,2. Hence each generation of new cancer cells is not identical or even similar to the parental ones. Therefore, after several generations of cancer cells, we conclude with multiple subsets of cancer cells with different features and behaviour to one another. This is what is called heterogeneity3. In addition, we have to consider that not all cancer subpopulations are able to leave the primary tumour and migrate to a distant organ. Only a small subset is able to regenerate a tumour in a distant place and these are called tumour initiating cells (TIC) or else cancer stem cell-like4,5. 58 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Also we have to keep in mind that the primary or metastatic tumour consists not only of cancerous cells, but also of normal cells that interact with cancer cells in order to support the formation of the lump and supply oxygen and nutrients to the cancer cells through neoangiogenesis. So when we harvest the primary tumour for diagnostic purposes, we ignore that many (actually almost half of them) are normal cells and they do not contribute to any valuable information about the disease6. In addition to the above, in a very early stage of a cancerâ&#x20AC;&#x2122;s progression, the small population of cancer cells will be able to shift their phenotype from an epithelial to a mesenchymal one in order to invade to the circulation (through neovascularisation). These cells are called circulating tumour cells, and the proportion of the CTCs that have TIC properties will be able to firstly migrate to organs that will allow them to develop their metastatic ability further. These organs are usually the bone marrow, the liver or the spleen. There they may stay in dormancy and they receive the influence of growth factors from the local organs (depositors), like bone morphogenic proteins etc., then they will reseed the organism from these organs (without developing their metastases). To this second step of reseeding they interact with multiple kinds of normal cells (like the bone marrow-derived monocytes) that will help them to create a new metastatic site to a distant organ (microcolony)7,8. The dormant cancer cells are disseminated to the depositor organ and the micrometastatic cells may stay in dormancy for a long time, since they have a communication between them through exosomes that may play an important role in cancer triggering and the initiation of macrometastases. It is well known that the inflammatory process may trigger the cancer progression and the cell may exit dormancy and progress into proliferation in an exponential growth pattern9,10. All the

above physiology actually reveals is that the present approach is very simplistic and actually ignores many of the steps of cancer physiology and mechanisms of migration, progress and metastases. Therefore, the proposed treatment options should be more plural (varied), as the disease is. Novel Treatment Options It is well known from literature and experimental data that tumour initiating cells are responsible for tumour relapse and progression. There are several candidate molecules as products of medicinal chemistry that can inhibit the development of this phenotype on cancer cells and therefore keep them in a dormant state. This kind of approach will minimise the risk of relapse and disease progression, especially to those patients reaching remission after surgery or radiation or both11. Unfortunately the cancer stem cellsâ&#x20AC;&#x2122; phenotype is not something static, which means that cancer cells that do not carry stemness properties may be able to develop them under the pressure of the micro-environment. Hence there are plenty of cells for which we have to consider their depletion. Through this concept, heterogeneity of the cancer cells limits the efficacy of cytotoxic chemotherapy. Even immunotherapy approaches using monoclonal antibodies may be proved less effective or not effective at all12. To that point, we need to have a more pluralistic as well as a more dynamic approach in the treatment field. The immune system is an equally dynamic system of defence that enhances humoral as well as adaptive cellular immunity, in order to eliminate abnormal cells. To that end, it is possible nowadays to activate ex vivo T lymphocytes derived from a patient and develop them into cytotoxic T lymphocytes against cancer cells without the influence of immunocompromising mechanism that engages cancer against the immune system (immune escape). Summer 2018 Volume 10 Issue 2


Drug Discovery, Development & Delivery Then these active CTLs may be able to eradicate the disseminated cancer cells when chemotherapy will never be effective to them in such a low burden13. Furthermore, it is possible today to harvest the monocytes from a patient and develop dendritic cells from them. The DCs are the main antigen presenting cells which actually trigger and activate the humoral and cellular immunity against any foreign organism, cell or virus. It is then possible to prime the DCs multiple specific cancer antigens and they will initiate the immune system through plasma cells and NK cells to make them able to recognise and destroy disseminated cancer cells. In addition, it is possible to generate memory cells from the DCs which may be quicker and more able to more effectively engage the immune reaction if these cells may reappear (immunisation)14. Moving to the area of medication, it is known that chemical molecules are able to target and block only a very small proportion of targets and, on the other hand, the biomolecules are able to target multiple targets

but it is difficult to reach them due to their high molecular weight. To that end, there is a new area of drug development which allows fragments of the biomolecules to sustain their active conformation with the help of organic chemical bridges and in so doing, both increase their efficacy, and on the other hand become smaller and more penetrable to the cells. As it is clearly demonstrated, we may be able to generate any small molecular weight biomolecule for many targets which are now beyond our reach15,16. Many articles have been written and much research has been done also for the epigenetic feature of cancer cells. In layman's terms the cancer cells, by altering the gene expression, may be able to change the phenotype and become adaptive to the new micro-environment. In this instance, when we use only one inhibitor for blocking cancer cells, by changing the relevant mRNA profile these may escape the treatment approach in time. Therefore we can actually interfere with the levels of specific mRNAs and actually prohibit

the expression of genes that may provide cancer cells with the ability to become resistant, proliferative, or aggressive. These molecules are small parts of oligonucleotides that are complementary to the sequence of interest. By that we mean we may be able to inhibit specific proteins by blocking their expression itself. This is the most specific way of knocking down a specific protein from a cell17,18. To that effect, however, we must not forget that we do not have to plan only for the depletion of the disseminated cancer cells but also for the macroscopic disease (primary or metastases). There are several approaches in that direction. For example, many tumours that may not be able to be excised can be efficiently removed by methods like chemoembolisation, locoregional therapy, radiofrequency ablation, microwave ablation, and cyberknife. By all these methods, the approaches become less invasive or even non-invasive, and actually the above methods lack the side-effects of major surgical processes, which

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 59


Drug Discovery, Development & Delivery

may hide a risk of after-surgical complications and side-effects19,20. Starting to analyse all the above approaches and their indications, we have to focus first on the oldest approach, which is widely known as locoregional therapy or stop flow techniques. All these approaches are known as embolisation methods, with or without medication. According to this, an intervention radiologist enters by a central vein or artery by the use of a catheter and reaches the area of the tumour by using the bigger vessels of the circulation. When the catheter is reaching the area of the tumour, then through the catheter the radiologist introduces to the tumour agents that immediately cause a time-limited blockade of the circulation and therefore there is loss of oxygen and nutrients to the tumour. Such agents can be lipiodol or others. In addition, the radiologist can introduce cytotoxic agents in a very low concentration, since the circulation blockade causes local increase of the cytostatic concentration, which is much higher than the system introduction and in this concentration, even resistant types of tumour respond very well to this application. Also, the radiologist can introduce agents that can immobilise the tumour such as nitrogen (nitrogen decreases the local temperature quickly to a level that 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

kills all cancer cells without actually causing a collapse of the cellular architecture). Such a technique can be useful when a tumour infiltrates vessels, and the removal of the tumour dramatically increases the risk of massive bleeding. Another version of this methodology can be the introduction by the catheter of a high temperature or energy by the use of laser beams locally. Usually the approach by the catheter takes place through arteries and, for that reason, the technique is named TACE (trans arterial chemoembolisation). The utility of these methodologies can be applied in tumours (primary or metastatic) which are very difficult or impossible to be surgically excised. Hence they can be applied in tumours that are multifocal in the lung, in the liver, in the bile tract, inside the bones, in the pancreas, in the kidney, etc21, 22. Another technique is based on the fact that the majority of the tumours respond very well to an increase in temperature to 41.5 degrees centigrade. This approach is known as hyperthermia therapy or hyperthermic ablation. The increase in temperature can be applied systematically by the use of chemical agents or locally by the use of physical methodologies. Widely known is the local ablation and much less so the systemic one, which is gradually withdrawn due to side-effects and difficulties of

application. The local ablation can be achieved either using catheters (see the above description) or by the use of microwaves or radiofrequencies (RFA). By using specific equipment, we may apply a local energy to an area of a tumour very precisely and cause a local increase in the tumourâ&#x20AC;&#x2122;s temperature, which causes massive apoptosis of the cancer cells. This kind of technique can be applied in combination with particles that contribute to an increase in energy in areas which are difficult to approach, like the central nervous system. These particles can be very lipophilic, enabling them to locate to the central nervous system, in the area of a tumour after application. After application of RF or microwaves, the particles release heat energy in the local area. Similarly, the ablation techniques can be applied in tumours that are difficult to be excised due to their location or because the presence of the disease is in multifocal mode 23â&#x20AC;&#x201C;25. Also, the application of radiation is not as precise and in that field, cyberknife can become very helpful. By increasing the precision, and taking into consideration that cyberknife can apply the energy from multiple different angles, it is possible to apply high energy in the area of the tumour without affecting the neighbouring healthy tissues. We may thus increase the efficacy, reducing the adverse Summer 2018 Volume 10 Issue 2


Drug Discovery, Development & Delivery reactions of radiation. It is also known that cyberknife has shown efficacy to tumours that conventional radiation couldn't 26. Finally one more technique can be photodynamic therapy by the use of photophores that can become active after explosion on a specific frequency laser beam to a local toxic agent, that may selectively deplete cancer cells but not normal tissue. Especially in difficult cases of oesophageal carcinoma, PDT has shown remarkable results without adding any toxic by-products that reduce the additional therapeutic options27. In order to decide which option is suitable for each individual and when, it is essential to follow a comprehensive analytical process for the primary, but equally for the disseminated, disease. More biomarkers are required to be applied in treatment management and the application of liquid biopsy is an additive option in order to increase the profiling of the disease. The analysis of each patient, incorporating analytical processes like molecular oncology, cellular biology, proteomics, epigenomics and genomics might contribute to obtaining valuable information about the diseaseâ&#x20AC;&#x2122;s features and patientsâ&#x20AC;&#x2122; status, and therefore pharmacokinetic and pharmacodynamic aspects will be covered. Conclusion Taking everything into consideration, all the above previously described methods can be implemented in the present options in order to increase the therapeutic spectrum, as applicable methods and options, not only to the handling of the primary macroscopic disease but also to the disseminated and residual disease, which is actually the cause of every relapse. If we manage to increase the therapeutic strategies, we may reduce the risk of relapse and by that it is possible to increase the time to relapse, or in advanced stages of the disease, to improve significantly the overall survival rate. REFERENCES 1. Yao, Y. & Dai, W. Genomic Instability and Cancer. J Carcinog Mutagen 5(2014). 2. McClelland, S.E. Role of chromosomal instability in cancer progression. Endocr Relat Cancer 24, T23-T31 (2017). www.ipimediaworld.com

3. Allison, K.H. & Sledge, G.W. Heterogeneity and cancer. Oncology (Williston Park) 28, 772-778 (2014). 4. Wei, W. & Lewis, M.T. Identifying and targeting tumor-initiating cells in the treatment of breast cancer. Endocr Relat Cancer 22, R135-155 (2015). 5. Klarmann, G.J. et al. Invasive prostate cancer cells are tumor initiating cells that have a stem cell-like genomic signature. Clin Exp Metastasis 26, 433-446 (2009). 6. Nishida, N., Yano, H., Nishida, T., Kamura, T. & Kojiro, M. Angiogenesis in cancer. Vasc Health Risk Manag 2, 213-219 (2006). 7. Thiery, J.P., Acloque, H., Huang, R.Y. & Nieto, M.A. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871-890 (2009). 8. Hunter, K.W., Crawford, N.P. & Alsarraj, J. Mechanisms of metastasis. Breast Cancer Res 10 Suppl 1, S2 (2008). 9. Gao, X.L., Zhang, M., Tang, Y.L. & Liang, X.H. Cancer cell dormancy: mechanisms and implications of cancer recurrence and metastasis. Onco Targets Ther 10, 52195228 (2017). 10. Landskron, G., De la Fuente, M., Thuwajit, P., Thuwajit, C. & Hermoso, M.A. Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res 2014, 149185 (2014). 11. Lamb, R., et al. Targeting tumor-initiating cells: eliminating anabolic cancer stem cells with inhibitors of protein synthesis or by mimicking caloric restriction. Oncotarget 6, 4585-4601 (2015). 12. Dougan, M. & Dranoff, G. Immune therapy for cancer. Annu Rev Immunol 27, 83-117 (2009). 13. Maher, J. & Davies, E.T. Targeting cytotoxic T lymphocytes for cancer immunotherapy. Br J Cancer 91, 817-821 (2004). 14. Le Gall, C.M., Weiden, J., Eggermont, L.J. & Figdor, C.G. Dendritic cells in cancer immunotherapy. Nat Mater 17, 474-475 (2018). 15. Hoelder, S., Clarke, P.A. & Workman, P. Discovery of small molecule cancer drugs: successes, challenges and opportunities. Mol Oncol 6, 155-176 (2012). 16. Iyer, V.V. A Review of Stapled Peptides and Small Molecules to Inhibit ProteinProtein Interactions in Cancer. Curr Med Chem 23, 3025-3043 (2016). 17. Lundin, K.E., Gissberg, O. & Smith, C.I. Oligonucleotide Therapies: The Past and the Present. Hum Gene Ther 26, 475-485 (2015). 18. Moreno, P.M. & Pego, A.P. Therapeutic antisense oligonucleotides against cancer: hurdling to the clinic. Front Chem 2, 87 (2014). 19. Hamza, A. & Elrefaey, S. Non-surgical treatment of early breast cancer: techniques on the way. Gland Surg 3, 149-150 (2014).

20. Leyendecker, J.R. & Dodd, G.D., 3rd. Minimally invasive techniques for the treatment of liver tumors. Semin Liver Dis 21, 283-291 (2001). 21. Van Schil, P.E., Furrer, M. & Friedel, G. Locoregional therapy. J Thorac Oncol 5, S151-154 (2010). 22. Shin, S.W. The current practice of transarterial chemoembolization for the treatment of hepatocellular carcinoma. Korean J Radiol 10, 425-434 (2009). 23. Nishimura, Y. et al. Radiofrequency (RF) capacitive hyperthermia combined with radiotherapy in the treatment of abdominal and pelvic deep-seated tumors. Radiother Oncol 16, 139-149 (1989). 24. Togni, P., Vrba, J. & Vannucci, L. Microwave applicator for hyperthermia treatment on in vivo melanoma model. Med Biol Eng Comput 48, 285-292 (2010). 25. Dietzel, F. Basic principles in hyperthermic tumor therapy. Recent Results Cancer Res 86, 177-190 (1983). 26. Brown, W.T. et al. CyberKnife radiosurgery for stage I lung cancer: results at 36 months. Clin Lung Cancer 8, 488-492 (2007). 27. Dolmans, D.E., Fukumura, D. & Jain, R.K. Photodynamic therapy for cancer. Nat Rev Cancer 3, 380-387 (2003).

Dr. Ioannis Papasotiriou Dr. Ioannis Papasotiriou, male, born in Munich, Germany. He graduated fromMedical School of ThessalonikiUniversity in 1997. He made his first specialty in Human Genetic (University of Zurich), and his second specialty in Hematology Oncology (MLU/UKH/Halle/Saale).He obtained two Master degrees, one in molecular biology in medicine from the Westminster University and one in Oncology from the University of Nottingham. He completed his promotion (MD) in MLU University in the area of TKIs in human cancer cells lines. Between 2001 and 2004 he established Arzt Genetik Zentrum in Thessaloniki where he was a director. Since May 2004 Dr. Papasotiriou is the medical director of R.G.C.C. S.A. where the major field of expertise is molecular oncology with main interest in the entity of Cancer Stem Cell (CTCs) like. Email: papasotiriou.ioannis@ rgcc-genlab.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 61


Advertorial

High Demands

Nurdan Citamak from Faubel explains how participants in the clinical trial supply chain can benefit from RFID and e-paper technology.

Melsungen, March 21, 2018 Over the centuries, the complexity of clinical trials has grown steadily from the development of statistical methods to multinational alignment with current regulatory frameworks such as Annexes VI and XIII. This is the reason why it is hardly surprising that the labelling of investigational medicinal products (IMPs) is no longer used as a mere carrier of specified contents. Labels have become multifunctional tools which are able to convey variable data in different languages, blind contents, indicate first opening or support ease of use. "Limited stability data are a good example of growing complexity. If the shelf life of IMPs increases, this also impacts IMP labeling and therefore the entire supply chain," says Nurdan Citamak, Director of Business Development and Sales North America at Faubel Pharma Services. At the beginning of each trial, the shelf life of investigational medicinal products is a factor which is difficult to quantify. During trials, new findings on the stability data of IMPs frequently emerge. If IMP shelf life is to be extended, study

Med Label Process: The Med Label allows automatic stability data updates. 62 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Faubel-Med Label: Apart from updating stability data, Faubel is planning to incorporate a study pooling option into the Med Label concept, which would further optimise the clinical trial supply chain.

co-coordinators usually initiate a re-labelling process, during which IMPs are applied with new labels featuring updated expiry dates. "The complete re-labelling process does not only mean additional time and cost, but compliance requirements for manual re-labelling are also high." Updating Stability Data Since 2010, Faubel has worked on an alternative to this risky and costly re-labelling process. The idea was to develop a so-called smart label that eliminates the traditional way of re-labelling when stability data change. “The smart label, which results from a seven-year development phase, is a hybrid label that consists of a booklet label, an RFID tag and an e-paper display. It has had the registered trade mark of Faubel-Med® Label since December 2014 and has been marketable since spring 2017 after proving its worth in a variety of mock-up studies,” explains Citamak. However, connecting digital elements such as hardware and software with analogue components, e.g. packaging, in a functional and user-friendly way has proved to be a challenge throughout the development phase. Nurdan Citamak emphasises, “At the end the target was that each element is authoritative and instrumental in optimising the labelling of investigational medicinal products."

Multilingual Product Description Vials, pens and pre-filled syringes are often used as primary packaging for investigational medicinal products. Vials, pens and syringes are often very small in diameter; because of that, booklet labels are frequently used as secondary packaging. The booklet label can be wrapped several times around the cylindrical form, thus providing sufficient space for reader-friendly detailed information. Label contents are specified by the European Union in Annex XIII. According to Annex XIII, there is a wide variety of information to be provided in the official language or languages of the respective participating countries. Further labelling guidelines are formulated in Annex VI. The layout, font size and symbols are dealt with in the Guideline of Readability. In the Good Practice Guide Booklet Labels, ISPE recommends a 6- to 7-point font size, whereas the European Commission even considers font size 9 to be adequate. Opting for booklet labels is therefore conclusive for Citamak, “because clear and legible product identification in several national languages can only be achieved using booklet labels, especially for labelling vials, pens and pre-filled syringes.” Data Transfer RFID technology is often integrated in product labelling, and this combination of label and RFID tag is usually called smart label. An RFID tag consists of a transponder. A transponder is a microchip with an antenna or coil, an analogue circuit for receiving and transmitting (transceiver) and a digital circuit and a permanent memory. If the transponder is located within the reception range of a reader, mutual communication is triggered through electromagnetic waves. Apart from these basic features of RFID systems, there are others that depend on the application concerned. In general, smart labels can be equipped with active or passive RFID tags or Summer 2018 Volume 10 Issue 2


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Update Vials: Updating can be performed on sealed kits and therefore complies with Annex VI.

transponders. Active RFID tags have built-in batteries and are therefore larger than passive transponders. Passive RFID tags do not have their own power supply. This is why passive tags have to be powered via the electromagnetic field of a reader. Each RFID tag carries a unique identifier (UID). The UID data and GPS location data can be combined to provide status information on the whereabouts of labelled packages and to enable monitoring across the entire value chain. Various characteristics of RFID technology had to be taken into account by the Faubel team when they were developing the Med Label in order to update IMP expiry dates remotely. “The RFID tag used in the FaubelMed® Label is a passive one, i.e. it has no battery of its own," explains Nurdan Citamak. The system is only powered when electromagnetic induction is performed by the reader. Only then can data transfer begin. “The reader that generates voltage for data transfer is called update device." Conventional RFID tags cannot display information without extra devices. To do so, the Faubel-Med® Label is equipped with e-paper display that is linked to the RFID tag. It features a segmented bistable display. The reader generates voltage for data transfer. When a voltage is applied, pigments are aligned in the display and can thereby show simple texts and numbers as well as 1D or 2D barcodes. The pigments will remain in this position without needing further voltage. Automated Expiry Update To consult all stakeholders in www.ipimediaworld.com

the clinical trial supply chain, Faubel surveyed contract research organisations, contract manufacturing organisations, depots, sites, and primary packaging manufacturers during the seven-year development phase. Citamak underlines, “To keep the Med Label, the associated hardware and software functional and user-friendly, we decided to only display two variable data, the expiry date and the counter. Therefore, the software was still easy enough to use and self-explanatory." The counter indicates how many updates have already been performed. Mock-up studies were conducted in Europe, the US and Asia in 2015 and 2016. Each of them included a small number of pilot series samples which had already been applied to ordinary IMP containers to make simulation appear more authentic. The questionnaires returned by the participants at the end of the mock-up studies were positive across the board. The handling of Smart Labels as well as that of the hardware and software was rated as efficient. Following these successful tests, it was possible to launch the Faubel-Med® Label in mid-2017. There are no requirements specifying that labels for investigational medicinal products may not incorporate RFID technology. Its individual components, e.g. antennas or sensors, are not even covered by guidelines of the European Union, the EU GMP Guidelines, or in the US Food and Drugs Administration (FDA) Code. "In the past, legal authorities had no objection to innovative labelling as long as the requirements on contents, durability and legibility were met. The Faubel-Med® Label fully complies with Annex XIII," reports Citamak. Besides, the label can easily meet Annex VI standards because it makes it possible for secondary packaging to update expiry dates and counters. “In other words, no need to open the kit to do that job.” Inside this kit, the marketable version of the Med Label can also accommodate several labelled containers whose expiry dates and counters can be simultaneously

updated by the update device – i.e. in a single operation. The UID of each individual RFID tag is stored in the software that belongs to the concept and controls updating. As soon as the RFID tag starts exchanging data with the update device for the purpose of updating, feedback on the status of the stability data on individual packages is received by the software in real time. However, the software can only control RFID tags whose UIDs are stored in it. The data of each labelled container are automatically stored in the software before merging into clear and comprehensive batch documentation. This automated batch documentation can also serve as a source of information for inventory management. Nurdan Citamak explains, “If, for example, an error has occurred in allocating containers when they are shipped from one depot to different sites, containers sent to the wrong address can be identified if data transfer is to be performed using an update device. The registered UID of the RFID tag is not connected to this particular site or update process. Therefore, the data appearing on the e-paper display will not change.” These containers can then be removed from the regular clinical trial supply chain. Compared to a conventional re-labelling process, the FaubelMed® Label can perform as many updates as you like on the investigational medicinal product; the counter process is recorded and traceable in the software. “As a result, leading to considerable savings to international clinical trials in terms of time and cost management. In addition, clinical trials can start earlier than in the past, and for the first time ever, it is even possible to conduct trials with very limited stability data,” says Nurdan Citamak, in conclusion. General Contact: Faubel & Co. Nachfolger GmbH Schwarzenberger Weg 45 34212 Melsungen / GERMANY Phone +49 5661 7309-0 Fax +49 5661 7309-149 Email: info@faubel.de Web: www.faubel.de INTERNATIONAL PHARMACEUTICAL INDUSTRY 63


Drug Discovery, Development & Delivery Simplifying NMR for Fluorine-containing Samples

Currently, more than 200 marketed medicines, and approximately one-third of the most successful – so called ‘blockbuster’ – drugs contain fluorine atoms in their structure1. Fluorine-containing compounds span a wide variety of therapeutic classes: anti-cancer drugs, anti-fungal agents and NSAIDs (non-steroidal anti-inflammatory drugs), for example. Fluorine is also now commonly found in illicit and illegal drugs, including synthetic cannabinoids and psychedelic phenethylamines.

This has led to a rise in the importance of fluorine chemistry and the spotlight has fallen on the techniques used for analysis of fluorine-containing pharmaceutical substances, including active pharmaceutical ingredients, brand and generic finished products, as well as for the detection of potentially counterfeited or illegal pharmaceuticals. Modern, accurate and easy-to-use assay methods are increasingly required throughout the R&D, QC and drug manufacture pipeline. Against this background, nuclear magnetic resonance spectroscopy (NMR) has emerged as a leading technique. NMR offers unparalleled breadth of information on the sample, including detailed structural information. NMR provides straightforward method development, allows rapid throughput without loss of the sample and, importantly, is a direct quantitative method with no requirement for response factors or calibration curves. As a result, the technique is useful in a multitude of applications including drugprotein binding, molecular structural characterisation, pharmacokinetics, studies of proteins and in vivo applications. With so many drugs on the market now fluorinated, 19F NMR spectroscopy is an important tool for their analysis. Initially 19F NMR was only utilised by synthetic chemists, 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

but now the technique is finding increasing applications in other areas. Traditionally, NMR analysis is based on 13C and 1H as both hydrogen and carbon are found in all organic chemical compounds. However, 19F NMR of fluorine-containing compounds can be very useful because of much higher 19 F NMR sensitivity. 19F also has less risk of signal overlap due to its broad response range, in comparison to 1H. 19 F NMR provides a wealth of detail, including the coupling (between fluorine nuclei and other atoms) and chemical shift data available, providing the assignment of both the location and nature of fluorine atoms within a molecule. But 19F sites in a molecule also do cause many spectral complications for other nuclei like 1 H and 13C. 19F j couplings split both 1 H and 13C NMR signals over many bonds, making the analysis of 1H and 13 C spectra complicated. So, a new ‘multinuclear NMR spectroscopy’ approach, of 19F NMR combined with other NMR nuclei, is being widely applied across the industry. Why NMR? Previously, chromatographic and spectroscopic techniques such as HPLC, gas chromatography or mass spectrometry have been used to analyse fluorinated compounds and detect impurities in samples. However, generally these methods require the use of expensive columns and large volumes of organic solvents. Furthermore, the analysis often needs time-consuming sample preparation and takes a long time. NMR, on the other hand, is simple, non-destructive, rapid and cost-effective per sample, in long-term comparisons. With the increasing pressures on the pharmaceutical industry, ensuring methods are cost-efficient is a top priority. NMR’s scope of application continues to increase. Recent innovations have provided marked improvements to both the NMR spectrometer’s flexibility and ease of use.

Difficulties Analysing Fluorinecontaining Samples Common challenges faced when analysing fluorine-containing samples include: •

• • •

Wide potential chemical shift of 500 ppm, 188 kHz at 9.4T (400 MHz for Protons) to 282 kHz at 14.1T (600 MHz for Protons). 19 F – 1H j coupling constants up to 60 Hz. 19 F – 13C j coupling constants up to 280 Hz. 19 F long range J coupling interactions are commonly observed and complicate NMR spectra, making interpretation difficult. These spectral features combine to make 19F difficult to excite and to decouple from other nuclei.

NMR Hardware and Probe Developments Previously, widespread use of a fluorine probe in NMR was not well implemented as it required specialised hardware to allow the uniform excitation of the broad 19F chemical shift range and was limited in capability. However, with modern hardware configurations on new NMR spectrometers, 19F NMR proves to be a useful tool for routine structure elucidation2. Modern NMR probes often allow easy, straightforward use of 19F NMR or 1H and 13C NMR, but not all three at the same time. JEOL’s latest ROYAL HFX NMR probe offers the ability to manipulate the 1H, 19F, and 13C spins simultaneously without the typical loss in performance associated with traditional NMR probes designed for proton-fluorine NMR spectroscopy. It is also the only probe on the market to use patent-pending magnetic coupling technology, which provides high-resolution NMR in HFX or HX mode with no performance loss in HX mode relative to a dedicated HX NMR probe. The magnetic coupling allows the high-frequency coil to be Summer 2018 Volume 10 Issue 2


Drug Discovery, Development & Delivery dual-tuned to 1H and 19F, or singletuned to 1H or 19F, acting as a pure on/off switch, so dual-tuned mode is at highest efficiency while singletune mode retains full performance and sensitivity of a dedicated HX NMR probe. The JEOL ROYAL HFX NMR probe also has the important added benefit of being able to observe other nuclei while pulsing or decoupling 1H and 19F. This results in no loss in performance or sensitivity for observing 13C or other hetero-nuclei. Improved sensitivity and spectral simplification for 13C when decoupling both 1H and 19F is a large advantage when collecting and analysing NMR data from unknown compounds containing one or more fluorine sites. Case Study: Application of HFX NMR to Facilitate the Complete Assignment of the Anti-fungal Agent Voriconazole Routine application of triple-resonance NMR was used to simplify the assignment of Voriconazole, a molecule containing proton, carbon and nitrogen molecules with many atoms exhibiting J-coupling to fluorine; the structure can be seen in Figure 1 below. The experiment was run on a JEOL 500 MHz ECZR spectrometer console with the JEOL ROYAL HFX NMR probe.

some of the couplings. The process is completed at the time the data is recorded. The results demonstrate that at first glance, with just 1H there is little fine structure to facilitate clear assignment. The resonances are all then significantly sharpened by the application of 19F decoupling.

Figure 3: HFCOSY 2D result for Voriconazole, mapping H-F connectivity in the sample.

Further information about the sample can also be obtained by looking at the interactions between 19 F and the 13C spectrum. Figure 4 demonstrates significant signal enhancement and simplification for the 13C spectrum, brought about by the dual decoupling of 1H and 19F, in comparison to just decoupling using 1 H. With the dual decoupling, carbon molecules with 19F atoms attached now become apparent. In addition, all 19F/13C coupling constants now can be extracted by simple visual inspection.

Figure 2: 1H NMR spectrum of Voriconazole with and without 19F decoupling. Right pane â&#x20AC;&#x201C; full spectrum; left pane â&#x20AC;&#x201C; expansion of the region revealing how the coupling details of the phenyl group are clarified by 19F decoupling.

The graph shows an expansion of the region where assignment was previously unclear, revealing further how the coupling details of the phenyl group are clarified by 19F decoupling. Decoupling 19F removed the confusion with the three resonances, PHe-6, PHe-3 and PHe-5, being revealed with simple ortho, ortho-meta and meta coupling patterns, respectively. These cannot be assigned visually without the addition of 19F decoupling and more information is clearly available.

Figure 1: Structure of the anti-fungal Voriconazole with a simplified numbering system. For example, Pym 3 would refer to the fluorine-containing carbon of the pyrimidine ring.

In Figure 2 the NMR spectrum of Voriconazole is presented with and without 19F decoupling. Decoupling is useful to help simplify the observed spectra, by removing www.ipimediaworld.com

Figure 2 also shows the interactions between 19F and 1H spectrums, however, more detail on this can be obtained by applying 2-dimensional NMR pulse sequences. In Figure 3, HFCOSY was applied to create this 2D result, mapping connectivity between protons and fluorines. This now shows unambiguous assignment of all the 19F molecules within the Voriconazole sample.

Figure 4: Comparison of 1D 13C NMR spectrum for Voriconazole comparing effects of 1H decoupling and dual {1H 19F} decoupling. The left pane better illustrates the profound simplifications from {1H 19F}.

Utilising fluorine NMR allowed spectral simplification and identified a straightforward pathway for the determination of structures in Voriconazole, which were not available through proton NMR. INTERNATIONAL PHARMACEUTICAL INDUSTRY 65


Drug Discovery, Development & Delivery Summary NMR is a valuable analytical tool for measuring 19F spectra and provides useful information for fluorine chemistry. NMR for 19F spectroscopic analysis demonstrates accuracy and reproducibility. This is particularly useful for applications such as routine analysis and quality control of fluorine-containing samples in pharmaceutical products. The ROYAL HFX NMR probe proves a powerful addition to NMR, simplifying spectral analysis of fluorinecontaining samples by allowing a straightforward and non-compromised

switch between dual-tune and single-tune modes with no loss of multinuclear experiment capabilities, in a full automation environment. REFERENCES 1.

Okaru AO, Brunner TS, Ackermann SM et al. Application of 19F NMR Spectroscopy for Content Determination of Fluorinated Pharmaceuticals. Journal of Analytical Methods in Chemistry. 2017;2017:9206297. doi:10.1155/2017/9206297. 2. Ampt K, Aspers R, Jaeger M, Geutjes P, Honing M and Wijmenga S (2011). Application of fluorine NMR for structure identification of steroids.  Magnetic Resonance in

Chemistry, 49(5), pp.221-230. 3. Okaru AO, Brunner TS, Ackermann SM et al. Application of 19F NMR Spectroscopy for Content Determination of Fluorinated Pharmaceuticals. Journal of Analytical Methods in Chemistry, vol. 2017, Article ID 9206297, 7 pages, 2017.  4. JEOL USA Inc. Application of HFX NMR to Facilitate the Complete Assignment of the Anti-fungal Agent Voriconazole. Application note. Available at: https:// www.jeolusa.com/DesktopModules/ Bring2mind/DMX/Download. aspx?EntryId=1230&Command=Core_ Download&language=enUS&PortalId=2&TabId=337 [accessed 31/05/2018]

Michael H. Frey Michael H. Frey, Analytical Instruments Product Manager, received his chemistry degree from Temple University and Ph.D. in Biological Solid-state NMR from the University of Pennsylvania. He was a post-doc at the ETH in Zürich working on Inverse Detection Bio-NMR. Michael joined JEOL USA in 1984, starting in NMR applications and has worked in a variety of NMR areas including software development and NMR spectrometer R&D. He is currently the Analytical Instruments Product Manager and is responsible for NMR, ESR, and mass spectrometry. Email: frey@jeol.com

Ron Crouch Ron Crouch, NMR Applications Consultant JEOL USA, Inc. obtained a Chemistry degree at Elon University. Ron joined the NMR Department at Burroughs Welcome and did NMR research for 23 years. He then accepted a position as R&D Manager for Nalorac; then moved into the Palo Alto Applications lab of Varian Inc. Ron spent 11 years with Varian/ Agilent, and has recently joined JEOL USA as an NMR Applications Consultant. Email: rcrouch@jeol.com

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Clinical and Medical Research

Patient Safety & Elemental Impurities ICH Q3D

From 1st January 2018, the European Pharmacopeia (EP) and the United States Pharmacopeia (USP) have replaced the old methods for testing of heavy metals (USP <231> and Ph.Eur. 2.4.8) in raw materials with a new harmonised guideline “ICH Q3D”. Drug product manufacturers are responsible for providing a riskbased assessment of the elemental impurities, justifying that the contents for each of the 24 elements are below the exposure limit as described in ICH Q3D. The elemental impurity level and variability must be established by validated analytical methods specific for each matrix to avoid biased results.

Elements All matter on Earth is composed of elements. The four elements common to all living organisms are oxygen (O), carbon (C), hydrogen (H), and nitrogen (N), which together make up about 96% of the human body1. Elements like mercury (Hg), lead (Pb) and cadmium (Cd) are toxic. For patient safety, ICH Q3D states a permitted daily exposure of 24 specific elemental impurities in drug products2. The risk-based approach, as defined by ICH Q3D, is established to limit the level of elemental impurities in pharmaceuticals for humans. The elemental Impurities may originate from multiple sources; catalysts and inorganic reagents intentionally added, impurities present in drug substances and excipients or elements released from manufacturing equipment and packaging. Risk Assessment The scope is patient safety – patients should not risk being poisoned with elemental impurities when dosing their medicine. Drug product manufacturers are responsible for ensuring and documenting that the elemental impurities are below the permitted daily exposure (PDE) levels. The processes must be based on scientific knowledge and should; (1) identify known and potential sources of elemental impurities (2) evaluate 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

their presence and (3) summarise and document the analytical data used for the risk assessment. Using such risk-based assessment, the drug manufacturers can reduce the requirement for full testing of all 24 elemental impurities. Compliant Testing The analytical determination of elemental impurities should be conducted using appropriate procedures suitable for their intended purposes. As long as the test is specific for each elemental impurity, any analytical procedures can be used2. The previously required pharmacopoeia tests for heavy metals USP <231> and Ph.Eur. 2.4.8 were both non-specific and were not developed to detect elements at low concentration levels, and are therefore not useful for the new risk-based approach for evaluation of possible critical content of elemental impurities in drug products. Instead multi-elemental detection techniques are recommended, e.g. ICP-OES (inductive coupled plasma with optical emission spectrophotometry), or ICP-MS (inductive coupled plasma with mass spectrometry), where the latter, i.e. ICP-MS can cover all 24 elements, with superior selectivity and sensitivity. Sample preparation is typically performed by digestion of the sample in a microwave oven using a mineral acid under high pressure and heat. This technique ensures that all matrix components are being dissolved and all elements are released into solution, making it possible for analysis of the resulting solution by ICP/OES or ICP/ MS. In order to perform a thorough risk evaluation of the content of elemental impurities, any analytical approach needs to be validated. All matrices behave differently when exposed to mineral acid digestion, which clearly shows that necessary caution must be exercised when determining which digestion technique is chosen when performing the analytical work. For proper evaluation of the performance of

the analytical technique used, a method validation must in all cases be performed for each specific matrix analysed. Only in this way is it ensured that the method is suitable for the intended use. Results based on methods that are not validated for a specific matrix type cannot be trusted as the results can be biased by negative matrix effects including precipitation, signal suppression or interferences. It is therefore critical that a thorough focus on digestion technique is always taken into consideration for all analytical work on elemental impurities. Laboratory Requirements Analytical determination of low level content of elemental impurities requires a super clean laboratory, equipped with special instrumentation and experienced staff. The majority of the contract laboratories (CROs) that offer testing for elemental impurities are not GMP approved or inspected by FDA. In addition, most CROs do not offer adequate testing services required for ICH Q3D. This service involves expertise in achievement of low detection limits and sufficient validation work, together with the required GMP documentation. Some of the typical pitfalls for most CROs, when analysing elemental impurities, are to document complete dissolution of silica, talc and other difficult matrices. For these matrices, special acids need to be used for complete digestion, e.g. hydrofluoric acid. Some CROs also experience problems in obtaining precise recovery of volatile elements such as mercury and osmium that need special care during analysis. Eurofins Metal Competence Center – Centre of Excellence The Metal Competence Center in Denmark has more than 40 years’ combined experience within metal testing and offers GMP testing for elemental impurities to support risk assessment, validations and routine testing of drug substance, excipients and final products. Summer 2018 Volume 10 Issue 2


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Clinical and Medical Research The lab is fully equipped with state-of-the-art ICP/MS and ICP/OES instrumentation. Furthermore, in order to ensure that the background level of any elemental impurity is kept at an absolute minimum, a high-pressure room facility with airlocks and mandatory garment change for the staff before entering the room is used routinely. Combined with highly experienced lab technicians and chemist, it is possible to test for elemental impurities at the absolute lowest obtainable level with a high degree of precision and accuracy in most pharmaceutical products. Analytical Approaches at Eurofins Biopharma Product Testing Denmark Self-validating Test For the purpose of performing risk

evaluation of content of elemental impurities, Eurofins BPT-DK A/S has developed a self-validating test procedure. This procedure can be used for analysis of the 24 ICH elements on several samples of the same matrix in the same test series. Aliquots from one of the samples are used for the determination of the method characteristics (accuracy, precision and LOQ). This is done by spike recovery tests combined with a repeatability study. This type of test is useful for the risk evaluation for a limited number of samples (different batches of the same sample material) that can be tested in one analytical series and is a useful as an alternative to a full

validation, that in most cases is much more time-consuming and costly. Full validation will be a preferred choice when the risk assessment has shown that specific elements are to be tested on a routine basis for each batch that needs to be released. The full validation approach can also be used for the risk assessment if more detailed information to the method uncertainty is required. For More Information Eurofins BioPharma Product Testing Denmark A/S pharma@Eurofins.dk ICH Q3D â&#x20AC;&#x201C; Elemental Impurities â&#x20AC;&#x201C; Are you ready? Eurofins BioPharma Product Testing is a global CRO offering biopharmaceutical product testing services for the biopharmaceutical industry. Eurofins is the largest contract laboratory in the world with more than 400 labs and >32,000 employees, and operates in 41 countries. REFERENCES 1. Russell PJ, Hertz PE, McMillan B. Biology: The Dynamic Science 4th ed. Cengage Learning 2016. 2. ICH Q3D Guideline for Elemental Impurities http://www.ich.org/ products/guidelines/quality/article/ quality-guidelines.html, Online 05. Dec 2017.

Dr. Rie Romme Rasmussen Dr. Rie Romme Rasmussen has a M.Sc in Environmental chemistry (2002) and a Ph.D. in Analytical chemistry (2010) and more than 15 years of experience in the analytical field; hereof 7 years focusing on trace element detection. Rie has co-authored 15 peer reviewed publications, >20 posters and 3 European Standards. Since 2017 Rie has focused on environmental impurities at Eurofins including validation, GMP analysis and quality control. Email: RieRommeRasmussen@eurofins.dk

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Clinical and Medical Research

Understanding the Challenges in Designing and Executing Clinical Trials for Screening Tests Clinical trials for screening tests of a drug candidate take place at the very early clinical development, i.e. Phase I clinical study. The aim of such studies is to assess drug candidate safety, its actual fate in human body after administration (PK/PD data, metabolite identification, mechanism of elimination and excretion, etc), its tolerance threshold (dose escalating) and its adverse effects. Other items can be studied too, according to the specific part of the studies, i.e. food effect, impact of renal or hepatic impairment.

To perform these studies, it is thus necessary to provide an informed consent form, a study protocol, a safety plan and an SOP on the administration of it. It is also required to present CMC (chemistry, manufacturing and control) information, and PK/PD, toxicology, mechanism of action and pharmacology data. All of that makes Phase I clinical trials crucial to the drug development process; designing and executing such clinical studies needs much preparation and planning. Design of a Phase I study is a key step as it can later allow saving time and preventing delays. It requires taking into consideration numerous aspects and parameters, such as the dose to be delivered, number of volunteers needed, study design which will fit the objectives of the trial, but also CRO and principal investigator choice, local regulatory rules and their updates… The final objective of this step is to design an effective clinical trial protocol in the course of which humans will be exposed to a new drug substance for the very first time. Because of incidents of unpredicted human toxicity in recent years, safety issues are dominant when identifying a clinical drug candidate. To plan human studies and to minimise risk, 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

prerequisites are to make plausible predictions about the fate of the drug candidate in the human body after administration, to characterise its metabolic transformations in the body and identify potential toxic metabolites. On top of that, proper risk management procedures should be put in place to allow the prediction and prevention of possible side-effects, to deal with serious adverse events (SAEs) (medical emergencies, including 24/7 access to a physician). Moreover, the conditions (or “stopping rules”) under which the trial must be stopped have to be defined. Lastly, a volunteer examination plan should also be defined based upon trial objectives, and expected fate and activity of the drug candidate. The trials are usually performed in healthy volunteers, or in patients who are not expected to benefit from the drug candidate. In a Phase I clinical study, the drug candidate is mainly compared to a placebo control. However, this leads to some concerns when the drug candidate is intended for life-threatening diseases or in oncology, as it may be not ethical to use a placebo control in such cases. Therefore, a reference medicine product can be used too, but then it is necessary to choose a good reference product. Trials are traditionally conducted in the logical sequence of single ascending dose, multiple ascending dose, examination of preliminary effect of food on exposure, and potential drug/drug interaction, but there is now an increasing trend to include all of these “sub-studies” in the first trial to generate the maximum amount of data in the shortest time. Therefore, the first clinical study often consists of a multiple study design (including single dose/multiple dose escalation study, ADME study, BA/BE study, food effect study, etc.) making study global design more complicated to define.

Then, one of the main challenges in clinical study design is to define the correct starting dose of the drug. This is done based on the “no observed adverse events” level (NOAEL) and on the selection of the human equivalent dose of the most appropriate pre-clinical animal model, applying a safety factor (at least 10-fold) to get the maximum recommended starting dose (MRSD), and adjusting the MRSD to the predicted drug action. Dose escalation requirements must also be determined. Usually, a study should start with a single ascending dose design, i.e. different groups of subjects receive subsequentially higher doses but each subject will only get the drug once. Later, this can be changed to a multiple ascending dose design, where the same subject will receive a specific dose several times. When required dosage strengths are defined, they have to be manufactured so that the right quantity of the investigational medicine product (IMP) arrives at the right place, i.e. the investigator sites, at the right time, i.e. before the clinical study starts to allow final setting up before first patient administration. To do that, selection of the most suitable contract development and manufacturing organisation (CDMO) is key to success! It has to be able to quickly manage different IMP and comparator formulations and process

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Clinical and Medical Research development, including analytical methods development and validation, and stability data, with small active substance quantities, and to adhere to good manufacturing practices (GMPs) to produce batches intended to be used for clinical trials. Synerlab Développement (Orléans, France) is a CDMO with a proven track-record of successfully supporting sponsors with flexible supplies of IMPs for early development programmes and of optimising in vitro performance of drug products. Executing a Phase I clinical study is at least as challenging as designing it, because everything rarely goes as planned! There are a number of potential unexpected situations, and staff conducting trials must be prepared for that. In Phase I research, it is necessary to always be prepared to expect the unexpected, as this is the first time a product is administered to humans. Volunteers follow-up is thus very intensive and strict, and requires strong medical teams. However, clinical trials execution has to be efficient. Once a trial protocol has been activated, the recruitment of patients requires a significant amount of time for several reasons as they have to fit the selection criteria of the study. When patient recruitment is difficult, during oncology trials for example, the trial is delayed, sometimes by years, until the number of patients required by the study protocol can be enrolled. It can also be difficult to keep patients engaged during the study because patients may reside far from study centres, and have to leave the care of their regular doctor and receive services from unfamiliar providers, for example.

minimise active substance waste, the CDMO has to be flexible and reactive in terms of manufacturing schedules to avoid any out of stock issues at the CRO. The manufacturing process has to be amenable both regarding batch size and dosage strengths range. At Synerlab Développement, formulation and process are designed early to offer such adjustment. Synerlab Développement offers state-of-the-art facilities to support an adequate supply chain with flexibility and reactivity in terms of schedules, integrating services for the development, manufacturing and testing of solid and liquid dosage forms.

During the execution of the study, the study protocol can be amended or even broken off for several reasons: safety alert identified during the safety meeting that takes place once the first dose is administered and between dosing; occurrence of an SAE or of some unexpected findings, such as longer than expected half-life, production of a significant active metabolite, etc.

Lastly, when volunteers’ recruitment takes longer than expected, it is also necessary to generate a rapid update of IMP stability data supporting shelf-life extension, or to manufacture a new IMP batch to resupply the study with additional therapeutic units in order to avoid study break. This point has to be anticipated jointly by the sponsor and the CRO with the CDMO.

Therefore, to manage recruitment fluctuation and dosing switch, and

Phase I clinical trials are crucial for the future development of a drug, but

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also, for many reasons, challenging during both their design and their execution. Therefore, it is absolutely necessary for the sponsor to work with an expert CRO and an expert CDMO, which is why Synerlab Développement always reinforces the importance of implementing efficient interactions and continuous collaboration between the study sponsor, the CRO and its multidisciplinary scientific team of pharmaceutical development experts.

Isabelle Decorte Responsable Développement Galénique et Opérations Pharmaceutiques, Pharmacien adjoint Synerlab Développement, Orléans (Groupe SYNERLAB) www.synerlab.com Head of Pharmaceutical Development and Opérations, QP at Synerlab Développement, Orléans – www. synerlab.com Email: isabelle.decorte@synerlab.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 73


Clinical and Medical Research

Digital Devices in Clinical Trials

Most pharmaceutical companies are investigating how digital devices can be utilised in clinical trials to improve the data foundation and potentially assist in securing a faster time to market and improving patient retention. One common challenge stands out: how do you create a setup robust enough to allow you to include the output data as evidence? This article discusses the common challenges faced and, based on network consultations with a group of pharmaceutical companies, it seeks to identify a viable path forward. The use of devices in clinical trials has been standard procedure for many years: syringes, spoons and other analogue devices are used but technology is evolving rapidly and at a pace where it can be difficult for regulated industries like life sciences to keep up. With the introduction of digital devices, it has become almost impossible for pharmaceutical companies to keep up with the development. The reality is that you can pick up consumer digital devices in local electronics stores, monitoring the human body, generating highquality, reliable, real-time data in a non-intrusive way. These devices are more advanced than any device a pharmaceutical company would be able to produce, as this requires state-ofthe-art technology competencies and expertise. These devices are capable of monitoring such things as: heart rate, activity weight, composition of food intake, blood sugar, acceleration, skin condition, moisture, sleep and much more. The devices range from more classic wristbands, to socks, wall-mounted sensors, ingestibles and bio tattoos. Each device fits a purpose and a situation, and with 74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the accelerating pace of innovation, it is not difficult to find a capable device.

The main challenges outlined and identified at these pharma companies were:

Challenges in Clinical Trials In clinical trials today, some of the biggest challenges are:

1. Device selection 2. Device validation 3. Device management 4. Data transfer 5. Data consolidation 6. Unclear guidance from authorities

Patient retention: The attrition is high in most trials and part of the reason is the patient’s time spent in doing measurements, showing up for interviews, etc. Time to market increases: more and more evidence is required and requirements are constantly increasing. Drug candidate selection is becoming more and more difficult: with more and more drugs on the market, the identification of candidates takes more time and better data is needed to be able to more quickly deselect candidates and focus on the right candidates.

How do Digital Devices Improve the Outcome of a Clinical Trial? The big question is why all of these technologically advanced devices, and the valuable data they generate, are not fully utilised to secure a faster time to market, improve the data foundation to select the right drug candidate and secure an easier collaboration with the patient? Through a series of meetings and network consultations with the industry, NNIT has sought to identify the biggest challenges and obstacles to successfully utilise digital devices in clinical trials. The companies participating range from mid-size pharma to top-10 pharma companies, covering various therapeutic areas from diabetes and neuro-degenerative disorders to depressive disorders and dermatology. Part of the group had tried to use digital devices in clinical trials, but not succeeded in implementing a sustainable setup that could ensure that data could be used as evidence in the clinical trials.

Device Selection Many pharmaceutical companies find it difficult to cope with the rapid development of the market, making it difficult to get an overview of the devices on the market and how they can support clinical trials. Furthermore, the project managers running the clinical trials rarely have much technological experience, making it difficult to grasp the opportunities that the device in itself can present. An imminent need is seen for support in presenting relevant digital devices based on input on the clinical trial itself; making sure to present only devices of relevance, and potentially a mix of devices, to support different angles of the clinical trial. Device Validation In order to use the data output of the device as evidence in your clinical trial, it is a prerequisite that the device is approved through a proper device validation. While many companies are experienced with validating devices, very few know how to get a digital device approved. FDA has set up guidelines to follow 3 on how to validate the devices. Once approved, they are open to use for everyone and it becomes available on the approved device list4. That means that there will be a hill to climb and the first companies must expect to put some resources into validation of devices. But over time, the list of approved devices will increase and it will be more and more obvious to choose from this list. Currently, however, this list is too short. Summer 2018 Volume 10 Issue 2


Clinical and Medical Research Device Management A low-practical, but challenging part of using devices in clinical trials is being in control of which patient has which device, monitoring the status of the device itself, delivering training and software updates, versioning and the low-practical part of handing out and returning the devices. Device management may be a new discipline in the clinical trials arena, but is something which has been solved many years ago in other lines of business. Just think about how your current employer manages devices as cell phones. Similar methodologies and approaches can be used for clinical trials, leveraging the experiences and expertise already existing. Secure Transfer of Data As most devices are coming from different vendors, the available data platforms are diverse. It basically means that with each device, you get a new, typically SaaS, solution, from which you need to fetch the data. This is smart for consumers, but poses a big problem for a pharmaceutical company wanting to use the data in a clinical trial: 1) It is difficult to guarantee the data transfer end-toend ensuring data integrity, that is, that no changes or interferences happen; 2) the cloud platforms are open, non-validated, rapidly updated platforms, which makes it difficult to stay in control of what happens to the data after the transfer; 3) each device has its own data format and output, typically incompatible with the others. In regard to transfer of data and consolidation of this, a digital device is, however, not much different from any other application; the software is as advanced and comes with several features. Again, methodologies and approaches used elsewhere in IT can be reapplied. Experience and tools used for doing integrations and interfaces from the device itself and to a specific target can be set up, potentially feeding data into a data hub that consolidates and prepares the data to be ingested into the clinical applications of your choice. Storage and Consolidation of Data After the transfer, the pharmaceutical www.ipimediaworld.com

companies need a consolidated dataset from all of the devices. This to avoid doing endless interfaces to your clinical systems, as setting up and maintaining such interfaces does not serve as an option as these are costly, and are often updated and changed. Instead, an intermediate layer is needed. Here useful data management tools can be used to combine, standardise and prepare the data to be moved to the clinical systems of choice. In this way, you create a buffer between the rapidly changing world of new devices and the stable and validated world of clinical systems. This allows for flexibility and scalability, enabling you to continuously add and introduce new devices into your portfolio of clinical trials.

The guidance that FDA gave was to:

Unclear Guidance from Authorities Even if there is a solution to the above five key issues outlined by our network group, some inaccuracies and lack of clarity in guidelines and regulations from authorities have hindered some of the speed of the technology uptake. FDA has addressed this head on, and announced publicly at the DIA RSIDM conference in North Bethesda, MD in February 20185, that "FDA wants to change the perception that such regulations as CFR 21 Pt. 116 hinders the technology adoption in pharma and while staying in control, (they) want to modernize the requirements to fit the modern world".

FDA came with some interesting statements:

Concretely, this means that CFR 21 Pt. 11 has been updated and some guidance given to address a range of concerns. FDA mentioned five areas of concern that they had addressed. It is important to state that below is a summary of an open session held at the conference; the exact details and explanations will be found when the updated version of CFR 21 Part 11 is published. Access Controls A lot of discussion has been ongoing on what requirements to access controls exist with regard to digital devices. Some devices do not come with screens or means of input, such as an ingestible, and some, for example a smartwatch, have a screen, but it would be almost impossible to implement access controls.

• •

Ensure access controls are in place for mobile technologies that rely on user entry. Obtain signed declaration from study participants, confirming that the device is solely used by the study patient. The above only applies if the device is not an ingestible. This answers these discussions and makes it much clearer what is actually needed.

Location of Source Data The location of the source data has been a hot topic. If it is considered on the device itself, suddenly GxP validation could apply for a wearable, which is difficult to apply.

• •

FDA does not consider the mobile technology to contain the source data. The earliest retainable record of the data is seen as the first destination after the mobile device. FDA will not inspect individual mobile devices. FDA will focus on the process for capturing, transmitting and recording the data from the device.

This is a small breakthrough on how you need to work with mobile devices in clinical trials, and it shows that the variety of devices you can use will be bigger, as long as you are in control of the data flow from the device and to your clinical systems, where CFR 21 part 11 applies. Audit Trails The digital device must record date and time stamps and transmit data, but only the first destination should capture a full audit trail including originator of the data. Once data has reached the first destination, only clinical investigators, delegated study personnel or similar personal should be authorised to make changes. All changes must be tracked by audit trail. This again opens up the use of standard devices while the strict requirements apply to the software systems that capture the data. INTERNATIONAL PHARMACEUTICAL INDUSTRY 75


Clinical and Medical Research Security Safeguards Some of the safeguards, which were discussed and given as best practice, were: •

• •

Digital devices must ensure security and confidentiality of data. Data must be encrypted. Depending on the technology, appropriate measures such as remote wiping, remote disabling, firewalls, etc., must be considered.

In other words, the sensible safeguards that you can take are the ones that you must implement. Training It is stressed that appropriate training must be conducted of patients to ensure correct output data and to avoid misuse and wrong use of the device, which could potentially alter the data. The interesting thing is that it was made very clear that training must occur before hand-out of the devices as well as during the trial, in order to

maintain a proper level of knowledge and avoid bad habits. So How Do You Proceed From Here? It may still seem like a lot to accomplish to use a digital device in a clinical trial; however, the output of doing so can have a significant impact on patient retention, assisting in faster drug candidate selection and overall time to market. It is important to realise that digitalisation has now entered the scene of clinical trials. It is no longer a question of whether you should do it, but rather how. It is evident that new types of skills and profiles are needed, some with more IT experience and merits in that space. But it is also an area that evolves so rapidly that it does not make sense to try to keep up with the developments entirely on your own. You need to build strong relationships with a partner that can guide and set direction together with you. Furthermore, it is crucial to follow the different programmes and guidelines that authorities launch to fast-track some of the innovation.

You may see competitive advantages arise from participating in exactly such programmes as the FDA digital health software recertification programme and read the FDA Digital Health Innovation Action Plan to see how authorities see the new world of digital innovation. REFERENCES 1. FDA Digital Health Innovation Action Plan: https://www.fda.gov/downloads/ medicaldevices/digitalhealth/ ucm568735.pdf 2. FDA Digital Health Software Precertification (Pre-Cert) Program: https://www.fda.gov/ MedicalDevices/DigitalHealth/DigitalHealthPreCertProgram/default.htm 3. Process of approving device https:// www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/ PremarketNotification510k/default.htm ) 4. Example of an existing device approved: https://www.accessdata.fda.gov/ scripts/cdrh/cfdocs/cfpmn/pmn. cfm?ID=K161717 5. DIA RSIDM https://www.diaglobal. org/en/conference-listing/meetings/ 2018/02/regulatory-submissionsinformation-and-documentmanagement-forum/agenda/06/ session-3-new-fda-draft-guidance-onpart-11-in-clinical-investigations-andmobile-technologies-in-clinical-investi gations?ref=Session3NewFDADra 6. https://www.fda.gov/RegulatoryInformation/Guidances/ucm125067.htm

Rune Bergendorff Rune Bergendorff is Director of Life Sciences Professional Services DK in NNIT. He has a background within business administration and computer sciences, and has within the past eight years worked with the digital transformation of life sciences companies, primarily within the regulatory affairs domain. He has been working as subject matter expert, project manager and programme lead on various projects within RIMS, IDMP, xEVMPD and labelling, with a focus on data, standardisation and transformation of the business area. Email: rrb@nnit.com

76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2018 Volume 10 Issue 2


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 77


Technology

AI and the Transformation of Life Sciences: What Does the Future Hold? Fro m a c c e l e r at i n g s c i e n t i f i c breakthrough and spotting previously elusive patterns in unwieldy global data masses, to enabling greater drug personalisation, AI and machine learning could help change the role and business models of life sciences in future, as part of a broader transformation of the health value chain. Siniša Belina of AMPLEXOR Life Sciences explores some of the potential opportunities, and considers how companies might start to prepare for what lies ahead

The manufacturing and business worlds are rapidly reaching an acceptance that, far from being a futuristic concept with as-yet undefined impact, artificial intelligence is already tangible, within reach and something they need to start planning for. Smart internet and content searches that adapt to user preferences, automated personal assistants like Alexa and Siri, and customer care channels such as web chat, are already exploiting AI in everyday situations. Via machine learning, a subset of artificial intelligence, algorithms don’t just make clever connections and spot trends in masses of data, they have also become increasingly refined and efficient at this over time, in response to the conditions they are exposed to and the results they find. All of which adds to the speed of discovery, and the next actions this makes possible. Automation is a big attraction of the AI proposition. If machines can get to grips with routine knowledge work, and do it more rapidly without needing breaks to sleep, rest and refuel, then it makes sense to apply technology to sift, fill, find and organise. As long as humans are overseeing and sense-checking the results, why not let IT systems take the load and let experts do the more interesting and mentally demanding tasks? Talk of new waves of automation may bring initial fear as people 78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

wonder about their jobs, and the risk of removing common sense and intuition from important or sensitive work. But where machines really can get through more of the work, plough through more of the data, and spot more subtle patterns that the human eye might miss, to deny automation’s potential is to limit progress. Machine-based Diagnostics as Smart Systems do the Heavy Lifting In primary care, it probably won’t be that long before AI-based systems are playing a more direct and prominent role in patient diagnostics. It makes sense, given that high-capacity computing resources – which are now much more readily available for everyday use thanks to cloud-based delivery models – can consolidate and crunch data in such high volumes and at such a rapid rate that their potential for an accurate diagnosis of even the rarest condition is far greater than that of even the most experienced and highly-qualified clinician. Just a few weeks ago, UK researchers at a hospital in Oxford announced the availability of AI technology that can diagnose heart disease and lung cancer at a much earlier stage from analysis of patient scans1. The heart disease technology will be made available to NHS hospitals for free within a matter of months. We are likely to see smart robots help with the heavy lifting of patients, as they are moved in and out of hospital beds, saving the backs of nurses and support staff. And connected devices will be used increasingly to feed patient data to the health practitioners managing their care, not only to monitor the progression of or any improvement in their condition, but to allow much earlier interventions if the continuous trackers begin to pick up signals that indicate certain types of subtle changes. Ongoing patient monitoring is part of a strategy for more pre-emptive, preventative care – a shift towards maintaining wellbeing rather than reacting to illness. All of which is

expected to lead to better outcomes for patients, and a reduced strain on healthcare resources, hospital beds, and so on. The Changing Role of Life Sciences So where does this leave big pharma and the wider life sciences industry – which has done so well, for so long, from providing treatments that alleviate, heal and manage existing patient conditions? How far might AI take them in transforming the way they operate, and indeed the role they play in the health cycle? The surge in technology-related events for the healthcare and life sciences industries is no coincidence. Over the year ahead, conferences and exhibitions offer to bring new awareness of the opportunities to the combined sector. In April, 'Next Generation Healthcare' is the central theme at BioTrinity 20182, whose sessions include 'AI and Drug Discovery'. And in June, AI summits will be hosted everywhere from London3 to Philadelphia4. Among the speakers at the London event are Alan Boehme, CIO/CTO of Procter & Gamble, and Juliet Bower, Chief Digital Officer at NHS England. Even if it’s just to have a response ready for funders, partners and patients, industry leaders recognise they need to have a position on AI. So what might that look like in life sciences currently? The organisers of June’s US healthcare and life sciences AI event note that the technology has substantial potential for enhancing research and development operations, through the ability to analyse large volumes of data leading to richer insights. To this end, applications, systems, and platforms have already been developed to transform clinical trial innovation. This isn’t just about teasing out finer details and subtler patterns from once untameable volumes of disparate data either. It’s also about modelling and extrapolating from such findings to arrive at bolder hypotheses and deeper and more targeted work, accelerating progress. Summer 2018 Volume 10 Issue 2


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 79


Technology Beyond traditional drug development, AI and machine learning in particular offer scope for new advances in medical imaging interpretation, genomic profiling, personalised medicine and treatments. Forming Closer Links with Patients AI technology also offers a way to track global patient trends, concerns, experiences, behaviour and needs, enabling the life sciences industry to understand what is happening in the real world to a level of granularity and completeness that hasn’t been possible before. This offers potential not only for more proactive and thorough monitoring of adverse events and other safety signals as drugs move into markets, but also for spotting untapped requirements, triggering new innovation. Where the life sciences industry has traditionally been one step removed from patients, public internet forums and social networks offer an opportunity to understand evolving demands and engage with patients in new ways. Although companies have to be very careful about disguising promotions as neutral information and advice, a greater dialogue with patient communities could be their best shot at capturing a share of the growing wellness/preventative medicine opportunity. The global nutraceutical market, valued at around $383.06 billion in 2016, is expected to be worth $561.38 billion by 20225, such is the growing consumer appetite for products that keep them healthy. Other research6 has shown that millennials are prime targets for proactive treatments in this category – a demographic that is very vocal on social media. Laying the Foundations for Innovation The scope for AI in transforming life sciences as we know it today is great. But this is not a fast-moving industry, and there are a number of things that need to happen first if companies are to adapt to and exploit the potential ahead of them in a sufficiently timely fashion. The first is a recognition and acceptance of the fact that change is coming, and that no industry is immune to disruption from emerging market entrants – new potential competitors with bold ideas and the advantage of 80 INTERNATIONAL PHARMACEUTICAL INDUSTRY

not being tethered to legacy thinking and ways of working. The second is preparing an IT and data environment that allows for new experimentation and insights – within the restrictions of regulatory control and privacy protection, of course. Already, today, the world is building knowledge at an unprecedented rate: IBM estimates that, by 2020, knowledge will double every 11–12 hours (compared with a rate of every 25 years, as was the case in 1945)7. So there is a growing urgency for companies to bring this situation under control in their own context, and harness it to maximum potential. This isn’t just about developing ‘big data’ strategies, but organising and preparing that data so it can be analysed efficiently, accurately and holistically using AI platforms – to spot emerging trends, anomalies, concerns and opportunities, at a speed and degree of precision which in time could become a market differentiator. Start From What You Know For now, regulatory pressures are behind a lot of data-related initiatives in life sciences. More data is being captured, consolidated and cleaned up now, but primarily this is for a specific purpose, and not one that will add significant value for the business. Innovation is not a part of the plan, when it really should be. If the work has to be done, far better to do it once and do it well – laying the foundations for all manner of future use cases, however ambitious and futuristic these might seem now. And, as mundane and mandatory as regulatory data initiatives might seem, they do in themselves offer a potential platform for experimenting with AI – even if just for taking over some of the more repetitive or preparatory stages of submission creation, or content checking, to accelerate speed to market. (Using machine learning, systems could ‘learn’ how to produce better output, or the conditions most likely to result in a new marketing submission being accepted first time.) The critical enabler for all of this is the creation of a comprehensive master data model – one that also includes inter-dependencies between the data, in a way that can drive new efficiencies and increased impact through proactive process

automation, boosted by AI/machine learning. All big journeys start with a first step, and the voyage towards a reenergised, more agile, responsive and patientcentric life sciences industry must begin with a strong sense of new purpose and a foundation of rich, ready-to-exploit data. The rest is mere detail. REFERENCES 1.

AI early diagnosis could save heart and cancer patients, BBC News, January 2nd 2018: http://www.bbc.co.uk/news/ health-42357257 2. https://www.biotrinity.com/ 3. https://theaisummit.com/london/

4. http://aiinnovationsummit.com/ 5.

Global Nutraceuticals Market - Growth, Trends and Forecasts (2017 - 2022), Mordor Intelligence, December 2017: https://www.mordorintelligence.com/ industry-reports/global-nutraceuticalsmarket-industry 6. Marketing to millennials: best practices in promoting nutraceuticals and functional foods to the influential consumer, tekno scienze publisher, Sept/Oct 2017: http://www.teknoscienze.com/ tks_article/marketing-to-millennialsbest-practices-in-promotingnutraceuticals-and-functional-foodsto-the-influential-consumer/ 7. Marc My Words: The Coming Knowledge Tsunami, Learning Solutions Magazine, October 2017: https:// www.learningsolutionsmag.com/ articles/2468/marc-my-words-thecoming-knowledge-tsunami

Siniša Belina Siniša Belina is 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

Summer 2018 Volume 10 Issue 2


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 81


Logistics & Supply Chain Management

Clinical Operations and Supply Chain Management: Sharing Perspectives to Maximise Patient Benefits Predicting patient enrolment in clinical trials is challenging. While early enrolment forecasts are often evolving, they are required by clinical supply groups to establish drug demand. The link between enrolment forecast and drug waste can be a source of frustration between clinical operations and clinical supply groups. How can supply planners create accurate drug forecasts from uncertain enrolment forecasts? Understanding this paradox and devising effective supply solutions requires scrutiny from both perspectives: clinical operations and clinical supply. Although this is not a new problem, the inherent link between patient recruitment forecasts and efficient supply planning is sometimes overlooked, introducing risk of stock out and patient impact.

Enhanced synergy between clinical operations and clinical supply groups can alleviate this risk and provide better experience for patients. Improved collaboration begins with an appreciation for the specific challenges faced by each functional group. The Clinical Perspective According to Louise Oliver, PhD, CRO Strategic Operations Manager at Almac Group, patient recruitment is one of the biggest challenges facing clinical trial delivery. She notes a multitude of obstacles that sit within this wider problem: “There are a number of common barriers that threaten patient recruitment. A lack of data, for example, can really hinder the ability to create accurate projections, either because there is limited information available for recruiting for a particular indication, or perhaps due to competing challenges with recruitment, we have to engage a number of new sites with no working history to benchmark against. “The protocols involved in clinical trials are becoming more complex, which can mean more patients are needed to participate. Protocol complexity is a challenge for 82 INTERNATIONAL PHARMACEUTICAL INDUSTRY

recruitment. For example, translating complex protocol information and design into layman’s terms, as part of the informed consent documentation, can result in lengthy and difficult to understand forms for patients; creating additional burden on sites and negatively impacting recruitment.” Operating in such a tightly regulated sector can also present problems to recruitment, as Louise explains: “Marketing activity – through social media, broadcast or press – can support recruitment by raising study awareness but marketing material used for recruitment is subject to ethics committee or IRB approval. Ethics committees review content and can request edits, which may dilute the impact of the campaign. “Another point to consider is inclusion and exclusion criteria. This is something we dedicate significant time and resource to in the planning phase but it’s often only after the study has started that we identify problems with criteria that lead to protocol amendments, delays, and – worst case scenario – lost patients.” Referencing enrolment strategy for a recent Phase II respiratory medicine study, Louise explains the thought process behind establishing how many patients would need to be identified to meet patient randomisation targets: “At first glance, and perhaps to those working outside of a clinical ops specialism, the number of patients we needed to recruit may have seemed small. However, data from previous studies evidenced that only one in 50 patients were likely to be eligible to screen for the study. Of those 50, only one in three were likely to provide consent, and of those remaining patients only 50% would complete the trial. When we scrutinise these details, known as the recruitment funnel, it soon becomes apparent that significant numbers of patients are needed to meet our

targets, evidencing the magnitude of work patient recruitment and clinical operations teams face.” Although it is generally acknowledged that rescheduling patient visits should be avoided, sometimes it is necessary. Rescheduling patients impacts multiple stakeholders and involves significant management and rework from clinical operations teams, as Louise explains: “Before we can initiate rescheduling, the approved protocol needs to be reviewed to ensure this is allowable. In conjunction with this, the research physician needs to be consulted to establish whether it is safe to move the patient’s visit. For example, the patient may need to rescreen if the rescheduled visit falls outside of the screening window. Questions arise surrounding the extra burden placed on patients because of the additional procedures. This in turn increases the risk of dropouts. Protocol visits are often linked with set timing between each visit so it’s quite often not just one appointment that needs to be rescheduled, but a whole series of processes and procedures, reallocation of facilities and resource and the added cost that comes with it.” The cost, compliance, and recruitment impact rescheduling has on a study is directly felt by the clinical operations teams, but are these details always as apparent to those further removed from patients: supply chain management (SCM) groups? The answer is often no, as Louise confirms: “Clinical ops and supply groups typically work in isolation from one another. It isn’t deliberate but is indicative of the silo mentality that is often prevalent in the industry and results in a low level of awareness regarding the specific challenges facing each division.” Supply Perspective The flip side of the clinical trials coin is SCM. Supply chain managers use Summer 2018 Volume 10 Issue 2


Logistics & Supply Chain Management enrolment predictions to make three important decisions: when to produce drugs, how much to produce, and how often to produce. The answers to each question shape the supply forecast. Like clinical operations, SCM is subject to several unique constraints, from unforeseen manufacturing failures to long lead times and restricted availability. These challenges can limit the ability to meet demand, especially when combined with evolving enrolment predictions. For global studies, creating a supply forecast starts at the country level. Once the number of sites per country and planned activation schedule is known, the enrolment rate (typically the number of patients enrolled per site, per month) is used in combination with dosing schedules and dosing units to forecast demand. This makes up a basic formula for demand planning but there are other factors to consider, as Luke Moyer, Supply Chain Solutions Manager at Almac Group,

explains: “In a perfect world, patients would enrol where and when we predict and remain for the duration of the study. We know this isn’t the case. Enrolment rates are an average across many sites. Seeding sites with supply buffer therefore becomes necessary to address the problem of unpredictable demand. However, a studyi by Tufts of approximately 16,000 sites participating in 153 Phase II and III clinical trials identified that 49% fall short of enrolment predictions. So we know that a significant percentage of seed stock will be lost. This becomes overage.” Overage is a form of insurance. It’s important to ask, ‘is the cost of this insurance high or low?’ For small molecules, lower manufacturing costs made even 100% overages affordable. With biologics and expensive comparators, this is no longer the case. Overage levels are directly impacted by factors like study footprint, randomisation approach, changing factors and screening windows. It is therefore important to

look at overage in the context of the specific study, consider percentages in relative terms, and not confuse overages with costs. Luke continues: “It isn’t enrolment forecast uncertainty that creates drug waste, but rather our staunch adherence to those uncertain enrolment forecasts. The question becomes, ‘do you know how accurate your enrolment forecast is?’ If we’re not tracking forecast accuracy, then we’re not able to adjust for margin of error. These margins are exacerbated by long planning horizons. It’s a common mistake, when taking the enrolment forecast at face value, to plan supply to the full extent of the available shelf life.” A solution to this, according to Luke, is to plan for smaller, more frequent production campaigns in the early stages of a clinical study, minimising the risk of overage until forecast accuracy is well established: “Measuring accuracy can be achieved by a calculation for mean average percentage error. This margin of

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Logistics & Supply Chain Management error is then subtracted from 100% to establish accuracy. Once established, this % is used to calculate safety stock levels and set smart production quantities.” Safety stock protects against higher than expected demand by establishing conservative replenishment triggers; but what if demand is lower than expected, as is often the case? How can supply groups prevent producing material that will expire before it is used? Luke offers a solution: “Expired material means higher overages, spikes in shipments to re-seed sites, and increased returns. Without considering forecast accuracy, we may make the mistake of producing to the expiry date. But, when forecast accuracy is used to produce a percentage of demand more likely to be consumed prior to expiry, we reduce waste caused by slow enrolment. Simultaneously, safety stock levels safeguard against faster than expected enrolment. In this way, we’re protected on both sides.” Working Together – Building Trust, Exploiting Synergies Un d e rs t a n d i n g e a c h g ro u p’s perspective helps nurture awareness and understanding. Louise advocates for a shift from the silos of clinical operations and supply groups and views forecasting as a team sport: “For synergies to exist, we need to stop working in isolation from our colleagues in supply. We need to appreciate that working effectively means working together. To achieve this, we need collaboration from the kick-off. To protect patients and limit waste, we need to openly discuss goals and constraints, along with the consequences of evolving recruitment forecasts, and plans for unpredictable outcomes.”

Echoing Louise’s sentiments, Luke adds: “Ultimately enrolment and supply forecasts represent two halves of the same whole, so we must stop treating them as separate and create a holistic approach. This needs to be done in a safe, collaborative and non-judgemental environment. Creating dedicated agenda topics for supply at regularly occurring team meetings throughout the trial will facilitate this approach. Clinical ops must consider how recruitment strategies impact the supply chain; while supply groups have a responsibility to understand the clinical landscape and embrace the agility needed for patient recruitment and retention.” The pendulum swings in favour of over-production to ensure uninterrupted supply to patients. Cost savings from lean supply strategies must always be balanced against the heightened risk of stock outs. But it isn’t necessarily an “either/ or” conundrum, as Luke points out: “Synergies can be achieved, patients prioritised, and supply waste minimised if we plan, monitor, and refine forecasts together. We must be open and honest about the information we’re working with. If a forecast is conservative, or based on limited data, we must be transparent about it so decisions can be made based on the quality of assumptions.” The message is simple. Shared perspectives and collaboration are vital to optimising supply and maximising patient benefits, as Louise concludes: “It’s clear when synergies exist because each department is able to anticipate the challenges of the other – it’s not an afterthought once a problem occurs.

There’s understanding of the hidden challenges behind seemingly simple requests and appreciation that the two disciplines, and forecasts, are inextricably linked. All stakeholders benefit when we shift from working in silos to working with the big picture, and the patient, front of mind.” REFERENCES 1. Tufts Center for the Study of Drug Development

Louise Oliver Louise holds a PhD in Biomedical Engineering from the University of Ulster in Ireland and has for the past fifteen years worked in early phase clinical trial delivery both in academic and CRO settings in the UK. She has held roles as a CRA, Patient Recruitment Manager, Clinical Project Manager and Head of Clinical Operations. She joined Almac Clinical Services in 2015 and currently works with the Almac teams on CRO account delivery at a portfolio level. Email: louise.oliver@almacgroup.com

Luke Moyer Luke has over 16 years of related Clinical Supply Chain Management experience in supply-planning, forecasting, packaging/labeling design, distribution, vendor selection and management, project management, IRT medication management, and comparator purchase. He has had direct supply management experience with small molecules, biologics, devices, and stem cell medicines. Luke has been with Almac for 7 years. As Supply Chain Solutions Manager, he is responsible for enhancing and supporting the growth of Almac’s Supply Chain Management consultation service. Email: luke.moyer@almacgroup.com

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Summer 2018 Volume 10 Issue 2


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Logistics & Supply Chain Management

GS1 Standards: Making Pharmacy Fit for the Future As our healthcare system faces increasing pressure to improve safety and efficiency, and to be a world leader in delivering care, for pharmacy this translates into the challenge of keeping medicines safe, using them more cost-effectively and keeping up to date with the latest legislation and technology. Counterfeit drugs are a global problem and medicines spend is once of the biggest costs to the NHS. Legislation such as the Falsified Medicines Directive will make our pharmacies safer and central initiatives such as the Global Digital Exemplar programme are pushing Trusts to stay ahead of the game in their use of data and technology – GS1 standards are key to both.

Counterfeit Medicines Counterfeit drugs are a worldwide issue. The World Health Organisation estimates the sales of counterfeit medicines are over $75 billion every year, with falsified drugs making up more than 50% of those sold online. In the first half of 2016, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) seized over 12,000,000 fake or unlicensed products and shut down more than 2000 online pharmacies, so there’s no doubt that it’s an issue here. And you probably know someone who is vulnerable – one in eight British teenagers have said they’re likely to buy diet pills online in the next 12 months. As you’d expect, countries all over the world are doing their best to combat this and legislation around labelling requirements for medicines is establishing how best to secure a safer future for pharmacy. The key focus for regulators is the need to identify and trace pharmaceutical products, so that we know that the medicine is what it says it is and can see exactly where it’s come from. More specifically in Europe, this has taken the form of the Falsified Medicines Directive, which requires a unique identifier to be placed on all medical products. Irrespective 86 INTERNATIONAL PHARMACEUTICAL INDUSTRY

of Brexit, the UK Government has agreed, like many non-EU countries in Europe to actively comply with the legislation. The Falsified Medicines Directive asks for all manufacturers of pharmaceuticals to put a two-dimensional barcode on the packaging of all products. This identifies the product, expiry date, batch number and serial number, and must appear in ‘human readable format’ too. It’s here that GS1 standards make the difference – the GS1 2D DataMatrix was chosen by the European Federation of Pharmaceutical Industries and Associations as their data carrier of choice, because of the need for globally unique codes to identify and authenticate these products. GS1 standards bring the interoperability that means that manufacturers, suppliers, pharmacies and hospitals will all be speaking the same language, using the same standards, and ensuring that they can work across markets, stakeholders and sectors. It’s why the Department of Health and Social Care has mandated the use of our standards in all Acute Trusts in England – to uniquely identify every person, product and place. And it’s another reason for suppliers to the NHS to become GS1 compliant; it will be written into their NHS contracts that they need to be so. Medicines Spend Medication safety can’t be taken for granted. As Andrew Davies, National Professional Lead for Hospital Pharmacy at NHS Improvement, stated at our recent healthcare conference, between 5% and 8% of hospital admissions are associated with medication-related issues. He also highlighted that 50% of patients don’t take their medicines as intended and that data around patients tells us that more than a million patients are taking over eight medicines a day. Using GS1 barcodes

in healthcare not only means we can check that they’re not counterfeited, it also means we can track those medicines to a patient. Since 2009, it has been recommended that GS1 standards are used on all patient wristbands to carry the NHS number. When the patient wristband and the medication prescribed are both scanned and stored by the hospital, if there’s an issue with that medicine, they can know every patient affected with the push of a button. At Derby Teaching Hospitals NHS Foundation Trust, they scan everything and everyone in theatre. As a result, recalls that used to take them 50 hours to trace, now only take them about 30 minutes. It’s not just safety that’s at stake here. Medicines spend is the biggest cost to the NHS after staff. Just as the NHS needs to keep getting safer, it also needs to keep becoming more efficient and the optimised use of medicines is vital to this. Clinicians need to know what the outcomes of medicines are and without accurate data, that’s very difficult. Medicine optimisation is about being able to help clinicians choose the right medicines for patients. It’s about improving patient outcomes and the key part is data – knowing what the outcomes are and turning that into intelligence about medicines. Data is also crucial for minimising wastage and managing stock. It all connects intrinsically to GS1 standards – the need for reliable data, captured through barcodes. The Carter Report suggested that the introduction of GS1 standards will allow every NHS hospital in England to save an average of £3million each year, while improving patient care. That’s why they’re being mandated in all Acute Trusts in England. How Standards Make a Difference For Trusts, the task at hand is to put it all into practice. When Mary Evans, Chief Pharmacist at Luton & Dunstable University Hospital NHS Foundation Summer 2018 Volume 10 Issue 2


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Logistics & Supply Chain Management Trust, spoke at our conference, the key focus for her was the traceability and interoperability that standards bring, but also the impact they have on patient safety. It means being able to document information properly into a patient’s notes and being sure that the prescription is checked and traceable from the manufacturer to the patient. Standards also make life a lot easier in the case of product recall where hospitals can be certain over what the patient’s been given, who gave it to them, and when they’ve been given it. At the moment at Luton & Dunstable, that’s almost impossible. The drivers to do this are out there. The Falsified Medicines Directive comes into play in 2019, GS1 implementation in Trusts is needed

by 2020, and Carter requirements are by 2019. Luton & Dunstable are also one of NHS England’s Global Digital Exemplars, which means they’re being supported by NHS England to deliver exceptional care, through the use of digital technology and information. For that, GS1 standards also need to be in place by 2020. For Mary, there’s still a long way to go. The aim is for a clinician to be able to bring up a prescription using the barcode on the patient, meaning they have all the information they need when prescribing. It would then be sent electronically to the pharmacist for verification, and then to prescription processing, where the robot will use barcodes to pick the products ready to go up to the wards. The nurse will then be able to scan

the patient to bring up the medicines, scan the product barcode to check it’s the right one and scan themselves to say they’re administering it. These checks all along the way are what GS1 standards enable, but what’s needed is a GS1 compliant stock control system, scanners that can scan barcodes on both the wards and in the pharmacy and medicines that have the GS1 data matrix. Luton & Dunstable are on the GS1 journey – they know what’s needed and they’re on their way to achieving this vision. All these changes represent an enormous change for pharmacy practice – but they also provide a fantastic opportunity for improving safety. They guarantee that every pack of medicine can be checked and verified at every stage of the supply chain. And in the case of a product recall, a product can be identified down to the individual packet, so healthcare professionals can know where drugs have come from, who has administered them and who they’ve come into contact with. Medicines are checked and verified at every point along the way. These standards are already embedded in the retail sector, they’ve been using them for over 40 years, and now they’re part of the future of pharmacy.

Glen Hodgson Glen joined GS1 UK in late 2014 as Head of Healthcare. He is charged with supporting the NHS and the healthcare industry to deliver greater efficiency and a more robust approach to patient safety. Glen is a highly accomplished senior executive, with over 15 years of national and international experience. He has served at board level in a variety of operational and commercial roles within complex organisational structures inside the pharmaceutical/ healthcare arena with particular interest in caring for patients outside the hospital setting and rare diseases.

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Manufacturing

The Excipient Challenge

Excipients are defined as any component(s) of a dosage form other than the drug substance. They are added for the purposes of enhancing production, aiding patient acceptability, improving stability and/ or controlling release. Moreover, they play an important role in enhancing the processability and bioavailability of drugs by modifying their solubility and/ or permeability1, which is important information when selecting excipients for any new formulation.

A Multifunctional Mineral Excipient Highly porous excipients can help tackle bioavailability limitations of active pharmaceutical ingredients (APIs) by increasing their solubility, e.g. holding the drug in its amorphous, more soluble form within its pores. Omya, a mineral manufacturer, has developed functionalised calcium carbonate (FCC), an excipient with high porosity and compressibility. FCC is manufactured from high-purity natural calcium carbonate which undergoes surface recrystallisation

Figure 1: Micrograph of natural calcium carbonate

Figure 2: Micrograph of functionalised calcium carbonate 90 INTERNATIONAL PHARMACEUTICAL INDUSTRY

(Figures 1 and 2). This process can be controlled to obtain specific surface areas ranging from 30 to 180 m2/g, a median particle size distribution of between 2 and 30 μm, and porosities higher than 60 per cent. It can be difficult to develop multifunctional excipients that do not multiply the already extensive regulatory burden. FCC offers the advantage of being a structured mineral comprising calcium carbonate and hydroxyapatite, both of which are monographed minerals. The external structure of its particles gives FCC a clear advantage compared to other porous excipients; its external lamellae morphology provides plenty of surface contact points among the particles, ensuring interlocking and enough mechanical strength during dry granulation in roller compactors, in order to be used as a dry binder. Tensile Strength vs. Compression Force Compactibility is the most important functional consideration in the production of a tablet2. Therefore, researchers compared tablets manufactured with FCC in powder form and FCC granules with conventional calcium carbonate, mannitol or microcrystalline cellulose (MCC) tablets3. The tensile strength and porosity of the tablets were analysed across a broad range of compression forces. At low compression forces, the tensile strength of tablets formulated with FCC powder or FCC granules was higher than that of tablets formulated with mannitol or calcium carbonate and was comparable to that of tablets formulated with MCC (Figure 3). The FCC tablets also had a higher porosity than those containing the other excipients tested. With FCC in the formulation, tablets were able to reach comparable or higher hardness at lower compression forces than other formulations. This allowed their porosity to remain higher than 50 per cent and provided a large volume of voids in which to accommodate APIs.

Figure 3: Tensile strength vs. mean compression force for tablets made using FCC and reference excipients. At lower compression forces, FCC tablets reach tensile strengths that are higher than or comparable to those of tablets formulated with other reference excipients.

Figure 4: Tensile strength vs. mean compression force for tablets formulated with paracetamol and one of the following: FCC powder or MCC. The tensile strength of FCC tablets was comparable to that of tablets formulated with MCC.

In a second step, the researchers analysed tablets formulated with paracetamol and one of the following: FCC powder or MCC. They concluded that despite the presence of an API, the decrease in porosity of the FCC tablets was significantly less than that of tablets formulated with MCC when compression force was increased. Additionally, the tensile strength of the FCC tablets was comparable to that of tablets formulated with MCC (Figure 4). Finally, the FCC tablets’ combination of high tensile strength and high porosity indicated that FCC is suitable for the preparation of solid oral dosage forms. Fast Disintegration Using a tensiometer in order to simulate residence time of a tablet in the mouth, another research group analysed the disintegration kinetics of 24 different formulations4 Summer 2018 Volume 10 Issue 2


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Manufacturing and identified four patterns. Type I was considered the ideal behaviour because it resembled the market formulation. Type II was characterised by very fast water uptake but no disintegration. Type III disintegrated in discrete steps, resulting in tablet pieces, while type IV disintegrated only partially. Tablets formulated with FCC and croscarmellose sodium exhibited a type I disintegration pattern, and their residence time was one half that of the market formulation used as a reference. FCC provides a solution that combines good compactibility with fast disintegration. Thus, it can also help to tackle challenges in the formulation of orally disintegrating tablets (ODTs). From the perspectives of cost and simplicity, the preferred method of preparing ODTs is direct compression. However, the disintegration capacity of ODTs produced in this way is limited by the hardness of the resulting tablets5,6. Therefore, when compressing ODTs, the main challenge is manufacturing a tablet that enables fast disintegration without compromising on its mechanical stability. This requires an excipient that offers optimum cohesiveness for compaction. It was FCCâ&#x20AC;&#x2122;s direct compressibility into granules without the use of a binder and its high porosity that allowed faster water uptake, which led to a disintegration time that was twice as fast as the market reference product. In fact, granules manufactured with FCC disintegrate in 2 seconds and their corresponding ODTs in less than 10 seconds. In a recent study7, scientists investigated the use of FCC to formulate ODTs with enhanced mouthfeel. It was shown that the tablets were well accepted by healthy volunteers. Mouthfeel was successfully enhanced to a pleasant result without losing the characteristics of FCC: the high compactibility and the resulting physical stability of tablets, plus the high porosity responsible for the fast liquid absorption necessary for the rapid tablet disintegration. Loading Capability FCC particles can also be loaded with certain APIs and can thus be used as drug carriers. 92 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Researchers at the University of Basel in Switzerland investigated the feasibility of using a particular grade of FCC as a carrier for poorly water-soluble APIs. Ibuprofen (IBU), nifedipine (NP), losartan potassium (LP) and metronidazole benzoate (MBZ) were selected as model substances with which to investigate drug loading8. The team analysed the loading capacity of FCC, the dissolution performance and whether the drug was loaded in its amorphous or crystalline form. The four APIs were dissolved in methanol or acetone and mixed with FCC. Using a rotary evaporator to evaporate the solvent under reduced pressure, the FCC-API particles were loaded with 25 to 50 per cent (w/w) of each API. For reference, the scientists also created FCC-API simple blends that contained equivalent API fractions but were not subject to a specific loading strategy. Loading efficiency was assessed using a scanning electron microscope. The presence of particle agglomerates or drug crystals outside the FCC particles indicated the maximum loading capacity was exceeded. It was shown that FCC particles can be successfully loaded with up to 40 per cent (w/w) API. The team also observed a reduction in intraparticle porosity after drug loading (63 per cent for MBZ, 58 per cent for IBU, 50 per cent for NP and 35 per cent for LP), which provided evidence of pore filling. In addition, the dissolution rate of FCC loaded with NP and MBZ was found to be faster than that of the FCC-API mixtures. Since only low percentages of amorphous NP (8.9 per cent) and MB (12.5 per cent) were detected, the authors concluded that the faster dissolution was related to the locally increased solubility caused by the larger surface area and not to the presence of an amorphous API. A recent study shows that FCC is also a suitable excipient for the delivery of proteins9. In this work, FCC was loaded with biomolecules such as lysozyme and bovine serum albumin in order to investigate its suitability for delivering protein-based drugs. Delivery of biologics, such as therapeutic proteins, critically depends on the availability of formulation strategies that can be used to deliver these macromolecules to target

tissues. The structural and functional integrity of the biologics also have to be preserved during manufacturing and storage. Loading efficiency for the studyâ&#x20AC;&#x2122;s model proteins was more than 90 per cent. The structure of both model macromolecules was not affected by the loading process or the interaction with the surface of FCC as confirmed by circular dichroism analysis. Moreover, enzyme activity of both model proteins after loading was demonstrated by Michaelis-Menten enzyme kinetic experiments. Outlook Several studies have shown that FCC is a versatile carrier with unique properties and processability. With this natural mineral excipient, fast disintegrating tablets, granules, floating and mucoadhesive drug delivery systems as well as microencapsulated products can be developed. ODTs manufactured with FCC do not require cost-intensive production equipment because they can be produced by direct compression of dry granulated FCC with the active of choice. The high mechanical strength of ODTs formulated with FCC enables the use of regular bottles and blisters as packaging, which significantly reduces the overall cost of production compared to other ODT technologies. FCC offers multiple functionalities with very simple chemistry and a straightforward granule and tablet manufacturing process. Additionally, it is possible to tailor the characteristics of FCC, such as specific surface area, particle and pore size distribution, according to the requirements of various applications. Furthermore, unlike many similar materials, FCC has the advantage of being highly biocompatible. Its composition is basically that of bone material: hydroxyapatite and calcium carbonate. Also, from a regulatory point of view, FCC has advantages: it is a co-processed excipient composed of only two monographed minerals. Bearing all of these advantages in mind, FCC is a very promising excipient for dry oral dosage forms. It will be interesting to see what kind of formulations this mineral will make possible in the near future. Summer 2018 Volume 10 Issue 2


Manufacturing REFERENCES 1.

2. 3.

4.

5.

6.

7.

8.

9.

Elder D.P. et al.: Pharmaceutical excipients – regulatory and biopharmaceutical considerations. Eur. J. Pharm. Sci., 87, 88-89. 2016. Levin. Pharmaceutical Process ScaleUp (2001), CRC Press. Stirnimann T. et al.: Compaction of functionalized calcium carbonate, a porous and crystalline microparticulate material with a lamellar surface. Int J Pharm. 2014; 466 (1-2): 266-75. Stirnimann T. et al.: Functionalized calcium carbonate as a novel pharmaceutical excipient for the preparation of orally dispersible tablets. Pharm Res 2013; 30 (7): 1915-25. Sreenivas S.A.: Orodispersible tablets: new-fangled drug delivery system a review. Indian J Pharm Educ Res. 2005;39(4):177–81. Kumar V.D. et al.: A comprehensive review on fast dissolving tablet technology. J App Pharm Sci. 2011; 1(5):50–8. Wagner-Hattler L. et al.: In vitro characterization and mouthfeel study of functionalized calcium carbonate in orally disintegrating tablets. Int J Pharm. 2017 Dec 20;534(1-2):50-59. Preisig D. et al.: Drug loading into porous calcium carbonate microparticles by solvent evaporation. Eur J Pharm Biopharm. 2014; 87: 548-58. Roth R. et al.: Functionalized calcium carbonate microparticles for the delivery of proteins. Eur J Pharm Biopharm. 2018 Jan;122:96-103.

Dr Carolina Diaz Quijano Dr Carolina Diaz Quijano joined Omya in 2013. She has worked as Senior Scientist for Mineral Surface Chemistry, as Manager for Technical Services and Innovation as well as Manager Innovation and Technical Marketing for pharma and nutraceutical applications. Currently, she holds the position of Head of Technical Services Consumer Goods. Previously, Dr Diaz Quijano has worked as a research collaborator in protein engineering at the University of Zurich and in diagnostics and genetic profiles at the start-up Stab Vida in Portugal. She earned a PhD in Life Sciences from ETH Zurich. Email: info.pharma@omya.com

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Manufacturing

What Pharma Producers Need to Know About Changing Regulations on Cleanroom Films and Anti-static Additives As current anti-stat additives face new regulatory hurdles, Clariant introduces a new alternative

With new USP <661.1> regulations on plastic packaging materials for pharmaceuticals set to take effect in May 2020, and following this, USP <665> (formerly known as USP <661.3>) for plastics used in the drug manufacturing process bringing new requirements, it is decision time for processors and pharmaceutical users of anti-static polyethylene and polypropylene films. So-called ‘cleanroom films’ are often used in pharmaceutical manufacturing processes to transfer API and other ingredients, and in many cases need to be capable of dissipating dangerous static charges. In addition, with several “food-grade” anti-static additives, including industry-standard amide- and amine-based agents, separately facing major hurdles and possible phase-out, the hunt is on for alternatives.

Three of the most widely used “migrating” anti-static additive systems – glycerol monostearate (GMS), GMS mixed with ethoxylated amines (2:1 ratio), or lauryl ethoxylated amides – face an uphill struggle to meet limitations in existing food contact regulations, as well as in the new USP <665> regulation. A fourth “permanent” anti-static additive, polyether block amide (PEBA) will remain available, but the films made with it can cost up to six times more than those using migrating amide-/ amine-based products. Along with these requirements, pharmaceutical companies also need to consider ICH Q3D guidelines resulting in more rigorous risk assessment of contaminants in drug products. Just as it said in USP <661.1> for final drug packaging, the USP is stating that risk assessments based on so-called ‘food-contact materials’ are NOT in themselves sufficient. With the new regulations potentially set to take hold in two years from now, and several additives already being

Photo 1. Cleanroom bag manufactured at STRUBL GmbH & Co. KG, Wendelstein, Germany 94 INTERNATIONAL PHARMACEUTICAL INDUSTRY

phased out, processors and users of anti-static cleanroom films face important near-term decisions: •

When should they phase out the use of anti-static films that contain additives that cannot comply with the new regulation or that could face market withdrawal? Should they produce and use films with higher-cost anti-static additives like PEBA or seek out new anti-static alternatives, such as the new anti-static additive concentrate, MEVOPUR® PEAM 176045, which was introduced at October’s CPhI Worldwide conference by Clariant Masterbatches (see sidebar)?

The implications of these decisions involve much more than the cost of switching additives and preserving process and plant safety. Because these films are so widely used and in contact with so many ingredients in the pharmaceutical manufacturing process, using films that do not address these new regulations risks warning letters and enforced changes. Where and How Anti-static Additives Work Anti-static films line containers, dispensers, and tubes used to store and transfer active pharmaceutical ingredients (APIs) in liquid and solid form during drug production. Plastics are naturally insulators (measured by surface resistivity ~1015 ohms/ square) and prone to build-up of static charges. Anti-static additives are incorporated into polyethylene ‘cleanroom films,’ where, through different mechanisms, they decrease the surface resistivity to 1010 ohms/ square, enabling the film to dissipate static electrical charges. That’s important because the static electricity that accumulates with material movement would otherwise introduce the risk that a stray spark could ignite a potentially deadly explosion. Summer 2018 Volume 10 Issue 2


Manufacturing higher conductivity throughout the polymer matrix, so their anti-static properties activate i m m e d i at e ly a n d re m a i n consistent. However, they must be used at relatively high concentrations, and many are relatively more expensive. This makes them about four to six times more costly than migrating type anti-stats. The required high concentrations of these additives can also make film processing more difficult. These anti-statics include polyether block amide (PEBA), used at a concentration of 15 to 20 per cent, and ionomers, at a 20-25 per cent loading.

Figure 1: Regulations governing the use of plastics in pharmaceutical manufacturing have come into sharper focus as the proposed USP <661.3> was expanded in scope and changed to USP <665>, “Plastic Systems Used for Manufacturing Pharmaceutical Products.” Note that USP standards with numbers <1000 are compulsory, while those with numbers >1000 are guidelines.

Generally, there are two basic types of anti-static additive technology, as seen in Figure 2: •

“Migrating” type anti-static agents continuously move, or migrate, toward the surface of a plastic film. Their molecules combine a hydrophilic “head” that attracts water vapour (and therefore, dissipates static electricity) with a hydrophobic “tail” that bonds with the underlying polymer matrix. Their effectiveness is related to their surface concentration which, due to migration, can take at least a week after processing to fully activate on the film surface. They can be temporary, because the

anti-static molecules eventually migrate out of the film or get washed away. In addition, their functionality is dependent on the level of humidity in the environment, and below 25% humidity some additives fully lose their properties. Most of the leading anti-static additives are “migrating” ethoxylated amine-/ amide-based compounds. These are used at relatively low concentrations, typically less than 1 per cent loading. •

“Permanent” type anti-static agents do not require any migration. They are based on an inter-penetrating network of fibrils of substances with

Figure 2: Migrating and non-migrating anti-static agents. “Migrating” anti-static agents (left), consisting of a hydrophilic head and a hydrophobic tail, continuously move toward the surface of polyethylene films, where the heads capture humidity from surrounding air and dissipate potentially explosive static electrical charges. They require one to four weeks after processing to achieve high levels of anti-static performance. “Permanent” anti-static agents (right), bond throughout the polymer matrix to provide instant and lasting anti-static protection. www.ipimediaworld.com

Because of their tremendous cost advantage and, in the past, their food-contact regulatory status, migrating-type anti-static additives – amide – and amine-based compounds and combinations – are by far the most widely used in pharmaceutical/ cleanroom films. So, Why the Problem with Current Anti-Statics? USP <665>, “Polymeric Components and Systems Used to Manufacture Pharmaceutical and Biopharmaceutical Drug Products” was issued as a draft in May 2016 and has a target date for publication in August 2018. It will, for the first time, mandate compliance with more stringent requirements for the characterisation, selection, and safety of plastics and plastic-containing components used in all phases of pharmaceutical manufacturing. The announcement of USP <665> is no surprise, since USP <661.1> mandates similar compliance for plastics used in pharmaceutical containers. (Note that USP <661.1> requirements were originally planned to take effect in May 2017, but received a compromise exemption until May 2020.) However, USP <665> is causing heartburn to anti-static film processors and pharmaceutical manufacturers because: •

It supersedes prior regulations for pharmaceutical manufacturing that have allowed the use of plastic materials containing INTERNATIONAL PHARMACEUTICAL INDUSTRY 95


Manufacturing

Alternatives? With film producers and users on the hunt for alternative anti-static solutions, some new ‘next generation ‘amine-/amide-free’ concentrates have recently become available that address the future regulatory concerns of current systems and with a reasonable cost/performance. They can be used at relatively low concentration levels (0.15-0.2% loading) and perform even at very low relative humidity levels – 10-15 per cent RH – that are common to pharmaceutical cleanroom environments. And, compared to other alternatives, including ‘permanent’ or non-migrating additives such as PEBA, they can be effectively used at a far lower cost.

Photo 2. Cleanroom film manufactured at STRUBL GmbH & Co. KG, Wendelstein, Germany

System

Performance Typical ppm in film (loading)

Static dissipation1 at 50% RH

Static dissipation1 at 25% RH

GMS/ethyoxylated amine 2:1 blend

1000–2500 (0.1–0.25%)

Good

Poor

Di-ethanol amides

1500–2500 (0.1–0.25%)

Good

Good

PEBA

(18-19%)

Good

Good

Next generation concentrate

1500–2000 (0.15–0.2%)

Good – 1e10 @ 3 wks. – 1e9 @ 5 wks.

Good – 1e10 @ 15% RH

1 Typical performance. Note that migrating systems require one to four weeks after manufacture to reach optimum anti-static performance.

Figure 3: Performance comparisons for four anti-static systems

“food-grade” anti-static additives, including low- and moderatecost additives like GMS, GMS mixed with ethoxylated amines (2:1 ratio), and lauryl ethoxylated amides. •

It significantly ups the ante, requiring all drug-contact plastics/ System

additives used in pharmaceutical manufacturing to have detailed characterisation and risk assessment. This means that all must have been evaluated to USP <661.1>, USP <87> (‘cytotoxity’) and, where applicable, USP <88> requirements based on extraction tests and biological evaluation Regulatory

EU 10/2011 Food Regulation

US FDA Food Regulation, 21 CFR-

USP <661.1>, <87>, <88>

GMS/ethyoxylated amine 2:1 blend

SML max 1.2 ppm (0.01 %)

178.3130 – Contains max PE 1000 ppm (<0.1%)

No

Di-ethanol amides

SML 5 ppm (0.05%)

178.3130 – Contains max PE 5000 ppm (0.5%), PP 2000 ppm

No

PEBA

SML may apply

177.2600 – Limited depending on co-monomer

Yes, available from some film suppliers

Next generation concentrate

No limits

No limits

Yes3

2 USP <87>, <88> biocompatibility evaluation is one requirement of USP <661.1> and USP <665> draft requirements. Drug-type dependent. 3 Declarations available as standard: USP <87>, <88>, USP <661.1>, ICH-Q3D extractable metals, European Pharmacopeia (EP) 3.1; ISO10993. Drug Master File available dates.

Figure 4: Regulatory status of four anti-static systems 96 INTERNATIONAL PHARMACEUTICAL INDUSTRY

These new products have been designed specifically for the needs of pharmaceutical applications by using ingredients that are extensively tested and supported by regulatory declarations based on evaluation of raw materials per the pending USP <661.1>, ICH-Q3D extractable metals, USP <87>, <88> (biological evaluations), European Pharmacopeia monograph 3.1 for polyolefins, as well as the ISO10993 typically used for evaluation of medical devices (see Figure 4). In addition, standard chemical substance requirements, such as REACh, RoHS, and ‘non-animal derived substances’ are supported. Besides regulatory issues, there are challenges confronting healthcarerelated industries and the approach to managing risk of changes. In order to do this, the industry is looking for suppliers that manufacture these concentrates using processes that are managed under ‘GMP’ quality systems, such as ISO13485, and that have established change-control protocols. The next-generation amine-/amide-free antistats, together with these additional processes and safeguards, assure film processors of additives help ensure compliance – now and into the future – and protect the value of their in-process APIs and finished drug products.

(often described as ‘USP Class VI’), as well as ICHQ3D risk assessments for any elemental impurities, such as extractable metals. Unlike USP <661.1>, which only looks for extractable metals ‘expected’ from the polymer Summer 2018 Volume 10 Issue 2


Manufacturing manufacturing process, ICH-Q3D looks for all ‘metals of concern’ listed in USP <232>. These metals could arrive as contaminants from, for example, processing equipment or even from pigments or additives used in the plastics. •

It reduces the relative humidity levels at which anti-static performance testing is conducted.

Instead of the previous test standard – 50 per cent RH – testing is now required at <25 per cent RH, a level more in keeping with the cleanroom environments typical of pharmaceutical manufacturing. However, at that RH level, films using the current industry standard anti-static agent – a 2:1 mix of GMS and ethoxylated amine – fail to perform.

Photo 3. Cleanroom film being extruded at STRUBL GmbH & Co. KG, Wendelstein, Germany

System

Relative cost

GMS/ethyoxylated amine 2: 1 blend

Industry standard

Di-ethanol amides

Moderate

PEBA

High

Next-generation concentrate

Moderate

Figure 5: Relative costs of four anti-static systems

Robust risk assessments are unlikely to ignore existing migration limits for anti-static substances from EU and US regulations. Regulations from 2010 and 2011 place “specific migration limits” (SMLs) for “processbased impurities”, which include any substances that migrate unintentionally from plastic materials into foods, APIs or drug products. To remain below these SMLs, the loading rates for migrating anti-static agents would have to be cut dramatically from effective levels. For example, as shown in Figure 3, a GMS/ ethoxylated amine 2:1 blend is typically present at levels of 1000-2500 ppm in anti-static film. However, the SML allowed under existing EU regulation is just 1.2 ppm, a fraction of the amount required for effective performance.

Steve Duckworth Steve Duckworth is Head of Global Segment Healthcare Polymer Solutions, Clariant. He joined Clariant in 2007 and was instrumental in launching the MEVOPUR® line of “Controlled, Consistent and Compliant” colour and additive masterbatch concentrates and polymer compounds used in the medical and pharmaceutical sectors. His global team works with manufacturers and their suppliers to minimise and manage risk while responding quickly to changing regulations. He is vice-chairman and executive board member of the cross-industry group MedPharmPlast Europe, and member of its regulatory affairs committee. Photo 4. Cleanroom bag production at STRUBL GmbH & Co. KG, Wendelstein, Germany. www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 97


Manufacturing Data Integrity and Preservation in Pharmaceutical Manufacturing: Technology’s Role in Safeguarding Compliance Throughout a Drug’s Entire Life Cycle The life sciences’ relationship with technology has come a long way since Deloitte’s 2015 global life sciences outlook, describing it as ‘operating in an era of significant transformation.’ Since the report was published, most in the industry have re-evaluated traditional methods of operations, put to bed (or at least put a plan in place to deal with) ineffective, costly, and disjointed systems and practices, and are embracing the positive change innovative technology can bring. The market is full of technologybased solutions that promise to deliver a compelling return on investment. From scheduling systems that work with real-time data to accurately forecast drug demand and identify potential gaps in supply, to automated production lines and temperature management devices that drive efficiency and promote safer and more profitable operations. In 2018, whatever process-based headache you’re experiencing, chances are there’s an ‘app for that’. Equally, the way we now access this technology is changing. The advent, and gradual acceptance, of the cloud is also transforming how we work. It is making sophisticated software more accessible – both financially (with monthly software-as-a-service subscriptions replacing the need for substantial upfront investment) and in terms of the ability to securely access these systems remotely. However, a common thread that weaves all of this technology together is that without data (without good, trustworthy data) the technology is rendered redundant. Without full confidence in the integrity of data, the whole point of the exercise (make drugs, help patients, be a trusted organisation, make profit) is compromised. Pharmaceutical manufacturing organisations face a set of specific 98 INTERNATIONAL PHARMACEUTICAL INDUSTRY

challenges relating to the documents and data they produce and store. And as more data is generated each day, as businesses consider replacement of legacy systems in favour of these more advanced alternatives, and as commercial factors dictate a need to migrate data from one system to another – or hold historical data for compliance purposes on an acquired system – the need to manage this process and safeguard compliance throughout a drug’s entire life cycle, and beyond, becomes a pressing one. But how should manufacturers best approach this task? What are the pitfalls to be wary of? How can technology help achieve best practices around data integrity? And, how can legacy data be preserved long into the future so that compliance is championed at every stage of a drug’s life cycle? Getting Compliant, Staying Compliant Before exploring the role data preservation can play in removing risk, it’s important to understand why data matters in the first place. The reason we should invest so heavily in protecting the integrity of the data is that this underpins each and every pharmaceutical manufacturing operation. Data integrity refers to maintaining the accuracy and consistency of data over its entire life cycle – from creation to deletion to preservation and everything in between. It is the bedrock of GLP, GCP and GMP; and is viewed by the FDA, as well as all other regulators, as ‘an important component of the industry ’s responsibility to ensure the safety, efficacy, and quality of drugs, and of the FDA’s ability to protect the public health.’1 Technology is simplifying the process of collecting, monitoring and analysing data; and making it quicker and easier for quality professionals to demonstrate compliance. Indeed, regulators recommend that ‘firms

should implement meaningful and effective strategies to manage their data integrity risks based upon their process understanding and knowledge management of technologies and business models’2. Knowing what data integrity best practice looks like is relatively straightforward. And, there are plenty of innovative applications, such as electronic quality management software (EQMS) available on the market to support it once systems and processes are established. The challenge is in the transition, the identification of current risks, understanding the data held within multiple disjointed systems, and migrating this information to more robust repositories. Manufacturing Data Challenges There are numerous data-related challenges that face life science manufacturers. Many of these challenges relate to managing the correct ownership of records with the current licence holder. Several common scenarios can present themselves here, such as a change of ownership because of merger and acquisition activity, the individual sale of a drug licence or facility, the closure or consolidation of facilities, or moving manufacturing operations to different parts of the manufacturing supply chain. All of these scenarios demand appropriate, and compliant, data archiving. They also demand that manufactures effectively identify and migrate relevant drug data from their own systems to the new owners of the licence or facility. It’s also worth considering that multiple organisations may need to access historical records and deal with regulatory, quality, and knowledge transfer demands to make processes such as the preparation of product quality review reports as efficient and effective as possible. Summer 2018 Volume 10 Issue 2


Manufacturing Moving data from one site to another will quite often mean that it is being moved to an environment where the standard quality management system is different. The receiving party, themselves, will then face challenges relating to the legacy system’s validation status. A further risk to data integrity for manufacturers, and the life science sector in general, results from the abundance of new technologybased solutions now on offer. The pace of technological advancement means older legacy systems are unsuccessfully competing with more modern, advanced, intuitive and affordable alternatives. These older systems are quickly becoming obsolete and unsupported by vendors; meanwhile, document formats are becoming incompatible with newer versions of software. All of these factors risk the integrity of digital information becoming compromised (readability and traceability required for regulatory demands) or lost entirely. This poses a problem for the data housed within the legacy software. According to a leading IT analyst firm, legal and regulatory requirements relating to document preservation often prevent retirement of legacy systems. This, in turn, can result in up to 80 per cent of IT budgets being spent on multiple archaic systems that add no additional value to the business. The knock-on effect of this is that life science manufacturers become hostages to their data. It becomes a headache to manage, rather than a resource to exploit. The need to retain and maintain data sets varies in scale and timeframe from business to business. Whereas clinical data needs to be kept during the entire time a drug is in circulation, manufacturing batch data need only be kept for the shelf life plus one or two additional years. Given these varying demands, where different sections of the same organisations may have changing requirements, flexible and robust archiving solutions are invaluable to meeting those needs and keeping the whole business compliant. www.ipimediaworld.com

One specific area of archiving functionality that can prove incredibly beneficial is the automatic destruction of data in a controlled and recordable manner. There are very few businesses willing, or even able, to store information for longer than they must. So, the ability to rely on a system which will only maintain the data it absolutely has to, can provide both peace of mind and significant cost savings for an organisation. Migrating Data with Cost and Compliance in Mind The solution to this is to retire unsupported legacy systems and migrate the data contained within them to a robust, singular and centralised, long-term electronic data preservation system. Utilising a manageable, system-agnostic and hosted solution to automate aspects of the data migration process, will facilitate quick, efficient, and precise data transfers. Retrieving documents from a series of systems and formats, collating, recording and migrating them into a centralised archiving system is not only achievable, but essential. With experts estimating that by 2020, 50 per cent of all current applications in the data centre will be retired, it’s clear to identify the wider trend and acknowledge the need to take action. Realising you need to take action is one thing. Knowing what precise action to take is another. A good place to start is by adopting an industry standard method such as OAIS, PAIMAS or ISO. These will give a route to proven conversion paths and accepted terminology. It is essential to ensure any storage system can then store both the native object and preservation object along with any associated metadata. The onus is on life science businesses to embrace a best practice approach to future-proofed, compliant, efficient and cost-effective document preservation. Overcoming the perceived barriers of retiring legacy systems and migrating data can be supported by tools that automate parts of the process. By doing so, migration activity can be sped up, validation activity reduced,

and potential areas of risk surrounding human error can be avoided. Systems that are able to preserve data in formats that are widely used today (CSV, TXT, PDF/A, TIFF), while also harnessing the metadata, stored as XML, so the original relationship between documents and the context in which they were created is preserved, will also add significant value and support both reduced compliance risk and IT overheads. Embracing Technology Today to Preserve Data for Tomorrow Implementing a data preservation system will provide manufacturers with enhanced confidence over the current and continued integrity of data. It will demonstrate compliance by facilitating improved access controls and audit history for digital records, as well as for all data that has been migrated in from multiple systems. This in turn will remove the challenges that legacy systems present relating to security and access controls failing to meet current requirements of CFR21 Part 11/Annex 11. It will also remove the cost and complexity of maintaining legacy systems, as there will be no further need to retain expertise or resource to maintain, run and manage information requests from the legacy system. A preservation system will also remove the need for hybrid systems, where master records are partially retained as paper documents. Once preservation systems are in place, they can be used to run periodic audits in an incredibly efficient manner. These audits can verify whether or not files have been altered since ingestion. If a file has been altered, these systems will quickly identify the ‘needle in the haystack’ and flag the issue. This can then be investigated to determine: if there was a legitimate reason for the file change and that it has been appropriately recorded; if the information relating to the reason for change is not fully defined; if the original file has been corrupted; or if there has been deliberate or accidental alteration to data. With this information available instantly, manufacturers are empowered to INTERNATIONAL PHARMACEUTICAL INDUSTRY 99


Manufacturing take appropriate and immediate action to safeguard data integrity and compliance. With an abundance of technology on offer, preservation systems represent a single way of maintaining controlled

records and data, and making that control simpler to manage, explain, and demonstrate both to internal teams and auditors. They also provide a simple platform to allow for bulk migration of additional records into the archive. These systems can also be

used to demonstrate business-critical risk reduction. For example, enabling the use of failover redundancy â&#x20AC;&#x201C; also known as mirrored backup â&#x20AC;&#x201C; between hosted environments that protects the data and guarantees availability. Understanding the role technology can play in managing records appropriately and preserving documents and data in secure, future-proofed repositories (while maintaining the integrity of data to bolster quality functions) should be considered a business-critical task. Not only does this technology provide a mechanism for more streamlined workflows and reduced IT spend, it provides regulated companies with a single way of controlling all electronic data, using a platform and model that meets the best practice associated with data integrity around the world. As manufacturing protocols become more complex and regulatory requirements show no signs of abating, the pressure is on to sit up, take note and act. REFERENCES 1. http://www.fda.gov/downloads/drugs/ guidancecomplianceregulatory information/guidances/ucm495891.pdf 2. http://www.fda.gov/downloads/drugs/ guidancecomplianceregulatory information/guidances/ucm495891.pdf

Mark Stevens Mark is the Managing Director and a founding member of the Life Science Division of Formpipe, which provides compliance software solutions and consulting services to the GxP regulated industries. He has a track record of successfully delivering business-critical GxP compliance consulting projects within the highly-regulated life science industry, covering areas such as vaccine manufacture, new product introduction, use of mobile devices and cloud computing technology. Email: info.ls@formpipe.com

100 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2018 Volume 10 Issue 2


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 101


Packaging

The Falsified Medicines Directive – Are You Ready? The Falsified Medicines Directive 2011/62/EU, which is due for adoption in February 2019, will require pharmaceutical companies to apply serialisation codes to every applicable pack (OTC and some minor exemptions). As a consequence, artwork changes will be required, which all too often are treated as a rushed after-thought.

The World Health Organisation estimates that around 50% of product recalls are still attributed to artwork errors and mislabelling. The industry’s ‘speed to market’ requirements have put more pressure on artwork teams across all aspects of the supply chain to deliver ‘right first time’ and ‘on-time’ for critical product launches. However, it is essential that all brand-owners consider the required changes in good time. Pharmaceutical artwork is a specialist market and artwork creation is often complex, so selecting an experienced partner can prevent damaging hard-earned reputations or even product recall. The impending legislation will affect all prescription medicines for the European market. The first step to comply with this legislation is to get your artwork amended and approved.

102 INTERNATIONAL PHARMACEUTICAL INDUSTRY

What Will Change? The legislation requires a ‘unique identifier’ to be placed on product/ packaging so it offers full traceability throughout the supply chain. This takes the form of a data matrix code, a randomly generated serial number as well as a national reimbursement number, if present, and batch and expiry dates. It can’t be too hard to add these extra codes to an existing pack – can it? The addition of a new code is relatively simple but creating the required space and its impact on the pack’s overall design is often more involved than imagined. As well as an area for the code, it will also require a surrounding ‘Quiet Zone’ that further reduces the availability of free space. In the past, this panel on the pack only needed to incorporate a batch code and expiry stamp so the additional code may force text to move onto another panel. As the pack’s graphics are reformatted it is essential that compliance with other existing legislation is not overlooked. The inclusion of the proprietary name, generic name and dosage to appear on three opposing faces also needs to be taken into consideration.

The Falsified Medicines Directive also requires a brand-owner to add a tamper-evident feature to their packaging, which can have a significant impact on a pack’s real-estate. Tamper-evident labels require varnish and text-free space, so this adds further pressure on already busy pack designs. If the brand-owner decides not to use a tamper-evident label, a mechanical or constructional solution is another option. However in order to achieve this, particularly if the brand-owner is already using a standard reverse tuck-end carton, it may force a move to another carton format, such as a skillet-glued, to further increase available space. It’s Here to Stay Whatever anyone thinks, Brexit won’t stop the UK implementation of the Falsified Medicines Directive, as it was passed into UK law in 2013. Furthermore, the UK Government is being urged to comply with EU legislation to ensure harmonisation and avoid disruptive supply chain issues across Europe. However, for UK companies, the EMA’s relocation to mainland Europe could have a potential impact, leading to another

Summer 2018 Volume 10 Issue 2


Packaging be sure it is delivering exactly what’s required. Selecting the Right Artwork Partner Pharmaceutical artwork is a specialist market and any supplier’s workflow should be compliant with PS9000 / ISO9001, audited and dedicated to providing an artwork service. A supplier’s artwork systems should fit in with your own ways of working and they should have enough capacity to deal with these changes, in addition to regular artwork lifecycle tasks. There should also be a clear understanding that the approved artwork file should not require any further manipulation by the print vendor, so there are no touch-points in the process. The use of an automated workflow will significantly reduce the potential of any errors. Non-compliance will put both supply and sales at risk. Remember, the clock is ticking…February 2019 isn’t that far away.

Gill Wright tranche of artwork changes for centrally registered products. The outcome is still unfolding and not yet clear, although it is likely to mean a change of MA holder address for centrally-licensed products. A Changing Supply Landscape It was previously commonplace for un-audited ‘local’ suppliers to produce market-specific artwork, with no asset control of artwork files and even less control if the process was global. The associated risks for error and for non-compliance were high in this scenario. A typical ‘big pharma’ organisation, even today, would have multiple vendors, some compliant and some not. The market is seeing a significant shift to control artwork lifecycle changes and new product launches via a truly complaint artwork partner. Why Do Things Still Go Wrong? In order to comply with the new www.ipimediaworld.com

directive, it is essential to allow adequate time for potentially significant artwork changes. The pressure to get compliant products quickly into the marketplace can impact on the quality of the artwork brief. This inevitably results in more artwork cycles due to errors and omissions, whilst further extending lead-times and escalating costs. The issues can be numerous and largely stem from a lack of understanding of what’s required. In order to develop the right artwork briefs, it’s essential to build a partnership that is set up for success, with both parties working to get the best output. Leading artwork providers will be dealing with many different customers, with thousands of artwork requests, all with differing needs and requirements. All customers are different and an agency will need to

Design & Development Director, Cirrus is based at Leicester, UK. Gill has responsibility for artwork management services and structural design. Gill has responsibility to ensure Cirrus’s various studios offer a full consultancy service covering constructional & graphic design, print and artwork management. Gill has 20 years’ experience in artwork management for pharmaceutical and healthcare industries with roles covering pre-press, artwork and structural design. A graphic design graduate by training, Gill had an early career in the design industry. Gill’s experience covers all paperboard packaging formats including cartons, labels, and leaflets and her role involves a close working relationship with customers. Gill regularly presents to the world’s leading healthcare companies and has an in-depth knowledge of the changing packaging requirements of this highly regulated sector.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 103


Packaging

Prefillable Vials for Dual Sourcing

Trends toward sophisticated, innovative medications and increasingly individualised medicine are increasing the quality demands on the primary packaging being used and are also creating a new division of labour between the pharmaceutical industry and packaging manufacturers. Qualityoptimised ready-to-fill products enable the pharmaceutical industry to focus on its core areas of expertise and free up capacity by eliminating the washing and sterilisation of packaging. This reduces the time to market and total cost of ownership considerably. After having utilised this tried-and-tested principle with syringes for 15 years, some are now expanding it to the field of injection bottle products as well. Standardisation is enabling dual sourcing of vials from two different manufacturers and the alternative filling of vials, syringes and cartridges with an absolute minimum of conversion work required for filling systems.

New Division of Labour Between the Pharmaceutical and Packaging Industries For years, the pharmaceutical market in industrialised countries has been characterised by two fundamental trends. On the one hand, growth is being driven primarily by innovative, often biotechnologically produced medications. These medications are highly effective and are opening up new treatment options for illnesses, which were previously essentially untreatable. At the same time, they are often extremely sensitive and costly as well. On the other hand, there is a clear trend toward increasingly specific treatments. Medications are being tailored for smaller and smaller groups of patients and, in extreme cases, even for a single patient. Both trends have significant effects on manufacturers of pharmaceutical primary packaging. In cost-sensitive healthcare systems, high prices and the individualisation of treatments are driving the self-administration of medication by patients and thus the prevalence of drug delivery systems. At the same time, the line between 104 INTERNATIONAL PHARMACEUTICAL INDUSTRY

primary packaging and the device is becoming blurred. The prefillable syringe, for example, which is enabling more cost-effective and precise handling of costly medications ever more frequently, is both of them at the same time. The highest quality standards are expected of both the packaging and the device here, whether itâ&#x20AC;&#x2122;s the flawlessness of products or the minimising of any interaction between the primary packaging and a sensitive agent. The pharmaceutical industry, on the other hand, has to say goodbye to the large-batch products of the past and prepare for small batches with correspondingly frequent conversions of the filling systems. The number of development projects running at the same time is growing, as is the pressure to meet deadlines and succeed in each individual project. Against this backdrop, the division of labour between the pharmaceutical industry and packaging manufacturers is changing. The pharmaceutical industry is focusing on its core area of business and leaving everything relating to the development, production and filling of agents to the packaging manufacturers. Medications and packaging are being developed in parallel through cooperation by both sides to the greatest degree possible to minimise the time to market and total cost of ownership and optimise use of the short patent protection phase. This requires flexible solutions, which can also be used to bring small product batches to the market in an economical way. Vials for Sophisticated Agents In the case of primary packaging for challenging medications in vials, high quality requirements are placed on the products being used. These quality requirements have since become orders of magnitude lower than the usual accepted quality limits (AQL). This initially concerns the smallest possible dimensional tolerances and the lowest possible number of cosmetic defects. The entire range of mechanical damage, from continuous cracks to surface

scratches, as well as contamination by particles in the sub-visual range (which largely arise during the production process itself) must then be ruled out. Decisive for achieving this level of quality for the most forward-thinking is a process chain where all moulding and transport steps are consistently designed to ensure material protection. Differences in temperature between glass and handling elements are kept as small as possible, glass-to-glass contact is avoided altogether, and glass-to-metal contact is reduced as much as possible. This is why polyether ether ketone (PEEK) materials are preferred for vial pick & place and transport. One hundred per cent inline monitoring using proprietary camera systems ensures that any defects, which do arise, are reliably dentified. In the past, the primary packaging of solutions with especially high or low pH values occasionally exhibited delamination phenomena in the vials used. This phenomenon, which involves the detachment of glass particles primarily in the lower section of the vials, thus contaminating the solution, has since been well understood and brought under control. It is initiated by vapourising glass during the demanding bottom-forming process, which condenses above the bottom and forms a layer susceptible to delamination. This phenomenon can be avoided thanks to camera-based inline monitoring of the temperature control. The tendency of produced vials to experience delamination is also reliably determined using a proprietary test procedure. This means that the pharmaceutical industry can be provided with products developed to meet the challenges in primary packaging of innovative medications in every way. Gx RTFÂŽ â&#x20AC;&#x201C; Sterile Primary Packaging for Direct Filling For a syringe as primary packaging, product concepts have now been developed which provide the pharmaceutical industry with sterile products, Summer 2018 Volume 10 Issue 2


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 105


Packaging

The packaging manufacturer handles all preparatory work

which can be fed into filling systems without any further preparatory work. Manufacturing and packaging processes optimised for flawlessness and the reduction of time to market and total cost of ownership are meeting the requirements of a new and different pharmaceutical market. This is why ready-to-fill (RTF®) syringes have quickly become established on the market and now make up the majority of sales in the syringe field. This concept, which has been tried and tested for 15 years, is now being expanded to the vial field. These vials are manufactured with the same level of quality already established for the syringe field, washed with water for injection (WFI) and dried with sterile air to remove sub-visible particles and depyrogenate the vials. The vials are

The entire process is carried out in cleanrooms of class C and B according to cGMP. Sterility testing is carried out and a certificate of conformance (CoC) issued for each batch. The vials can then be filled directly by the customer after being unpacked. With corresponding filling systems, the vials can also stay in the nests or trays for filling to avoid defect-causing glass-toglass contact over the entire process chain up to the filled and sealed end product. This means that the customer no longer needs to reserve capacity for washing, sterilisation and packing. This not only reduces the amount of time required, but also the necessary cleanroom space and the expenditure for validating the preparation processes and thus the total cost of ownership.

The vials are delivered to the customer sterilised in nests/tubs or trays

then inserted into nests/tubs or trays as desired. Both forms of packaging are sealed with two protective layers of Tyvek® to prevent contamination with particles. The sealed tubs are then packed in single or double bags (depending on the customer’s requirements) and sterilised with ethylene oxide according to ISO 11135.

106 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Ompi EZ-fill – A Platform for Flexibility and Dual Sourcing Gx RTF® vials can now be tailored to the Ompi EZ-fill® format. This platform creates a standardised interface for the packaging line, thus making it possible to process a large number of primary packaging types with minimal conversion required. The previous common method of filling bulk products forced the pharmaceutical industry to deal with a large number of packaging solutions during the development process and batch production. Filling for clinical tests occurs under different conditions than smallbatch production and subsequent large-batch production. Differing formats resulting from dual sourcing further increase complexity. This approach is only economical for the large-scale filling of a single medication into the same vial type. The conversion and validation costs for smaller and ®

more widely varied production, which are required more and more frequently, are disproportionately high, however. The loss of time before market readiness, which reduces the profitability of a new product considerably, must also be factored in. Using the established Ompi EZ-fill® format, the vial dimensions and packaging geometry remain the same over the entire development process through to batch production. Either 24, 48 or 120 vials are placed in nests, which are then put into tubs. Packing in trays of 96 or 228 vials is also possible, for example, whether it’s upright for filling in the tray itself or with the bottom up for removal and processing via traditional large-batch filling. It is primarily the switch from nests/tubs to trays with the identical packaging format, which simplifies the jump from small to large batches considerably. Another advantage is dual sourcing, where products from any manufacturer can be used to increase supply reliability for the end consumer. By packing vials in nests/tubs, they can be filled on the same line as syringes with minimal conversion required. Many filling system providers rely on the principle of multi-use lines here, which offer extraordinary flexibility when switching between different primary containers. Product Range and Availability Vials made of type I borosilicate glass fulfill all the requirements of the relevant ISO standards and pharmacopoeias (USP and Ph. Eur.). They can be manufactured in accordance with ISO standards or based on a customer’s own specifications, either with or without blowback, and thus tailored to a wide variety of different filling and closure systems. The vials are currently available in the 2R, 6R and 10R (4 – 13.5 ml) formats. Other formats will follow.

Maximilian Vogl Maximilian Vogl is Product Manager of Gx® Solutions at Gerresheimer Regensburg GmbH Email: m.vogl@gerresheimer.com

Summer 2018 Volume 10 Issue 2


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Exhibitions & Conferences

NORDIC LIFE SCIENCE PARTNERING AT ITS BEST Event name: NLSDays 2018 Nordic Life Science Days 2018 Tag line: Nordic life science partnering at its best • 2.5 days for meeting the best the Nordic region has to offer • 2.5 days for new partnering opportunities • 2.5 days for entering into new deals Location: Stockholm, Sweden Date: September 10-12, 2018 Venue: Stockholm Waterfront Conference Center Venue address: Nils Ericsons Plan 4, Stockholm – Sweden Venue website: http://www.stockholmwaterfront.com Event Website: http://www.nlsdays.com

Nordic Life Science Days – What’s in it for you? Nordic Life Science Days is the largest Nordic partnering conference for the global life science industry. Bringing together the best talents in life science, offering amazing networking and partnering opportunities, providing inputs and content on the most recent trends. Nordic Life Science Days attracts leading decision-makers from the life science sector, not only from biotech, pharma and medtech, but also from finance, research, policy and regulatory authorities. Based on cutting-edge and advanced partnering and networking tools, Nordic Life Science Days showcases the best the Nordic region has to offer. 108 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The Nordic Way of Doing Life Science Business NLSDays offers networking and knowledge for anyone interested in Nordic life science, biotechnologies, pharmaceuticals, medical devices and e-health business. We offer plenty of opportunities to connect. Meetings on Your Terms Every meeting is an opportunity. At NLSDays, we focus on meeting quality, not quantity. We provide ample time for you to meet your fellow delegates in a stress-free environment. The Nordic region is proud to host some of the world’s most innovative biotech, medtech and pharma companies. It also has the 12th strongest economy, making it the perfect place to invest. Set in the vibrant city of Stockholm, the conference offers conference super sessions, workshops, company presentations and innovation posters, exhibition, face-to-face meetings and unique receptions, providing many opportunities to network with peers, potential partners and investors. The 2018 conference design will feature a new exhibition layout, creating more interactions with the exhibitors, an enriched programme featuring nine super sessions, four topical workshops, academic and startup contests, innovative 6mn and 12mn company presentations bringing more value to the presenters and the audience, new partnering areas allowing more comfort and privacy, and extended informal networking opportunities. NLSDays 2018 will take place in Stockholm on September 10–12. Based on attendance at previous events, NLSDays 2018 expects 1000 to 1200 international delegates. Highlights 1300+ 40 3000+

from NLSDays 2017: Participants Countries Scheduled Meetings

Partnering at NLSDays is powered by partneringONE ®, the leading

conference solution for helping life science delegates meet efficiently and effectively. partneringONE® has the unique ability to manage the complex interactions among thousands of executives from many different companies. This sophisticated web-based partnering system enables delegates to screen potential partners, prearrange meetings and manage the entire conference partnering process. Delegates can log in and connect with the conference community, anytime, anywhere. NLSDays is a SwedenBIO event, produced by Bionordic Services AB. Contacts: General information, registrations, company presentations, exhibition and sponsorship: Olivier Duchamp, Director General, Nordic Life Science Days, CEO, Bionordic Services AB olivier.duchamp@bionordic.com Tel: + 33 (0) 608 804 515 Industry: Biotech, Pharma Academics, Research Medtech, E-Health, HealthTech CRO, CMO, Services IP, Law Firms Public, Non-Profit Investors Intended for: Executives from: • Established and emerging biotech, medtech and e-health companies • Mid-sized and large pharmaceutical companies • Institutional financial firms • Private investors including venture capital and private equity firms • Other industry-related services companies • Regulatory authorities, medical agencies • Academic research, tech transfer • Incubators, science parks • Regional and national development agencies, innovation agencies Please see website: http://www.nlsdays.com Summer 2018 Volume 10 Issue 2


PDA Europe Conference, Exhibition, Education

Pharmaceutical Freeze Drying Technology Freeze Drying of the Future

Register by 14 Oct 2018 and SAVE! pda.org/EU/FreezeDrying2018 www.ipimediaworld.com

27-28 November 2018 MELIĂ Hotel

Seville | Spain

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Pharmaceutical Powerhouse of the Future 28 – 30 August 2018 COEX • Seoul

Reg i for F ster REE

Organised by:

Register Now: http://gotocphi.com/IPI_Korea2018 110 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2018 Volume 10 Issue 2


Save EUR 200, Early Bird deadline is August 31 24TH ANNUAL INTERNATIONAL PARTNERING CONFERENCE

NOVEMBER 5–7, 2018 ‍ ‍ ‍ / /‍ ‍ ‍  ‍ COPENHAGEN, DENMARK

Photo by Martin Heiberg, Copenhagen Media Center.

This "must-attend" event is Europe's largest life science partnering conference. BIO-Europe's world-class workshops, panels and active exhibition along with thousands of prescheduled one-to-one meetings make this event an unrivaled forum for companies across the biotech value chain to meet and do business.

WHAT YOU CAN EXPECT:

4,000+ Attendees

150+

Company presentations

5,000+ Licensing Opportunities

24,000+ 2,000+ 100+ One-to-one meetings

Companies

Exhibitors

Find out more: ebdgroup.com/bioeurope Produced by

In collaboration with

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Advertisers Index Page 7 Abzena PLC Page 89 AirBridgeCargo Airlines LLC Page 105 ARaymond Page 111 Bio-Europe 2018 Page 23 Biopharma Group Page 15 Butterworth Laboratories IFC Capsugel Page 110 CPhI Korea 2018 Page 71 Datatrial Ltd Page 79 Dokasch Temperature Solutions GmbH Page 87 Ecocool GmbH Page 43 ExpreS2ion Biotechnologies ApS Page 62 & 63 Faubel & Co. Nachfolger GmbH IBC Gaplast GmbH Page 85 InMark LLC Page 13 MA micro automation GmbH Page 5 Mikron Automation Page 77 Multi Packaging Solutions Page 91 MĂźller GmbH Page 101 Natoli Engineering Company Inc. Page 39 Nemera Page 108 Nordic Life Science days 2018 Page 57 Novo Nordisk Pharmatech A/S Page 107 Owen Mumford Page 51 PCI Pharma Services Page 25 Philips Medisize Page 69 Quick International Courier Page 11 R.G.C.C. Group Page 21 Research Quality Association Page 3 Schott AG Page 59 Taconic Biosciences Inc Page 67 Terumo Page 81 Thermo Fisher Scientific Page 109 The Parenteral Drug Association Page 49 TLX Cargo BC Turkish Cargo Pages 27 & 83 Valsteam ADCA Engineering SA Page 33 West Pharmaceutical Services Inc. Page 29 White Horse Scientific Ltd Page 17 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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Summer 2018 Volume 10 Issue 2

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