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Volume 11 Issue 2

Peer Reviewed

Biologic Medicines and Patient-centricity A New Phase of Hope A Novel Valuation Model for Medical Intervention Development Overall Equipment Effectiveness A Crucial Component in Process Performance Improvement Digitalisation Quality & Efficiency in Pharmaceutical Distribution

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Contents 06 Editor’s Letter REGULATORY & MARKETPLACE

DIRECTORS: Martin Wright Mark A. Barker BUSINESS DEVELOPMENT: Thomas Kurse thomas@ipimedia.com EDITORIAL: Virginia Toteva virginia@pharmapubs.com DESIGN DIRECTOR: Jana Sukenikova www.fanahshapeless.com FINANCE DEPARTMENT: Martin Wright martin@ipimedia.com RESEARCH & CIRCULATION: Freya Gavaghan freya@pharmapubs.com COVER IMAGE: iStockphoto © PUBLISHED BY: Pharma Publications 50 D, City Business Centre London, SE16 2XB United Kingdom 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 2019. 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. 2019 PHARMA PUBLICATIONS / Volume 11 issue 2 – Summer – 2019

06 Emerging Trends in Regulatory Expectations The ultimate target in the pharmaceutical and medical device industries is to ensure patient safety within the entire product lifecycle, from R&D to distribution. The final user/patient trusts the medical products’ efficacy and simply relies on them. Gilda D’Incerti at PQE Group explains why a continuous commitment from manufacturing companies and from those involved in the product lifecycle is needed to continue gaining patient confidence. 10 Striving for Patient-centricity throughout the Entire Product Lifecycle This article by Susan Najjar from Sciformix, a Covance Company, discusses the complexity organisations face when developing a business strategy around “The Patient Journey” and how they are quickly adapting and implementing programmes that foster information-sharing and collaboration, while providing faster and greater access to life-changing products. 14 A No-deal Brexit may be Harmful for the Pharmaceutical Industry Dr Paul Peter Tak of GlaxoSmithKline describes the possible, disadvantageous consequences of a no-deal Brexit. 16 The Importance of a Patient-centric Approach in Healthcare and Clinical Research In recent years, the term “patient-centric” has become more commonplace in the world of clinical and medical research, indicating greater interest in putting the patient first. Rosamund Round at PAREXEL explores how we are optimising the opportunity to take a patient-centric approach to connect healthcare and clinical research, and how we can accelerate adoption. 20 Recent Regulatory Reforms and their Impact on Chinese Pharmaceuticals: A Regulatory Outlook In recent years, the term “patient-centric” has become more commonplace in the world of clinical and medical research, indicating greater interest in putting the patient first. Rosamund Round at PAREXEL explores how we are optimising the opportunity to take a patient-centric approach to connect healthcare and clinical research, and how we can accelerate adoption. 24 Turkey’s Pharmaceutical Industry and Key Developments In Turkey, the active population, retirees and their dependents are covered by health insurance provided by the Social Security Institution (SSI). The increase in the number of imported products and the lack of domestic manufacturing pushed the government to identify a new solution to enliven the local economy and enable a ‘know-how’ transfer. Özge Atılgan Karakulak, Dicle Doğan and Sevde Tan at Gün + Partners explain the regulatory changes in the country. 28 Digital Transformation and the Medical Device Sector Modern patients have an interest in and expectation of playing a part in their own health matters, enabled by new digital connections and advanced technology. In this emerging Medicine 2.0 era, as healthcare starts to harness this in earnest, the scope for personalised treatment becomes significant. ProductLife Group’s Loetitia Jabri asks where this is heading, and what challenges might crop up for medical device manufacturers.

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Contents DRUG DISCOVERY, DEVELOPMENT & DELIVERY 30 Beyond the Pill Personalisation by Integrating Oral Medication and Digitalisation Pharmaceutical innovation has accelerated, but the way of dosing oral medicines to patients has broadly stayed the same. Martin Olovsson at OnDosis discusses the advantages of oral medicine formulated as granules coupled with digital technology. 34 Biologic Medicines and Patient-centricity – A New Phase of Hope The global pharmaceutical industry has entered an exciting new era of drug development, bringing new hope to patients around the world. Justin Schroeder at PCI Pharma Services explains how the advances in biotech medicine have transformed therapy and should provide hope and optimism to us all. 38 The Correlations Between Viscosity, Needle Diameter, Flow Rate and Dose Accuracy in a Patch Pump Therapy Patch pump therapy is a convenient way of drug administration. The devices can be worn directly on the body as no tubing has to be attached and the cannula or needle can be inserted automatically. Michael Girschweiler at Sensile Medical discusses the dependencies of usage of smaller needles. CLINICAL AND MEDICAL RESEARCH 40 A Clever Combination: Calcium plus Vitamins One of the largest demographics in the bone and joint market is the aging population. Dr Carolina Diaz Quijano at Omya states that for this demographic, evolution and lifestyle trends such as dietary habits mean that a preventive strategy is key to mitigating the future healthcare burden. 42 Understanding the Challenges Experienced in the Investigator-initiated Study Supply Chain Investigator-initiated Studies (IIS) are an integral part of the investigational drug development process and are increasing gradually, year on year, on a global scale. Victoria Maguire of Almac discusses that to keep patients, their safety and experience at the heart of IIS trials, investigators need to define the IMP supply strategy at the earliest opportunity. 46 A Novel Valuation Model for Medical Intervention Development All stakeholders involved in the development, licensing and market access of healthcare technologies use a stage-specific valuation match that integrates risks and outcomes to inform their decision-making. Dr Jonathan Dando and Maximilian Lebmeier of Aestimo discuss the work done to potentially identify and address gaps in the development programmes of medical interventions. LABS 50 Filtration – The Forgotten Process Across all industrial sectors, there is a requirement for some form of solid‐liquid separation. Noel Quigley at BPE discusses how during the development of new processes, this step is largely overlooked and can become a major obstacle in scaling up new processes from the lab to commercial plant. TECHNOLOGY 54 Overall Equipment Effectiveness: A Crucial Component in Process Performance Improvement By the end of 2019, more than 75% of the world’s prescription medications will be considered under different legislations. The development of regulations to safeguard the pharmaceutical supply chain is evidence of the fact that the pharmaceutical world has woken up to the problems of counterfeit medicines. Ettore Cucchetti at ACG Inspection Systems Pvt. 2 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Ltd explains why it is crucial that organisations implement robust serialisation processes to curtail counterfeiting. 58 Monitor and Support Patient Medication Adherence through Connected Health Healthcare is increasingly digital, from wearable medical devices to remote patient monitoring to telemedicine. Kevin Deane at Phillips-Medisize identifies medication as being one glaring example of the critical health data components that remain outside the digital environment or struggle to integrate effectively into electronic health records. 62 Tracking Devices: Lessons from Big Pharma as Medical Device Manufacturers Prepare for New Reporting Obligations Big pharma has long had to contend with rigorous electronic reporting standards, designed to protect patients. Now it’s the turn of medical device manufacturers, which have so far escaped the same transparency measures. So, what does best practice data management and reporting look like? Elvis Paćelat of Amplexor distils some tips from the pharmaceutical industry’s experiences. LOGISTICS & SUPPLY CHAIN MANAGEMENT 64 Digitalisation, Quality & Efficiency in Pharmaceutical Distribution Why are digital technologies rising in importance in pharmaceutical cold chain logistics? The reasons are intertwined and not easily separated. JP Asikainen and Ossi Laakkonen, at Sensire Ltd, identify reasons, the convergence of mutually supporting technologies and the way in which regulations and pharmaceutical quality practices affect each other. 68 Evaluating a Verification Router Service: Four Key Questions to Consider The Drug Supply Chain Security Act (DSCSA) Saleable Returns Verification requirement is being phased in, requiring wholesale distributors to verify saleable returned products before they can be placed back into inventory and resold. Dan Walles at TraceLink explains the requirements. MANUFACTURING 70 In-house ‘SWAT Team’ Helped Lower PMI Rising industry concerns about environmental footprints and the global need for cleaner and greener initiatives are driving the pharmaceutical industry. Joshua Zhang at STA Pharmaceutical explains how pharma can reduce its environmental impact. PACKAGING 74 How Packaging Suppliers in the Drug Delivery Industry Contribute to a Healthier Tomorrow The challenges to the healthcare industry are constantly changing, causing industry leaders to adapt their offerings to meet varying customer needs and technological advancements. Kelly McCarry at Datwyler discusses industry collaboration in parenteral packaging. 76 How Feasible are Sustainable Packaging Solutions in the Pharma Sector? Packaging has never been more in the news – but right now it’s making headlines for all the wrong reasons. High-profile media coverage of ocean pollution and concerns over the impact on the planet of single-use materials have put packaging under the microscope as never before – as the most visual contributor to a global problem. Josie Morris at Woolcool discusses how pharma can adapt to this challenge. Summer 2019 Volume 11 Issue 2


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Editor's Letter Summer seems to be never ending this year but soon will be over, and as we look to the autumn there is one thing that we cannot escape from in the life science sector – the question, “Is Brexit going to happen and how is this going to affect our industry?” In “A No-deal Brexit May be Harmful for the Pharmaceutical Industry”, Dr Paul Peter Tak of GlaxoSmithKline describes the possible, disadvantageous consequences of a no-deal Brexit. Patient-centred care in healthcare is defined as care provision that is consistent with the values, needs, and desires of patients and is achieved when clinicians involve patients in healthcare discussions and decisions. The “Patientcentred Clinical Method” identifies that patient-centredness is achieved in part by understanding patients experiences with illness and disease as well as understanding patients holistically. Patient-centred care is thought to have many benefits and has been proposed as a means of achieving better health outcomes, greater patient satisfaction, and reduced health costs. Are we really moving towards a patientcentric approach in healthcare and clinical research? “The Importance of a Patient-centric Approach in Healthcare and Clinical Research” – this article by Susan Najjar from Sciformix, a Covance

Company, discusses the complexity organisations face when developing a business strategy around “The Patient Journey”. Modern patients have an interest in and expectation of playing a part in their own health matters which is leading to a digital transformation and causing the medical device sector to ask where this is heading and what are the challenges which might crop up for medical device manufacturers. Loetitia Jabri of ProductLife Group discusses this question. We have some fantastic Market Reports in this issue. As the Chinese start to grow even more, so do their nation’s medical needs, making the country the world’s largest producer of pharmaceuticals. We look at “Recent Regulatory Reforms and their Impact on Chinese Pharmaceuticals: A Regulatory Outlook”, with Balimuralidhara V and Mahima. R at JSS College of Pharmacy providing an overview of the regulatory reforms of the China Food and Drug Administration. Turkey is also a nation that is going to increase the number of imported products and they are explaining that there is a lack of domestic manufacturing which has pushed the government to identify a new solution and enable a “know-how” transfer of knowledge. A report by Özge Atılgan Karakulak, Dicle Doğan and Sevde Tan at Gün + Partners explains the

regulatory changes in the country. Starting on your 51st birthday, current government guidelines say you're supposed to consume 1,200 milligrams (mg) of calcium daily. With advancing years, both men and women begin to experience a decline in the density of bones that makes them weaker and more likely to break. In essence, your bone becomes more porous, and calcium supposedly fills in the holes. But the amount of calcium adults need continues to be debated. The critics say there's little evidence that high intake has more than a marginal effect on bone density and fracture prevention. They say exercise and reversing vitamin D deficiency are not promoted enough and are more important for bone health. People are becoming ever mindful of what they are eating, which is why Dr Carolina Diaz Quijano at Omya is explaining about a clever combination of calcium and vitamins which is massively important in mitigating the future healthcare burden for patients with bone and joints that need to be cared for.

Welcome to the Summer 2019 issue of the IPI Journal. Climate change and global warming is certainly the talk of the town now a days. How does it relate to the pharmaceutical industry? As climate change alters environmental conditions, the incidence and global patterns of human diseases are

changing. Climate-related environmental changes are associated with a rise in the incidence of chronic diseases for example, cardiovascular disease and mental illness. Sufferers of respiratory diseases may exhibit exacerbated symptoms due to altered environmental conditions Respiratory, water-borne, and food-borne toxicants and infections, including those that are vector borne, may become more common as new disease threats emerge,

substantially higher pharmaceutical use appears inevitable. Besides finding cure for new diseases, or enhanced health issues, can the industry make other contributions to counter the environmental threat to the planet? Is sustainability in our industry possible? I will endeavour to explore this area with articles in the future issues. Stay tuned. Virginia Toteva Editorial Manager – IPI

I hope you enjoy this issue, and look forward to catching up with all of you at various exhibitions coming up soon. Lucy Robertshaw Director, Lucy J.Robertshow Consulting

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

and Executive Vice President, Vienna School of Clinical Research

Catherine Lund, Vice Chairman, OnQ Consulting

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

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

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

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

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

Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group

Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

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

Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

Georg Mathis Founder and Managing Director, Appletree AG Heinrich Klech, Professor of Medicine, CEO 4 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Maha Al-Farhan, Chair of the GCC Chapter of the ACRP Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmacy Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai) Stefan Astrom, Founder and CEO of Astrom Research International HB Steve Heath, Head of EMEA - Medidata Solutions, Inc T S Jaishankar, Managing Director, QUEST Life Sciences Summer 2019 Volume 11 Issue 2


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Regulatory & Marketplace

Emerging Trends in Regulatory Expectations

Introduction The ULTIMATE TARGET in the pharmaceutical and medical device industries is to ensure patient safety within the entire product life cycle, from R&D to distribution.

regulations in the sense of giving guidelines to address the following: •

Quality of medical products (both drugs and devices) becomes a social and ethical responsibility as products are developed, produced and distributed for preventing, treating, and reducing discomforts of diseases. The final user/patient trusts the medical products’ efficacy and simply relies on them. A continuous commitment from manufacturing companies and from those involved in the product life-cycle is needed to continue gaining the patient’s confidence.

Together with the principles and guidelines that the regulatory authorities are laying down for the industry (i.e. regulatory requirements) we can say that quality of medicines is not only mandatory by law, but is also a social and ethical responsibility.

Responsibility implies the importance of the human factor when considering regulatory requirements: people are at the heart of doing, and it is the failures of people – often the combined failures of a number of people – which result in non-compliance in most cases. Globalisation has fundamentally altered the economic and security landscape and demands a major change in the way regulators/medical products manufacturers, distributors and suppliers fulfill their mission. Globalisation processes, characterised by longer and more complex supply chains, and greater risk of counterfeiting problems, have been forcing the industry and inspectorates/ enforcement agencies to challenge their current practices. Regulatory expectations nowadays focus on harmonisation of global 6 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Overall process-oriented approach. Since quality should be built within the product, testing alone cannot be relied on to ensure product quality. Increasingly validation of computerised systems is process-oriented, to ensure both the reliability of GxP/business processes and the integrity of data managed by each system, including laboratory and manufacturing. Many manufacturing sites have multiple systems from multiple vendors and different release versions: integration of manufacturing applications often takes 50%–80% of a project’s cost. An effective integration of business logistics systems and manufacturing operations (production, maintenance, laboratories, material handling, storage etc.) suggests corporate validation approach as a cost-effective opportunity. Quality by design (QbD) is an understanding of the product and the relevant development and manufacturing process along with a knowledge of the risks involved in manufacturing the product and how best to mitigate those risks. Quality by design principles have been adopted recently by the regulatory authorities as the initiative attempts to provide guidance on pharmaceutical development to facilitate design of products and mitigate the risk through design. Increased utilisation of risk management and change management have become paramount for understanding where to buy, which supplier and sources need to be more controlled and how changes impact product registrations. Increased reliance on suppliers and outsourced processes.There is rising complexity in controlling larger supply chains, with raw

materials, components, subassemblies, finished goods and packaging materials coming from different sources from around the world. Business players need to be aware of the supply chains they participate in and to understand the roles they play. As the environment becomes more complex in terms of products and technology and due to the fact that business margins are more and more limited, companies are forced to rely more on suppliers and outsourced processes. Leveraging suppliers’ knowledge, sharing it and applying it in supply chains can promote the business performance and efficiency. •

Growing focus on data integrity as key evidence of supply chain reliability and ultimately of the product quality. In order to achieve these targets through a feasible and cost-effective strategy, a harmonised approach is required to create validation common standards, not only for the traditional owned IT applications, but also for stand-alone laboratory and production systems usually managed by the engineering/ maintenance department.

Globalisation Impact Globalisation can be described as: rapid flows of goods, capital, services, labour and information around the world. Integration of national industries into global ones is becoming a commonplace and it is increasingly unhindered. One of the strongest driving forces of this globalisation is the revolution in information and communication technologies, which are now reaching some of the poorest and most remote locations in the world. A big concern for medical products companies occurs due to high costs for research and development, international competition, reduced lifetime of products and measures of health policy and cost saving considerations. This pressure in pricing and competition leads to Summer 2019 Volume 11 Issue 2


Regulatory & Marketplace

development and manufacture at lower cost, in innovative developing countries like India, China and Brazil. While the various functions of the industry were traditionally all located within the same company, now the vertically integrated supply chains are breaking apart into component activities that can be outsourced. The challenges for the quality of medical products which are triggered by globalisation include the assurance of Good Manufacturing & Distribution Practice compliance, new impurities in drug substances induced by alternative manufacturing routes, long-lasting transport of medical products passing through various climatic zones, complex supply chains and product transfers. All these factors make the changes in global supply chain inevitable. Regulatory systems of all kinds – whether dealing with flows of www.ipimediaworld.com

finances, goods or information – find it difficult to keep up with the pace of change. Worldwide recognised regulators (EU & US) together with other active regulatory authorities like Japan, Brazil, Canada and Australia have gradually evolved to respond to the increasingly global challenge of medical product development and distribution. Risk-based approaches, decisionmaking techniques, global cooperation and harmonisation initiatives, and validation common standard are valuable tools to deal with the uprising challenges to ensure that safe, effective and high quality medical products are developed, registered, manufactured and distributed in the most resourceefficient manner. Global Compliance A model for global compliance is the challenge currently faced by all global regulated companies.

In order to design an effective strategy and tactic, it is recommended to create teams including all the skills required to implement a feasible and scientifically sound approach. Such an approach has to be supported by a centralised organisation since a regulated company shall ensure a uniform level of compliance across its sites and its suppliers. The best solution is to establish a central organisation for data integrity in order to create standards and support the sites to assess, correct and monitor the compliance level. This organisation (termed centre of excellence) will create the validation common standard (golden packages) to be provided to the sites in order to facilitate the creation of validation documentation for the computer systems used at the site. INTERNATIONAL PHARMACEUTICAL INDUSTRY 7


Regulatory & Marketplace The global strategy of regulated manufacturers for data integrity shall be based upon the following key steps:

A supplier audit and monitoring programme is another subject that receives great benefit from a centralisedtailored approach.

Establish a Central Team to Achieve

Process-oriented Approach The classical company interpretation model based on ISA95 implies the need for creating common standards consistent and integrated at all levels. These standards provide definitions around people, materials and equipment, as well as procedural models on how these are combined to make products.

• • • • • •

Common quality approach preliminary agreed with global team Continuous consistency between central and local teams Centralised control of validation deliverables A tailored team for each customer need Dedicated local teams to specific geographical area Allow a timely fashion response

Establish Centre of Excellence (CoE), Assess Current Status and Plan Remediation • •

• •

• •

Implement a sustainable model to ensure compliance across all company sites Execute a feasible assessment and remediation based upon global QA SOP, site risk priority and risk associated to each computer system Assessment to verify the validation status of site control, production and computer systems Assessment outputs to be evaluated to mitigate bias for consistent results across customer network Remediation plans to be defined centrally Approach to ensure that sites will not deviate

Create and Deploy Validation Golden Standards •

• •

Develop documentation packages for each type of system mostly used in the laboratory and manufacturing environment Provide system-specific guidance and training to each site Ensure harmonised approach for systems across sites

The rollout of this strategy allows regulated manufacturers to achieve sustainable and harmonised compliance of computer systems and, ultimately, to ensure the integrity of data where the product quality is built upon. 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Validation common standards and templates can be considered one of the milestones for the implementation of the ISA95 model, not only for the traditional owned IT applications, but also for the systems, such as stand-alone laboratory and production systems,  traditionally managed by the engineering / technical services department. The relevance of assuring the validated status of compliance is emphasised not only in projects implementation, but also during the ongoing phase. This new vision considers the medical product during its whole lifecycle, starting from development through technical transfer to routine manufacturing and decommissioning. Risk management tools and a robust quality system are the pillars for building a more systematic approach to validation. All data and information should be secured, accurate, and reliable and only those personnel who need to view, add, or update a given piece of data are in fact allowed to access it. Reliable data collection shall be in place: any delay in releasing a batch of product is not only costly, but the cost of non-compliance consumes additional resources of the company. It is therefore crucial that during the manufacturing phase, analytical data be collected, compiled, and submitted in a timely, accurate and reliable manner.

incomplete or faulty record-keeping; repeated and undetected errors in critical data; reduced capability to recall drugs and medical devices; release of contaminated blood and components. The numbers of US/FDA warning letters related to data integrity has strongly and consistently increased in the last twelve months. This regulatory pressure together with the technology and environment complexity shall be counterbalanced by: validation, quality risk management, record management and supplier management. Data integrity became one of the highest priorities and can be described as “The condition existing when data is unchanged from its source and has not been accidentally or maliciously modified, altered or destroyed” [National Information Assurance Glossary]. Reliability of data defines consistency also referred to as: repeatability, method precision or system precision. It is imperative to demonstrate that: •

Regulated data collected through logistics, laboratory, production, distribution and other systems have been generated and maintained with care, and are technically and procedurally protected against manipulations.

Documentation and result reporting have been done in real time (action), can be clearly identified, and have been standardised, predefined and authorised (and person recording must be clearly identifiable).

Data integrity control ensures the chain of evidences backward from the final documents; the audit trail review process is required to ensure that data show no violation patterns. Each regulated company is required to assess the level of compliance to regulations (e.g. EU cGMP Annex 11) and to correct any deficiency in order to reach the required compliance level. Conclusions

Need for Data Integrity In the last two-three years, regulatory authorities became focused more on software and computerised systems. The agencies detected problems in the computer compliance, such as:

Quality of product (including raw materials, components, subassemblies, packaging materials) rely upon integrity of laboratory and production records and is the Summer 2019 Volume 11 Issue 2


Regulatory & Marketplace

• •

• •

ultimate responsibility of market authorisation holders (MAHs) New challenges are triggered by global supply chain process A number of different enforcement measures have been defined by regulatory bodies to mitigate risk to product quality Compliance with new regulatory requirements is ultimately based upon data integrity Outsourcing can be used by regulated companies, provided that an effective provider qualification / monitoring process is in place

Validated technology might be the only chance MAHs may have to face the current challenges for the medical products industry (globalisation, cost reduction, data integrity). Applicable Rules and Guidelines Analysis described in this document has been executed according to the following rules and guidelines: RULES: 1.

US Food & Drug Administration – Code of Federal Regulations, Title 21, part 210, “Current Good Manufacturing Practice in Manufacturing, Processing, Packaging, or Holding of Drugs; General” 2. US Food & Drug Administration – Code of Federal Regulations, Title 21, part 211, “Current Good Manufacturing Practice (GMP) For Finished Pharmaceuticals” 3. European Community – Guide to Good Manufacturing Practice for Medicinal Products (The Rules Governing Medicinal Products in the European Community, Volume IV) 4. US Food & Drug Administration - Code of Federal Regulations, Title 21, part 820: “Medical Devices Current Good Manufacturing Practice” 5. US FDA Code of Federal Regulations, Title 21, Part 803, “Medical Device Reporting” 6. US Food & Drug Administration – Code of Federal Regulations, Title 21, part 11: “Electronic Records; Electronic Signatures; Final Rule” 7. European Commission, The Rules Governing Medicinal Products in the European Union – Volume 4: Good Manufacturing Practices Medicinal Products for Human and Veterinary Use, Annex 11 – June 2011 8. European Commission – The Rules Governing Medicinal Products in the European Union – Volume 4 – Part III: Quality Risk Management – March www.ipimediaworld.com

2008 (Adoption as ICH Q9 guideline Step 4) 9. European Commission – The Rules Governing Medicinal Products in the European Union – Volume 4 – Part III: Pharmaceutical Quality System – June 2008 (Adoption as ICH Q10 guideline Step 4) 10. Resolution – RDC N° 17, of 16/04/2010: Union Official Gazette Section 1 “Provides for the Good Practices of Medicament Manufacturing” (Anvisa) 11. NOM-059-SSA1-2013,  “Buenas p rá c t i c a s d e fa b r i c a c i ó n d e medicamentos”, Mexican GMP 12. Resolution - 2013019704, of 05/07/2013,  “Por la cual se adopta el Sistema Integrado de Gestión de Calidad del Instituto Nacional de Vigilancia de Medicamientos y Alimentos INVIMA” 13. R e g l a m e n t o S u s t i t u t i v o d e l Reglamento de Buenas Prácticas de Manufactura (BPM) para Laboratorios Farmacéuticos - Acuerdo Ministerial 00000760 Registro Oficial 359 del 10 de enero del 20 14. RESOLUÇÃO - RDC Nº 59, DE 27 DE JUNHO DE 2000 - Agência Nacional de Vigilância Sanitária -  BOAS PRÁTICAS  DE FABRICAÇÃO DE PRODUTOS MÉDICOS 15. DIGEMID (Direccion General Medicamentos, Insumos y Drogas) - Manual de Buenas Practicas de Fabricacion RM n° 055-99-SA/DM 16. Russian Ministry Of Industry And Trade Of The Russian Federation – Appendix N 11 to Regulation Good Manufacturing Practices – June 2013 17. Chinese Annex 1 of Good Manufacturing Practice for Drugs – May 2015 18. Order of ministry of industry and trade of the Russian Federation from June 14, 2013 n.916 On approval of rules of Good Manufacturing Practice

GUIDELINES: 19. US Food & Drug Administration – Guidance for Industry Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations, September 2006 20. US Food & Drug Administration – Guidance for Industry Process Validation: General Principles and Practices – Revision 1, January 2011 21. US Food & Drug Administration – General Principles of Software Validation; Final Guidance for Industry and FDA Staff, January 2002 22. US Food & Drug Administration – Guidance for Industry: 21 CFR Part 11 – Electronic Records and Electronic Signatures: Scope and Application, August 2003 23. PIC/S Good Practices for Computerized systems in regulated “GxP” environ-

ment, Pharmaceutical Inspection Co-operation Scheme guidance, September 2007 24. PIC/s Guidance Draft August 2016 PI-041-1 "Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments" 25. GAMP Forum – GAMP Guide, A RiskBased Approach to Compliant GxP Computerized Systems – Ver. 5.0 26. GAMP Forum – GAMP Good Practice Guide: The Validation of Legacy Systems 27. GAMP Forum – GAMP Good Practice Guide, Testing of GxP Systems 28. GAMP Forum – GAMP Good Practice Guide, IT Infrastructure Control and Compliance 29. GAMP Forum – GAMP Good Practice Guide: Validation of Process Control Systems 30. GAMP Forum – GAMP Good Practice Guide, Global Information Systems Control and Compliance 31. GAMP Forum – GAMP Good Practice Guide, A Risk-Based Approach to Compliant Electronic Records and Signatures 32. GAMP Forum – GAMP Good Practice Guide, A Risk-Based Approach to Operation of GxP Computerized Systems 33. MHRA GMP Data Integrity Definitions and Guidance for Industry (March 2015) 34. Agência Nacional de Vigilância Sanitária - Guia de Validação de Sistemas Computadorizados 35. WHO Annex 5 Guidance on Good Data and record management practices May 2016 36. FDA-Data Integrity and compliance with CGMP (Draft, April 2016) 37. ICH E6(R2) Good Clinical Practice Te c h n i c a l and Regulatory Considerations for Pharmaceutical Product Lifecycle Management (2014) 38. OECD Series On Principles Of GLP And Compliance Monitoring Number 17 Application of GLP Principles to Computerised Systems 39. ISPE GAMP Guide_Records and Data Integrity 40. CFDA Drug Data Management Standard

Gilda D'Incerti Gilda D'Incerti founded PQE Group in 1998 with a clear vision: invest in people, diversity and ethic. Being a quality expert in the Life Science industry means to think about the well being of all of us as consumer.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 9


Regulatory & Marketplace

Striving for Patient-centricity Throughout the Entire Product Lifecycle Perhaps one of the most notable changes in the pharmaceutical industry over the past 10 years is the marked shift towards implementing patient-centric practices, programmes and initiatives as patients become more knowledgeable, empowered and involved in their treatment. As a result, many life science companies are adapting their entire businesses to revolve around the patient at every step of the product lifecycle. This shift from product-centricity to patientcentricity is moving at varying rates, but it’s generally agreed that better patient-centricity results in better business and patient outcomes1.

“Patient-centricity” can be thought of as the process of designing a product, service or solution around the patient. In the case of medical products, patientcentricity (while evolving) is often the focus during clinical development, with the safety and outcome of every patient who is in a clinical trial being paramount. During post-approval, however, the focus is also distributed across payers, healthcare providers, regulators and other company stakeholders. Ensuring patient-centricity after approval is a growing area of interest and will be explored further in this article. Building patient-centricity into every phase of the drug development process requires a comprehensive approach that draws upon numerous stakeholders within the healthcare ecosystem.

additional means of support; all while gathering valuable data and evidence such as from portable devices and observational studies. Patient support, market access, real-world evidence and Phase IV programmes not only allow patients to gain access to safe and effective treatments, but also receive a more personalised and informed treatment, thereby positively influencing their treatment outcome. The ability to demonstrate patient-focused clinical and post-marketing outcomes helps shape the commercial success of a medical product. A lot can and should be done to gather, interpret and disseminate information and knowledge about health economics and outcomes to demonstrate product value. Patient-centricity: From Clinical Trials to Post-marketing “Patient-centricity” and “patientcentric trials” have become industry buzzwords, yet there is still much to do when it comes to implementation in the real world. Figure 1, below, illustrates the clinical trial continuum from a participant perspective 2. Organisations must address the patient needs at every phase of the process to ensure that their trials are designed in a way that is not just scientifically

rigorous, but also incorporates patient perspectives. Achieving Patient-centricity in Clinical Trials Trial planning activities to improve patient-centricity may include live protocol simulations, patient advisory boards, other means of soliciting patient and caregiver input on what a trial should include, and protocol review committees consisting of a wide range of interested stakeholders from outside of the organisation.

Once the trial gets started, it’s advisable to schedule regular patient experience evaluations on top of standard clinical assessments. The use of e-diaries, wearable devices, and “bring your own devices” (BYOD) can make participation in the trial easier and more interactive. Communication with participants is key and simple measures such as participant newsletters and brochures written in lay language can be impactful. As the trial comes to a close, a simple “thank you” for trial participation can go a long way and might help a patient consider participation in a

This article discusses the complexity organisations face when developing a business strategy around “The Patient Journey” and how they are quickly adapting and implementing programmes that foster information sharing and collaboration, while providing faster and greater access to life-changing products. Today, life science companies are looking holistically at the entire patient journey, remaining close to patients and providing them with new support mechanisms, i.e. online forums and 10 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 1: Overview of typical clinical trial phases and examples of patient-centricity gaps throughout2. Summer 2019 Volume 11 Issue 2


Regulatory & Marketplace future study or share their experience as positive with others. Sharing trial results with participants in simple terms is a must-do for improving engagement, but is often overlooked. Soliciting feedback and measuring patient satisfaction following the study can also be helpful2.

Achieving Patient-centricity during Post-marketing When it comes to the post-marketing phase, patients can sometimes take a back seat to commercial imperatives. An ever-changing array of economic drivers, decisionmakers, reimbursement models and regulations may impact the commercial value of a treatment in today’s marketplace. There are a wide range of activities that need to be undertaken to build patient-centricity into the post-marketing phase. At this stage of the product lifecycle, engagement and collaboration with diverse members of the healthcare ecosystem is critical. Some key areas of focus include: patient safety and risk management; realworld evidence (RWE); market access (MA); patient support programmes; healthcare professional (HCP) support; payer relations and clinical outcomes assessments.

Patient Safety and Risk Management Due to the ever-increasing regulatory requirements, product safety and the ongoing monitoring of the benefit-risk relationship continues to dominate the imperatives of life science organisations. The patient perspective is an essential component of drug safety and pharmacovigilance (PV), yet many organisations haven’t turned the curve and moved from a product-centric approach to a proactive patient-centric approach. PV organisations that incorporate the patient’s “voice” in PV systems and processes are better positioned over the long term to ensure patient safety and add real value to patients by enhancing product benefit-risk profiles. The shift from pure safety analysis to benefit-risk evaluation, and thereby the overall implementation approach for an effective patient-centric PV model, is entrenched in four main steps; namely to educate, encourage, engage and enable patients. www.ipimediaworld.com

Educate: one of the key approaches in patient-centric PV is raising patient awareness regarding the importance of reporting ADRs (adverse drug reactions) and continuously highlighting the critical role they can play in PV from AE (adverse event) reporting through risk communication. Encourage: High-quality information empowers patients to play their role in the PV system, for better patient safety and high quality of care. EU Directive 2010/84/EU [Chapter 2 of title IX] contains crucial provisions from the patients’ perspective concerning transparency and communication regarding medicines and PV via established national medicines web portals. Engage: The Directive 2010/84/EU [Article 102] proposes guidance encouraging direct patient reporting, via appropriate measures including web-based formats and alternative formats [Article 102(b)], to encourage patients and HCPs to report suspected ADRs to the national competent authorities (NCAs). Enable: Active involvement of patients and the public in AE reporting is possible by the use of effective and patient-friendly reporting systems, channels and processes (both technology independent and driven). This can be achieved by designing and deploying simple and easy-to-use ADR reporting tools and processes.

Overall, adopting a patient-centric approach and partnering with patients and healthcare professionals for reporting, analysis and communication of safety data is advisable. At the same time, it is critical to remember that patient-centricity is more about listening, communicating and disseminating to the patients, to ultimately empower them to participate in the decision-making process, and is not about putting the decision-making solely in their hands. Real-world Evidence and Market Access Demonstrating the value of a drug with comparative analysis to existing treatments/drugs is important in empowering patients to make informed

choices. Patient-centric RWE and MA activities create meaningful value-based evidence for physicians, patients, regulators and payers by developing global and/or local dossiers, economic models and publications. These tools can be used to help demonstrate the value proposition of a product utilising clinical, economic and observational data. Armed with this information, patients and payers can better manage budgets and estimate the risk-benefit comparison of interventions. Sponsors are better able to understand the treatment landscape with respect to comparators and outcome measures, stakeholder needs and payer value drivers across different markets and the product lifecycle. In addition, payer perspectives can influence patient access and patient perspectives can drive utilisation. In the US, payers are increasingly encouraged, via initiatives such as the IHI Triple Aim, to consider RWE from sources such as value assessment frameworks, and embark on deeper collaborations with the pharma industry. To support the involvement of patients, The Prescription Drug User Fee Act (PDUFA) re-authorisation and the 21st Century Cures Act emphasises the use of patient outcome data for drug development. Patients can make more informed health decisions based on information from the Patient Centered Outcomes Research Institute, National Health Council, virtual networks such as ‘Patients Like Me’, and digital technology like mHealth. Although an emerging area of post-market access, mHealth is starting to be employed in the US. For example, Johnson & Johnson collaborated with Aetna to use wearable technology in atrial fibrillation (AFib) screening for RWE generation. They were able to identify people with asymptomatic AFib earlier and more efficiently than from routine care. Health PROMISE, a patientreported outcome tool integrated with EHRs, helped IBD patients and providers to visualise real-time data; thus improving their quality of life. INTERNATIONAL PHARMACEUTICAL INDUSTRY 11


Regulatory & Marketplace Late-phase and Phase IV studies (non-observational and observational) are a key source of engaging with the patients and monitoring outcomes, safety and effectiveness at the individual patient level. Patient Support Historically, pharmaceutical companies have not had as much direct communication with patients, relying instead on other stakeholders such as payers, pharmacists and physicians to gather feedback and provide information. Establishing closer relationships with these constituents AND patients can be beneficial in ensuring adherence to treatment and better outcomes, thus helping realise the commercial potential of a treatment. Customer-centric field and call centre services which enable pharma companies to support patients and various stakeholders directly are essential elements of a patient-centric organisation. •

Reimbursement/financial support: Patients often struggle with complex reimbursement processes or may even be uninsured. By providing reimbursement and financial support services to patients and doctors, pharma companies can ensure their treatment is accessible to those who need it. They can also better understand the reimbursement landscape and design appropriate assistance programmes. Patient experience analysis: By employing patient experience programmes, organisations can understand what aspects of the patient experience might negatively impact outcomes and provide assistance or solutions to improve them. Adherence support: Patients may suffer stress or anxiety in relation to their treatment or condition, or may be on a complex treatment plan. Delivering support to ensure adherence can maximise outcomes and build trust.

Healthcare Professionals (HCPs) and Field Support Educating and collaborating with HCPs to deliver more effective treatment to their patients is critical in achieving market success. Supporting patients directly by answering questions 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

about their treatment and providing information can also help take the strain off time-poor HCPs. What’s important, though, is developing closer links to patients, as well as HCPs and other stakeholders, so that every person involved in a patient’s journey is well informed and better able to support that patient throughout their treatment. Other support during the postmarketing phase that helps contribute towards patient-centricity includes: •

Payer relations: Providing payers with on-site, hands-on help with billing, pharmacy interactions, affordability and other issues shows your commitment to ensuring product access. Clinical outcomes assessments: With patients increasingly having to pay for innovative treatments themselves, the importance of strong clinical outcomes evidence is growing.

Summary As patients are taking more interest in their health and healthcare, they support the maxim of ‘‘Nothing about me, without me’’ and expect caregivers to engage in shared decision making, so that the patient voice is always included. When it comes to developing and launching new treatments, life science companies are realising the importance of building patient-centricity into the entire product lifecycle. It is widely reported that patients who have more involvement with and control over their treatment tend to have better outcomes. There are clear commercial and health benefits to adopting a patient-centric model. This can only be achieved by collaborating with diverse stakeholders in the healthcare ecosystem, including the right partner for the whole patient journey from development, trials and launch to post-market support.

As a world-leading CRO, Covance has comprehensive experience in every facet of the product lifecycle, including post-launch activities such as patient safety, real-world evidence & market access and Phase IV solutions. By employing a seamless and streamlined approach throughout the product lifecycle that’s focused on patient-centricity, we help our clients gain a competitive advantage through direct patient involvement, and higher quality of data. Adopting a patientcentric approach, and partnering with the patients, life science organisations are better positioned to facilitate patient access and safety, enhance patient knowledge and engagement, and therefore add real value back to patients. REFERENCES 1. 73% of patients and 83% of employees said that focusing on patients’ needs leads to better business outcomes, The Path to Patient-Centricity, Phillips G and Elliott J, Ipsos and The Aurora Project/ Excellerate, Aug 2018 2. Hélène L. Svahnqvist, Anna Skabeev, 2017. A Practical Overview of PatientCentric Trials. Applied Clinical Trials (Internet) http://www.appliedclinical trialsonline.com/practical-overviewpatient-centric-trials?pageID=1 [accessed 18/01/2019]

Susan Najjar Susan Najjar has over 25 years of industry experience with several years in senior leadership and consulting positions. Susan oversaw global marketing activities for Thermo Fisher Scientific’s Informatics division, developing growth strategies and implementing innovative marketing programmes. Prior to Thermo, she was accountable for: establishing the Gillette Company’s North American Blades and Razors forecasting & planning; executing software product launches at Sun Microsystems; and consulting senior pharmaceutical executive teams at Deloitte & Touche. Susan has an MS in Biochemical Engineering from Tufts University and MBA from MIT Sloan. Email: susan.najjar@sciformix.com

Summer 2019 Volume 11 Issue 2


Our Commitment, The Industry Leading Experience

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We invite you to learn more about what our commitment can do for the success of your product.

Š Copyright 2018 Packaging Coordinators, Inc. All Rights Reserved. AndersonBrecon (UK) Limited trading as Packaging Coordinators, Inc. is a company registered in England and Wales with company number 02543975 and VAT registration number GB 549 7026 19 whose registered office is at The Broadgate Tower, Third Floor, 20 Primrose Street, London, EC2A 2RS. Penn Pharma, a PCI company, is a Trading Name of Penn Pharmaceuticals Services Limited, Registered in England and Wales No.1331447 Registered Office: Tredegar, Gwent NP22 3AA UK. VAT Reg. No.762 3299 16. Biotec Services International is part of Biotec Worldwide Supplies Group of companies, Registered in Wales No. 3483803. VAT Registration No. GB 108216149.

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Regulatory & Marketplace A No-deal Brexit May Be Harmful for the Pharmaceutical Industry Q&A with Dr Paul Peter Tak

(Venture Partner at Flagship Pioneering, former Senior Vice President, Development Leader and Chief Immunology Officer of GlaxoSmithKline) Brexit, and certainly a 'no-deal' Brexit will be bad for patients, academic research, the life sciences sector and the economy, according to Dr Paul Peter Tak.

He answers our top four questions about what Brexit really means for the pharmaceutical industry. 1. Will a no-deal Brexit affect academic research and scientists in the UK? Academic research in the UK, which has benefited disproportionally from EU funding, will incur significant losses as the UK will no longer be eligible for European grants.

Considering that science is a collaborative effort, this is not only important in terms of money but also in light of the important consortiums and networks that are created by EU programmes, like the Innovative Medicines Initiative (IMI). The UK will also lose influence over the European Medicines Agency (EMA), the regulator that approves medicines for use within the EU. The EMA has already moved to Amsterdam as a direct result of Brexit – and it will also no longer be able to shape the European research agenda. As a result of these events, there may be the risk of many European academic researchers and scientists in the UK moving to other countries as they will be looking for an environment where they perceive the open mentality that makes science flourish.

2. How will it impact the industry across borders, and drug delivery in the UK? Because medicines benefit from free movement across Europe and the supply industry has adapted to these arrangements, any significant change to this delicately balanced system may lead to major problems for the pharmaceutical industry. 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

If there is a no-deal Brexit, the sector will face a challenge around the time it takes to develop drugs and other products. With the pharmaceutical industry having close ties to the EU, the development process depends heavily on the political and regulatory conditions of different countries. This means that supply chain planning often happens years in advance – for example, product development can take 10 to 15 years and manufacturing schedules are made significantly early. A no-deal Brexit would prolong disruption at borders, which could threaten supplies of drugs in the UK and in Europe. While we’ll be able to increase the stock of some items such as tablets, other imported drugs like insulin often need to be refrigerated and may therefore pose bigger logistical challenges. There is also a risk of the UK being excluded from the European Rare Diseases Network, which would raise concerns around orphan medicines and whether such medicines will even reach the UK market. If this is the case, the treatment of rare diseases will be hindered due to a lack of medication.

3. Will a no-deal Brexit impact the NHS? It certainly will, as the NHS is expected to face a significant shortage of many thousands of nurses, social workers and physicians as a result of Brexit. In addition to this, the NHS’s ability to recruit new doctors and medical staff from EU countries may be affected by new immigration rules. Replacing staff could also be a challenge, considering that most employees want stable, long-term contracts. Another key EU body partnership that will be lost is the European Centre for Disease Prevention and Control. This will weaken the UK’s response to pandemics which could result in the spread of diseases.

In terms of treating ill patients, stockpiling will be required by the NHS to counter the effects of medication shortages.

4. What will a no-deal Brexit mean for the greater economy? Life sciences firms contribute hugely to the British economy, and therefore a shift within this sector could have economic implications. A  report by PricewaterhouseCoopers  noted that in 2015, the industry employed 482,000 people and contributed £30.4 billion to the country’s GDP.

One of the consequences of Brexit will be that the UK and the EU will need to have separate databases on pharmaceutical products in the market, which would lead to an increase in spending by the UK. Furthermore, biotech and pharmaceutical companies that want to conduct multi-country clinical trials currently register on a single EU clinical trial database, but after Brexit, UK companies will need to apply individually to each country. This will represent a huge administrative burden and of course, higher costs for the UK.

Dr Tak is not alone in his opinion that a no-deal Brexit will be bad for the industry. A recent GlobalData report shows that when pharmaceutical professionals were asked about the impact of Brexit on the healthcare sector, 59% of participants indicated a negative sentiment.

Dr Paul Peter Tak Venture Partner at Flagship Pioneering, former Senior Vice President, Development Leader and Chief Immunology Officer of GlaxoSmithKline.

Summer 2019 Volume 11 Issue 2


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Regulatory & Marketplace

The Importance of a Patient-centric Approach in Healthcare and Clinical Research Introduction In recent years, the term “patientcentric” has become more commonplace in the world of clinical and medical research, indicating greater interest in putting the patient first. However, a recent report produced by The Economist Intelligence Unit (EIU) and commissioned by PAREXEL1 that identified patient-centricity as a key innovation within the healthcare industry, also showed that only 5.2 per cent of Phase II and III trials actually utilised this approach. While this indicates that industry adoption is currently falling far behind the buzz surrounding the topic, there has been a sharp increase in the number of clinical trials citing patient-centric designs in PubMed since 2011, which is an encouraging trend. So, how are we optimising the opportunity to take a patient-centric approach to connect healthcare and clinical research, and how can we accelerate adoption?

Supporting Creation of Patient-centric Study Design Regulatory agencies such as the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) are increasingly advocating for patient input into study design, which certainly empowers sponsors and contract research organisations (CRO)s to take action. For example, the FDA’s Guidance for Industry on Patient-reported Outcome (PRO) Measures supports involving patients in the selection of measures so that studies are designed with a clear focus on meaningful benefit for patients. Of particular interest to the FDA are direct measures of how a patient ‘feels, functions or survives’, and PROs are a vital part of assessing concepts like these that are only known to patients – for example, symptoms, treatment satisfaction and quality of life. Having a clear vision of what matters to patients and addressing them accordingly is incredibly important to ensure a patient-centric approach. In a similar way, the overall study design also needs to factor in patient 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

needs, particularly from a practical perspective. At the recent Patients as Partners US conference, many stories were shared by patients about the challenges they faced as research participants, usually from the perspective of practical and financial burden. Some patients shared stories about being unable to afford parking at the hospital for a lengthy appointment, while others shared burdens such as a patient being late for every appointment due to childcare commitments without knowing that they had the option to rearrange to a time more convenient for them. Early engagement with patients will ensure that, from the very beginning, sponsors are building studies with the patient in mind and are not inadvertently building challenges into their protocols. Feedback from sites is also important, as their perspective incorporates both the human and medical elements and can help shape a more “doable” study. For example, during a recent insights project, nurses highlighted that questionnaires related to an exploratory endpoint added five hours to a study visit. This enabled the sponsor to make the necessary adjustment to avoid such a burden on study participants. It is also crucial that regulatory bodies continue advocating for patient involvement in study design in order to demonstrate the value of this approach to stakeholders, thereby optimising adoption and, in time, making it standard practice. Creation of Patient Experts Patient feedback can take many forms: via patient advocacy groups (PAGs), market research agencies or online communities. Some have reported feeling worried about sharing feedback as they are interacting with highly specialised experts. The European Patients’ Academy (EUPATI) is a great example of how this issue can be overcome. EUPATI provides in-depth training programmes to train patient experts well-versed

in medicines development, clinical trials, medicines regulation and health technology assessment, who are able to effectively provide feedback to the industry. In addition, the organisation offers a training toolbox that helps guide patients in their learning about clinical research. By bringing together stakeholders from the pharmaceutical industry, patients, and academia, they were able to create comprehensive and accessible resources with information to help facilitate increased patient engagement. Involvement at patient-centricity conferences also brings together stakeholders from many different groups to openly discuss, debate and collaborate. Having the opportunity to share best practices around how to involve patients throughout the entire medicines development life cycle to drive greater efficiencies in clinical research is time well spent. And, for those within the industry who do not tend to regularly interact with patients, hearing real-life stories of clinical research participants is incredibly impactful. Many sponsors have their own patient insights programmes to enable access to patient experts. However, some sponsors are unable to attain patient insights due to resource constraints. Therefore, CROs can support their sponsors with patient insight programme activities, often within a very short timeframe and at minimal cost. Even if early engagement has not been possible, some patient feedback is preferable to none at all. Enabling Effective Patient Education Health literacy is defined as the degree to which individuals can obtain, process and understand health information to enable them to make appropriate health decisions. When providing education materials to patients, both literacy and health literacy considerations are important. Institutional review boards (IRBs) and ethics committees are very experienced at reviewing materials and Summer 2019 Volume 11 Issue 2


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 17


Regulatory & Marketplace acting as gatekeepers to ensure that a fair, balanced, and clear picture of the research opportunity is made available to patients. It can sometimes be challenging for experienced clinical research professionals to condense vast and complex medical information into an easily digestible format for patients, but it’s important that patients fully understand what they are consenting to. By sponsors and CROs taking literacy into consideration and supporting sites with clear information, they are helping to facilitate a more positive patient experience. Ultimately, patients who understand exactly what they are enrolling in are less likely to drop out due to unmet expectations. Supporting Research Participation Much has been done in recent years to improve the patient journey in clinical trials. Improvements have ranged from transportation support and visit reminder messages to online information resources and direct-to-patient drug shipments. By mapping the patient journey and thinking about potential challenges for that patient group, a clear strategy can be created to overcome many practical challenges. Recently, virtual trials (sometimes called “remote”, “decentralised”, or “siteless”) are being deployed in a truly patient-centric manner. They are designed to make it as easy as possible for patients to participate in clinical research by taking all or part of the study to them in their homes and overcome the many barriers to trial recruitment and retention. The barriers virtual trials help overcome include: a) Geographical barriers, such as living too far from the site b) Financial barriers, such as being unable to afford time off work c) Practical barriers, such as a lack of childcare To create the correct combination of visits occurring in the clinic and those in the home, multi-stakeholder engagement is imperative. Medical staff can help advise sponsors and CROs on the visit schedule and IRBs help ensure that patient safety is of paramount importance before they provide approval to proceed. Of course, patient feedback 18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

ensures that no assumptions are made on their behalf when determining the most favourable approach to reducing the burden for them. For example, during early planning for a recent virtual trial strategy in an older patient population that would require weekly site visits for a year (the majority purely for dosing), it was assumed that home nursing could be utilised to reduce the time and travel burden. However, a large survey of patients with the disease showed that the majority of patients actually preferred the idea of attending appointments at the clinic as they enjoyed the social element. So, despite best intentions, if patient feedback had not been obtained, an incorrect approach could have been taken. Patient and caregiver feedback during early planning on another virtual trial had a very different outcome. For this study, adolescent patients were required to participate in repeated blood draws throughout the course of the day, starting very early in the morning. Knowing that early mornings can be a challenge for teenagers, we proposed using home nursing on those occasions, which was received highly favourably by the patient population. Similarly, other visits did not require intervention and, with adolescents so familiar and comfortable with cellphone usage, turning them into telemedicine visits (with direct, real-time communication between site staff and the patient using technology similar to FaceTime of a WhatsApp video call) was agreed upon, based on positive feedback.

Supporting Post-participation Information-sharing A common complaint from patient groups is that study participants often are not thanked for their efforts at the end of a trial, and that they do not learn about the study outcome. This can be rectified with a couple of simple steps: 1) Deploy patient thank you cards at the end of every study. A little gratitude goes a long way to making people feel valued and creates advocates for clinical research. 2) Disseminate lay summaries to participants once results of the trial are known. Though they are often published in scientific journals, knowing where to look for this information and being able to understand the complex scientific terminology can be challenging. However, the EMA has mandated that lay summaries be made available to patients via their new portal. Taking this further and providing the information to sites to share with their patients makes the data much more accessible. This approach is important to show patients that the industry recognises the importance of their contribution to clinical research. Patient-centric trial designs positively contribute to efficacy and success, so drug developers need to understand stakeholders’ perspectives and build a trust with patients by sharing information in a way that’s easy to understand. Impact of a Patient-centric Approach There is a significant shift occurring Summer 2019 Volume 11 Issue 2


Regulatory & Marketplace •

in the industry towards greater acceptance of patient-centric practices. The recent EIU report that explored the business impact of patient-centricity across Phase II and III trials found that, compared to traditional trials, when a patient-centric approach was taken: • • •

On average, the drug had a 19 per cent greater likelihood of launch It took almost half the time to recruit 100 participants (four months vs. seven months) The trial recruited an average of double the number of participants (533 vs 271)

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Drugs developed using innovative trial methods (including patientcentric trials) are adopted by payers more quickly

In the future, we foresee greater adoption of patient-centric trials. Patient-centricity is not only the right thing to do, but it can also improve patients’ overall experience with the clinical trial. and help get new medications in the hands of patients faster. Conclusion Patient-centric solutions can globally connect healthcare and clinical research by empowering and enabling connectivity between sites, sponsors, CROs, IRBs and other industry stakeholders. With a patient-centric approach, sponsors can improve the drug development process by reducing the practical, financial and geographical barriers that both patients and caregivers often face and optimise patient involvement and engagement. Simplifying the patient journey with a focus on the patients’ needs and

experiences has been proven to enhance the drug development and commercialisation process. Let us all work together to spread the patientcentricity message and optimise adoption in our own workplace. As the EIU research shows, it’s no longer a nice to have, it’s a business imperative.

Rosamund Round Rosamund is Director of PAREXEL’s Patient Innovation Center and spends her time devoted to simplifying the patient journey in clinical trials. Focused on the reduction of geographical, financial and practical barriers to study participation, Rosamund is excited by the industry shift towards a truly patient-centric approach. Always looking for the next best thing in patient recruitment, Rosamund is delighted to share her learnings around patient-centricity and innovation in patient engagement.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 19


Regulatory & Marketplace

Recent Regulatory Reforms and their Impact on Chinese Pharmaceuticals: A Regulatory Outlook China’s population has reached billions, larger than any other country in the world. This population growth has increased the medical needs and has made China the world’s largest producer of pharmaceuticals. ‘With the vision of regulatory science, service for life.’ China is widely recognised as the second-largest pharmaceutical market in the world. Chinese pharmaceuticals are considered highly challenging due to major historical issues with respect to quality, when compared with international standards and some local products manufactured. Additionally, the time taken for approval of imported innovative and generic drugs as well as domestic new drugs is longer than major developed countries. A lack of capacity in the regulatory authority has resulted in a backlog of applications. To overcome these issues, China has implemented a series of regulatory changes and improvements through a comprehensive regulatory reform starting in August 2015, and these reforms have impacted Chinese pharmaceuticals enormously. The objective of our study is to give a brief overview of the regulatory reforms of the China Food and Drug Administration (CFDA) and their impact on pharmaceuticals. Key Words: CFDA , Regulatory Reforms, Pharmaceuticals, Backlog, Innovative, Generic Etc.

2013 and elevated to a ministeriallevel agency. The China Food and Drug Administration is now part of the State Council of the People's Republic of China. Now the China Food and Drug Administration (CFDA) is the country’s highest regulatory body that oversees the introduction of food, health products, and cosmetics in mainland China. Its responsibilities include drafting laws and regulations for food safety, drugs, medical devices, and cosmetics, as well as establishing medical device standards and classification systems.1 Recent Regulatory Reforms and their Impact Registering API in China ‘On Nov 23, 2017 China announced adjustments concerned with review and approval of active pharmaceutical ingredients, pharmaceutical excipients and packaging materials.’ The review and approval of APIs, excipients and packaging materials has switched from a formal system of separate approvals to a single approval system. That means the premarketing approval policy has been replaced by the DMF (drug master files) filing policy. Since Jan 1, 2018 the CFDA no longer accepts the pharmaceutical excipients registration alone.

Foreign API, pharmaceutical excipients and packaging manufacturers can export the products to China, and it is no longer necessary to apply for an imported pharmaceutical product licence in advance. This was very expensive and time-consuming, usually costing hundreds of thousands to a million USD and needing 2–8 years. According to new DMF regulations, the applicant only needs to submit a dossier (which includes API, pharmaceutical excipients, and packaging materials) to the CFDA. After passing administrative review, the DMF filing acceptance notice (pre-assignment of DMF numbers) will be obtained. After obtaining the DMF number, the pharmaceutical manufacturer can sell their products in China.2 New Classification / Definition of New Drugs – A Globally Aligned Model for Registration of Medicinal Products On March 4, 2016, the CFDA issued a new regulation: ‘the work plan for performing chemical drug registration classification system’. According to this, new chemical drug classification is divided into five categories. The new classification system (2016 version) changed the

Introduction T h e C h i n a Fo o d a n d D r u g Administration (CFDA) is the Chinese agency for regulating food, drugs, and medical devices. The predecessor to the CFDA was initially founded in 1998 to oversee drugs and medical devices. When it was given jurisdiction over food in 2003, it was renamed the State Food and Drug Administration and reported to the State Council. A series of scandals took place in 2008, due to which the regulatory body was put under the supervision of the Ministry of Health (MoH). The state food and drug administration (SFDA) was restructured in March 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Regulatory & Marketplace previous classification system (2007 version) and set forth new registration requirements for application. C h i n a h a s c re at e d a n ew classification category, ‘new to the world’, to replace the ‘new to China’ category. This is based on global marketing authorisation approval status and location of manufacturing site (inside and outside China). This removes the previous definitions that were based on specific status in China and aligns classification more closely to other regulatory agencies. Drugs are classified into ‘new drugs’ and ‘generic drugs’. The definition of ‘new drugs’ has been revised from the current definition (‘drugs which have not been marketed in China’) to the new definition of ‘drugs which have not been marketed in or outside of China’. ‘New drugs’ have been further divided into ‘innovative drugs’ and ‘improved new drugs’. The definition of ‘generic drugs’ has been revised from the current definition (‘drugs generic to established national standards’), to the new definition ‘drugs generic to brand-name drugs with similar quality and efficacy’. Accordingly, the review and approval of generic drugs will now take the brand-name (originator) drug as the reference to ensure that the quality and efficacy of the generic drug is consistent with that of the originator drug.3 No Need for Certificate of Pharmaceutical Product (CPP) for Import Drug Registration Previously, foreign applicants registered their new chemical drug products through a three-submission / threeapproval process (import drugs). 1) Multinational clinical trial submission to request global Phase II and Phase III trial in China. 2) After the drug has been approved and a certificate of pharmaceutical product (CPP) is available from the US or EU (or any other countries), submission to the CFDA to request clinical trial waiver (requesting exemption from need to do any additional local trial). 3) New drug application to the CFDA for marketing approvals.4 www.ipimediaworld.com

The current reforms in the China regulatory system changes this threesubmission / three-approval process to a two-submission / two-approval process. Under this new policy there is no need for the certificate of pharmaceutical product (CPP) (submission to CFDA to request clinical trial waiver), and the sponsor can move directly to the NDA/MAA submission. This simplified process will shorten the whole approval process by at least one year. Previously, the CFDA required that a foreign-developed drug must be approved in another country, and then proceed to China for the NDA/MAA. Even if there is MNCT data in China, the applicant had to wait for the CPP from the US, EU or other countries, and only then could there be a second

submission (submission to CFDA to request clinical trial waiver). Under the new policy, there is no need for the CPP. After completing the MNCT and with a relevant clinical study report (CSR), the sponsor can make an NDA/ MAA submission to CFDA without CPP. This means, theoretically, China NDA/ MAA submission and approval can be in parallel with (or even earlier than) foreign MAA approval. The time required for approval of new drugs has been reduced as compared with the US and EU. Although the data is still limited, a clear trend emerges indicating that the reforms in China have had a positive impact on drug development by reducing approval timelines and processes for INDs and NDAs, as well as reducing drug lag compared INTERNATIONAL PHARMACEUTICAL INDUSTRY 21


Regulatory & Marketplace to approvals in the US and/or EU. The addition of more drug reviewers within the CDE since 2016 has had a significant impact: for NDAs submitted in 2014, 2015 or early 2016, it still took a long time to obtain approval (about 15 to 40 months with an average of 21.4 months). However, for NDAs submitted at the end of 2016 or early in 2017, the timeline has been much shorter with a range from two to 10 months (average 6.8 months).5 Generic Drug Quality and Efficacy Consistency The quality of generic drugs approved in China varies widely. To improve quality, the CFDA has required generic drug manufacturers to start drug consistency research on quality and efficacy with a target completion date by the end of 2018. A product list has been developed by CFDA to inform which generic drugs need this consistency evaluation. For evaluation purposes, the comparator product should be the ‘innovator drug’, or a globally recognised similar drug. Innovator drug means the first marketed drug globally with the full data package to support its safety and efficacy. This would be the situation in which a generic company has previously performed the consistency evaluation, but the comparator was not the innovator drug, so the generic company must re-evaluate against the innovator drug. Comparison studies include formulation, quality standard, crystal form, particulate size, impurities and dissolution profile and in vivo BE studies. Many generic drug manufacturers are seeking clarity on the requirements, and, as a result, the CFDA commenced relevant training in August 2016 and is open to further applicants participating in future training.6

term-extension mechanism was created in order to compensate for the time lost in obtaining market approval, such that the drug innovators remain incentivised to develop new drugs. On April 25, 2018, the CFDA released Pharmaceutical Data Exclusivity Implementing Rules, which also covers innovative therapeutic biologics, orphan drugs and paediatric drugs, as well as drug products that have succeeded in a patent challenge (‘first generics’). Data exclusivity periods are six years for innovative drugs and twelve years for therapeutic biologics if the drug applicant uses data from clinical trials conducted in China, or data from an international multicentre clinical trial in China and a drug application is either submitted in China (first) or submitted in China concurrently with other countries/regions. The exclusivity period may be reduced or revoked under any of the following scenarios: a. When a drug application uses data from an international multicentre clinical trial in China and the drug application filed in China is later than those outside of China, the exclusivity period is one to five years depending on the delay. When the delay is more than six years, there is no data exclusivity. b. If the drug application uses data from clinical trials conducted outside of China with no Chinese patients, the data exclusivity period is 25 per cent of the above. c. If the drug application is supplemented with clinical trial

data in China, the data exclusivity period is 50 per cent of the above. d. The data exclusivity is revoked if a company fails to bring a drug to market within one year after obtaining regulatory approval. For orphan drugs and paediatric drugs, the data exclusivity periods are six years, regardless of the source of the data and the timing of the drug application filing.7 Increasing Drug Review Capacity in CDE (Center for Drug Evaluation) The CFDA’s clinical trial registration and approval process differs from other countries – for example, the USFDA process, in that the FDA uses an investigational filing system, whereas in China there is a clinical trial application (CTA) process. In this process the CFDA will review each trial protocol individually, even if the trial is for a generic drug. Any applicant who is willing to conduct a clinical trial in China has to obtain permission from the Center for Drug Evaluation before conducting each trial, and after completing several steps of the CTA approval process, the applicant can submit a new drug application.8 However, despite the issues associated with the CFDA in 2015, around 70 reviewers were tasked with processing more than 7000 drug applications that were received annually at the CDE. Through recent hiring activity, 600 drug reviewers were added by the end of 2016, and there were more than 800 reviewers employed by the CDE by the end of 2017, with more hiring planned for 2018. Increased human capacity at the CDE led to the resolution of the backlog of applications.

The Reform of the Drug Review System in China – Background9

Data Exclusivity Patent term invention is 20 years from the date of filling. However, even if the company receives the patent for a drug, the company cannot bring the drug to market without regulatory approval. For regulatory approval, clinical trials are needed for regulatory review but to conduct a clinical trial requires almost 6–7 years. Therefore by the time the drug hits the market, the patent may only have a few years of protection left so to address this problem, a patent22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Regulatory & Marketplace a generalised idea on major reforms in Chinese regulatory environments and their impact on the registration of pharmaceuticals.

REFERENCES 1. https://en.wikipedia.org/wiki/China_ Food_and_Drug_Administration 2. http://www.rjs.cn/info/203-1.htm 3. http://www.sfdachina.com/info/202-1. htm 4. http://www.toxicology.org/groups/ss/ rsess/doc/China%20regulatory%20 SOT%20New%20Oleans%20160315.pdf 5. https://pdfs.semanticscholar.org/5d84/ bd8a3cfc024b8d89fe309bf4a802d0f1 d50d.pdf 6. https://www.lexology.com/library/ detail.aspx?g=8721c9d6-124c-4053864d-2f90e299bed7 7. https://www.hoganlovells.com /~/media/hogan-lovells/pdf/2018/ 2018_05_08_pharma_alert_china_ drug_administration_publishes_a_key _draft_guidance.pdf?la=en 8. https://www.raps.org/regulatoryfocus%E2%84%A2/news-articles/ 2017/2/china-works-to-reducemassive-backlog-of-clinical-trial-andmarketing-applications 9. http://www.swiss-chinese-life-sciencesforum.ch/keynote-3-ruyi-he

Mahima R. Mahima R is pursuing a Masters in Regulatory Affairs, Department of Pharmaceutics, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India. Email: mahimrr768@gmail.com

Review Standards and Drug Quality Improvements: New Step to Become a Member of the ICH The International Council for Harmonisation met in Montreal, Canada on 27 May to 1 June, 2017; the ICH assembly approved the CFDA as a new regulatory member. Conclusion Rationalising China’s pharmaceutical environment is critical to the success of www.ipimediaworld.com

China’s ambitious healthcare reforms and health improvements for the people of China. Pharmaceuticals account for about half of total health spending in China, representing 43 per cent of spending per in-patient episode and 51 per cent of spending per out-patient visit. The government wants to develop the domestic pharmaceutical industry and encourage innovation. The eventual goal of all these reforms is to promote public health. Our study gives

Balamuralidhara V. Balamuralidhara V. is an Assistant Professor in the 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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Regulatory & Marketplace

Turkey’s Pharmaceutical Industry and Key Developments In Turkey, the active population, retirees and their dependants are covered by health insurance provided by the Social Security Institution (‘SSI’). Employers must pay monthly contributions for their employees, who automatically become covered. Those who are self-employed may also benefit from this insurance coverage by voluntarily paying monthly contributions. Health insurance provided by the SSI covers practically every physical examination, test and treatment (both outpatient and inpatient) carried out at public healthcare institutions and university hospitals. Any treatment or surgery which is not directly linked to an individual’s actual health is not covered, such as cosmetic surgery, for example. The SSI also covers emergency services undertaken at private health institutions.

Much of the public is covered by SSI health insurance, while only a small proportion benefits from private insurance by paying monthly contributions. As of January 2012, under general health insurance, every citizen in Turkey is now covered by SSI health insurance. The aim is that all citizens who were not covered by SSI health insurance packages now benefit from public health insurance. For a pharmaceutical product to be reimbursed, it will be registered in the ‘reimbursement list’ of the SSI. The price is subject to obligatory discounts to be registered in the reimbursement list. As the SSI is the biggest buyer of pharmaceutical products, for pharmaceutical companies, sales of pharmaceuticals start with entering the reimbursement list. All products sold to the SSI by foreign or domestic producers must be listed on a reimbursement list. Key Developments On April 2, 2019, the European Union (‘EU’) requested a consultation before the World Trade Organisation (‘WTO’) regarding measures adopted by Turkey in relation to the production, importation 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and marketing of pharmaceutical products, which it claimed would be non-compliant with international agreements. Background to the Request The increase in the number of imported products and the lack of domestic manufacturing pushed the government to identify a new solution to enliven the local economy and enable a ‘know-how’ transfer. Following the announcement of the Structural Transformation Programme Action Plan for Healthcare Industries by the Prime Minister, Ahmet Davutoğlu on November 7, 2014, Turkey started adopting measures to localise the production of a substantial amount of pharmaceutical products sold in Turkey. On December 10, 2015, the 64th government announced the 2016 Action Plan (64th Government Action Plan), and according to action item No. 46: •

It will be ensured that the medicines for which application is made to be manufactured in Turkey are prioritised in licensing registered by the Ministry of Health (‘MoH’) upon being considered together with reimbursement policies of the Social Security Institution (‘SSI’). The SSI will make the relevant arrangements in the legislation and accelerate the evaluation process for the inclusion of healthcare products manufactured domestically into the reimbursement list. Imported products to be delisted from the reimbursement list will be identified, provided that relevant guarantees are issued for the provision of treatment.

The plan implied that imported products having a locally manufactured equivalence will be delisted from the reimbursement list. Following the 64th Government Action Plan, a Health Industries Steering Committee (SEYK) was formed by the Prime Ministry. One of

the major topics in the SEYK agenda was set for ‘transition from import to local manufacturing’. Accordingly, in line with the 64th Government Action Plan, a localisation process started for imported pharmaceuticals. On March 4, 2016, the MoH and the SSI published an announcement regarding the localisation process. In this announcement, it was stated that in accordance with Action Item No. 46 of the 64th Government Action Plan, sales figures for imported products having more than one generic available in the market would be examined. In order to prevent any supply shortage in the market, a timetable was created as a result of the negotiations with the related associations, trade unions and companies for the localisation of the products having more than 50% local manufacturing market share. Within this context, companies were asked to provide an undertaking with respect to local manufacturing of the imported pharmaceuticals (which do fall within the determined category) or provide suitable reasons if they are not able to provide an undertaking for local manufacturing by March 22, 2016. The announcement also provided information about the foundation of the ‘Transition from Import to Local Manufacturing Commission’ (‘Transition Commission’). Although the announcement dated March 04, 2016 stated that the aim of the process was not to delist the imported products but to ‘incentivise’ local manufacturing, if companies did not agree to manufacture the relevant products locally, they would be delisted. Following the announcement, the MoH held several meetings with company representatives, outlining the process and timeline. Each company individually negotiated with the MoH about their plans (if any) with respect to local manufacturing of their imported products which fall within the category set by the government. Since the SSI’s announcements on February 8, 2017, it has removed from the reimbursement list two groups of Summer 2019 Volume 11 Issue 2


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Regulatory & Marketplace products which have two or three local alternative generics. EU’s Legal Grounds In the consultation request circulated to WTO members on April 10, 2019, the EU claimed that the various measures implemented by Turkey via legal and administrative tools are inconsistent with Turkey’s obligations covered under the provisions of the General Agreement on Tariffs and Trade 1994 (‘GATT 1994’), Trade Related Investment Measures (‘TRIMs Agreement’), Agreement on Trade-Related Aspects of Intellectual Property Rights (‘TRIPS Agreement’) and Agreement on Subsidies and Countervailing Measures (‘ASCM’), in particular: • Article III:4 of the GATT 1994, because, by excluding imported pharmaceutical products for which localisation commitments have not been given, have not been accepted or have not been fulfilled from the reimbursement scheme, the localisation requirement accords to imported pharmaceutical products being treated less favourably than similar products of national origin covered by that scheme in respect of laws, regulations and requirements affecting their internal sale, offering for sale, purchase, transportation, distribution or use. • Article III:4 of the GATT 1994, because, by according priority to the review of applications for inclusion in the reimbursement scheme, as well as with respect to any other pricing and licensing policies and processes of pharmaceutical products of national origin, the prioritisation measure is more favourable than to similar imported products. • Article X:1 of the GATT 1994, because Turkey failed to publish all general application matters relating to the localisation and technology transfer requirements, and the prioritisation measure promptly, and in such a manner as to enable governments and traders to become acquainted with them. • Article X:2 of the GATT 1994, because, through these measures, Turkey applies a new or more burdensome requirement, restriction or prohibition on imports which is enforced before being officially published. 26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Article X:3(a) of the GATT 1994, because Turkey failed to administer its laws, regulations, decisions and rulings in relation to the localisation requirement, the technology and transfer requirements and the prioritisation measure in a uniform, impartial and reasonable manner. Article XI:1 of the GATT 1994, because, once a foreign producer locally produces a particular pharmaceutical product pursuant to the localisation requirement, applied in conjunction with the Turkish rules for approving the importation and marketing of pharmaceutical products, that product can no longer be imported, and, therefore, Turkey institutes and maintains a prohibition or restriction, other than duties, taxes or other charges on the importation of products of other contracting parties. Article 2.1 of the TRIMs agreement, b e c a u s e t h e l o c a l i s at i o n requirement is an investment measure inconsistent with Article III:4 of the GATT 1994. Article 3.1 of the TRIPS agreement, because the technology transfer requirement does not apply to domestic producers of pharmaceutical products; it, therefore, treats the producers of other Member States less favourably than the domestic producers in respect of their protection of intellectual property. Article 27.1 of the TRIPS agreement, because the technology transfer requirement may cover patent rights and does not apply to domestic producers and patents are not available and patent rights are not enjoyable without discrimination as to whether products are imported or locally produced. Article 28.2 of the TRIPs agreement, because the technology transfer requirement may cover patent rights and because it restricts or infringes the right of patent owners to assign, or transfer by succession the patent and to conclude licensing contracts. Articles 39.1 and 39.2 of the TRIPS agreement, because the technology transfer requirement may require foreign producers to transfer undisclosed information protected

by those provisions to a Turkish producer. Article 3.1 b) of the ASCM, because the reimbursement scheme operated by the Turkish social security system involves the granting of a subsidy within the meaning of Article 1.1 of the ASCM. The localisation requirement makes that subsidy contingent upon the use of domestic goods over imported goods, thereby violating Article 3.1 b) of the ASCM. A statement of available evidence about the existence and nature of that subsidy is annexed to this request.

Consequently, the EU stated that competitive opportunities in the Turkish market on imported pharmaceutical products are significantly impaired, compared to domestically produced products. Consultation Procedure and Next Steps The Dispute Settlement Understanding, on which the EU made this consultation application, will be applied to disputes brought pursuant to the consultation and dispute settlement provisions of the agreements listed in Appendix 1 of the Dispute Settlement Understanding which covers the agreements on which the EU grounded its allegations. The dispute settlement system of the WTO established under the Dispute Settlement Understanding is a key element to provide security and predictability to the multilateral trading system. The members of the WTO recognise that the dispute settlement system is intended to preserve the rights and obligations of members under the covered agreements, and to clarify the existing provisions of those agreements in accordance with customary rules of interpretation of public international law. With

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Regulatory & Marketplace on more time than the 60-day period. It will be interesting to see if the various parties will extend the consultation period once they publish the result of the meeting in Geneva.

Özge Atılgan Karakulak Article 2 of the Dispute Settlement Understanding, the Dispute Settlement Body (“DSB”) has been established to administer these rules and procedures and, except as otherwise provided in a covered agreement, the consultation and dispute settlement provisions of the covered agreements. Accordingly, the DSB has the authority to establish panels, adopt panel and appellate body reports, maintain surveillance of the implementation of rulings and recommendations, and authorise the suspension of concessions and other obligations under covered agreements. Further to the Dispute Settlement Understanding, before bringing a case, a member must exercise their judgment as to whether action under these procedures would be fruitful. The aim of the dispute settlement mechanism is to secure a positive solution to a dispute. A solution mutually acceptable to the parties to a dispute and consistent with the covered agreements is clearly preferable. In the absence of a mutually agreed solution, the first objective of the dispute settlement mechanism is usually to secure the withdrawal of the measures concerned if these are found to be inconsistent with the provisions of any of the covered agreements. Provision of any compensation should only be looked at if the immediate withdrawal of the measure is impracticable, and be used temporarily pending the withdrawal of the measure which is inconsistent with a covered agreement. The last resort which the Dispute Settlement Understanding provides to the member invoking the dispute settlement procedures is the possibility of suspending the application of concessions or other obligations under the covered agreements on a discriminatory basis vis-à-vis the other applicant member, subject to www.ipimediaworld.com

authorisation by the DSB of such measures. Pursuant to the provisions of the Dispute Settlement Understanding, the EU, therefore, made a consultation request on 2 April 2019. Additionally, on 24 April 2019, the United States (‘US’) requested to join in these consultations, pursuant to Article 4.11 of the Dispute Settlement Understanding. The US stated that they have a substantial trade interest in these consultations, as they are one of the world leaders in the development, production, licensing, and marketing of pharmaceuticals and in 2018, the US exported $219 million of pharmaceutical products to Turkey. The US is also of the opinion that measures adopted by Turkey in relation to the production, importation, and marketing of pharmaceutical products, including localisation and technology transfer requirements, an import ban on localised products, and a prioritisation measure, are inconsistent with Turkey's obligations under covered agreements. Under the provisions of the Dispute Settlement Understanding, the complainant is required to reply to the request within 10 days following the date of receipt and enter into consultations in good faith within no more than 30 days following the date of receipt. Turkey positively replied and entered into the consultation period and the various parties met in Geneva on 9 and 10 May 2019. If the dispute is not settled within 60 days from the date of receipt, the EU may request that a panel be established. The EU may request such a panel if the parties collectively believe that the consultations failed in settling the dispute. The parties may agree also

Özge Atılgan Karakulak has been with the firm Gün + Partners since 2005 and has been a partner since 2013. With the combination of Özge’s advisory and litigation expertise and in-depth knowledge of the life sciences sector, she advises clients across all phases of the business cycle of life science products, such as registration / authorization procedures, promotion practices, pricing and reimbursement regulations, distribution relationships and co-marketing deals. Email: ozge.atilgan@gun.av.tr

Dicle Doğan Dicle Doğan is a managing associate in Gün + Partners and she has been working for the firm since 2011. Dicle has been specialized on Life Sciences, and intellectual property with a special focus on trademarks and designs. She advises corporate clients from life sciences sector, especially multinational pharmaceutical and medical device companies. Email: dicle.dogan@gun.av.tr

Fatma Sevde Tan Fatma Sevde Tan is an Associate at Gün + Partners. She represents clients before the Civil Courts for Industrial and Intellectual Property Rights and Commercial Courts in actions relating to patents, utility models, invalidations, infringements and unfair competition. Email: fatmasevde.tan@gun.av.tr

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Digital Transformation and the Medical Device Sector Modern patients have an interest in and expectation of playing a part in their own health matters, enabled by new digital connections and advanced technology. In this emerging Medicine 2.0 era, as healthcare starts to harness this in earnest, the scope for personalised treatment becomes significant. ProductLife Group’s Loetitia Jabri asks where this is heading, and what challenges might crop up for medical device manufacturers in particular

Aided by modern technology, the once-formal distance between physicians and patients is closing, contributing to a new revolution in medicine. As digital life becomes the norm, patients are feeling increasingly empowered and eager to engage in their own health matters, able to connect with information, help and care in new ways. All of this is defining a new era – dubbed Medicine 2.0 – in which healthcare catches up with the kinds of advances technology has enabled in other industries. Innovations include the digitalisation of diagnosis, and disease prevention, through the use of wireless/mobile health solutions including smartphone apps, wearables, gamification and remote monitoring.

All of the medical information generated is playing an increasingly important role in the new doctor–patient relationship, which in turn is becoming more collaborative. ‘Connected’ medical devices give patients greater control over their health data, and in turn enable doctors to use the data to prompt beneficial patient behaviour. With advances in telemedicine, meanwhile, and with rapid increases in the numbers of next-generation medical devices capable of harnessing artificial intelligence, both doctors and patients now have even more medical information available to them. Even Regulators Welcome Progress Regulatory authorities, too, are eager to promote Medicine 2.0 through the development of wireless devices. In October 2010, the US Federal Communications Commission and the US Food and Drug Administration (FDA) partnered to encourage investment in wireless healthcare devices, and the European authorities have become increasingly willing to give such solutions the CE marking required on drug products to be sold in Europe.

Modernising Medical Devices The medical device sector, in particular, represents a natural fit for Medicine 2.0, and innovative companies have been quick to take advantage of the possibilities.

Despite regulators’ moves to encourage digital innovation, the complex nature of the new types of devices, added to their speed of development, the ways data is used, and who by, means both the life sciences industry and the authorities will have to prepare for change. Policymakers and regulators must keep pace with the innovations emerging across the industry.

Over the last 10–15 years, the technological revolution has seen the emergence of digital medical devices that empower patients and close the communication gap with healthcare providers. Today smartphone apps and devices such as Fitbit, the Apple Watch, and other connected objects – such as connected blood pressure monitors – keep track of patient activity and generate valuable data.

One of the biggest challenges involves efficiently achieving validations of digital health devices and smartphone apps – that is, ensuring the intended use of a medical device and the management of its data. Companies must have objective evidence of validation to meet product specifications. Consider, for example, wireless technologies, whose validations will be needed to ensure the quality of the device, and

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to protect patients from interference and unsecured lines. Complexity arises because device validation will also depend on the network being used to transmit and receive data. As medical devices increasingly look to harness advances in artificial intelligence – enabling devices to guide patient therapy, for instance – regulatory processes will have to adapt here too. Another issue may be a future requirement to perform double-blind studies involving large patient cohorts for combination products. Indeed, the FDA has encouraged randomised, double-blind, sham-control trials for class III devices such as pacemakers. Blurring Boundaries Regulators must also take into account the changing patient–physician relationship. Today’s patients expect to be more involved in their own care, and digital medical device solutions are making that increasingly possible. But how that involvement might affect the regulatory framework is not fully understood, despite ongoing workshops between the European Commission and medical device manufacturers. Certainly, medical device manufacturers will need to tread a fine line between innovation and patient safety. Data from patient sensors must be properly integrated with medical information; otherwise, there’s a risk that the information could be misinterpreted and endanger the patient. Beyond patients’ physical wellbeing, there are inevitable concerns about data privacy. There are strong defences in place to protect personal data now, and medical data is among the most vigorously safeguarded because of its ultra-sensitive nature. So developers will need to ensure, and build confidence in the expectation, that a patient’s data is secure from external access and use. Summer 2019 Volume 11 Issue 2


Regulatory & Marketplace who are unable to easily communicate their health issues.

And what about patient-developed devices, and the potential regulatory and safety consequences that could result from these? For example, the #WeAreNotWaiting diabetes movement resulted in the development of apps, cloud-based platforms, and reverseengineering of currently marketed products aimed at helping people with diabetes. Most notable was the development of an artificial pancreas. But because the associated system was developed without regulatory oversight, its reliability is unknown, which raises concerns that patients could be put at risk. Perhaps the most complex issue to keep on top of is accelerating change in other markets. For example, China has made significant changes to its medical device regulations, aimed at reducing the complexity of the approval process and making it easier for smaller medical technology companies to bring products to market. That change removes a lot of complexity for medical devices companies in China and enables them to become more competitive. Practising Due Care Without Curbing Creativity Whatever the regulatory challenges and other issues digitised devices can introduce, there is enormous potential for companies to leverage new capabilities in the age of Medicine 2.0: from wireless body sensors; to patientspecific, 3D-printed implantable devices; pumps that enable people with diabetes to deliver insulin to themselves; and even implants with sensors via which a patient can send a message to the doctor. Companies can take advantage of the widespread use of smartphones to develop medical device apps for patients, too. Another powerful avenue could be to develop monitoring devices for children – particularly young children www.ipimediaworld.com

The Rise of Intelligent Automation: Medicine 3.0 As we move closer to an even more advanced age, Medicine 3.0 – which will see artificial intelligence capabilities being integrated into medical devices – companies will need to be nimble in responding to the market’s demands and expectations, and regulators will have to be ready to adapt to ever-changing innovation. The future is here, and patients are ready to embrace it. Personalised medicine means giving doctors and patients the abilities to adjust and calibrate treatment through the use of data derived from a range of self-indicators. Equally, the rise of big data – the combination of data collected about and by the patient – has the potential to be a treasure trove of real-world data if managed properly. Medical device companies must find ways to efficiently gather such data so they can extract knowledge and information for the benefit of patients, for population health, and for overcoming potential technological and therapeutic challenges. Without the right approaches, that treasure-trove of knowledge will be nothing more than a chaotic jumble of data. To thrive in a patient-centric era, medical device manufacturers will need to stay a step ahead. This is likely to require partnership with a variety of companies – from telecommunications providers to biotech firms – as well as regulators, to ensure that progress is not impeded, yet that patient safety remains sacrosanct. Innovation in Action Among today’s more creative, digitally-enabled medical device manufacturers are:

Micrima, whose handheld breast cancer screening system, MARIA, uses benign radio waves to detect cancer – in place of traditional mammography, which uses ionising radiation. Organovo, which developed ExVive, a 3D bioprinting of human tissue models that

is designed to enable humantissue-specific data to be captured for better evaluation of drug compounds than in traditional animal studies. Medtronic, which is partnering with Fitbit to provide a tracking platform for patients with diabetes. The iPro2 myLog app lets patients with type 2 diabetes capture their information and, combined with their glucose sensors, manage their glucose levels. Livermore, which partnered with BioLuminate to develop Smart Probe, which can distinguish between cancerous and healthy tissue. Sensors on the probe measure optical, electrical and chemical properties. Similarly, Sandia’s smart scalpel aids surgeons in the removal of cancer cells, helping them reduce the amount of healthy tissue removed. Novartis and Qualcomm, which have been collaborating to develop connected inhalers that send the patient medication reminders and transmit real-time data to the physician. Apple, which has received FDA approval for an atrialfibrillation-detecting algorithm and an electrocardiogram built into the Apple Watch. If this detects an irregular rhythm consistent with atrial fibrillation, it sends the patient a notification.

Loetitia Jabri Loetitia Jabri is pharmaceutical & medical devices platforms associate director at ProductLife Group – with responsibility for organising and managing regulatory and pharmaceutical platform services as well as leading the development of delivery activities for the medical device sector. www.productlifegroup.com

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Drug Discovery, Development & Delivery

Beyond the Pill Personalisation by Integrating Oral Medication and Digitalisation Pharmaceutical innovation has accelerated, but the way of dosing oral medicines to patients has broadly stayed the same. Prescription medicine delivered as tablets in a bottle often does not provide a good fit for patients or treatment goals. However, better personalisation and improved treatment outcomes could be achieved if oral medicines could be integrated into a handheld digital device. Oral medicine formulated as granules coupled with digital technology could provide the flexibility that patients and physicians are looking for, thus helping with the goal of moving beyond the pill.

Treatment goals, depending on the therapeutic area and patient group, can be significantly impacted in the simplest way. The formulation may be appropriate, but the patient can be the source of the challenge, whilst at other times, the patient is willing, but the formulation can be the issue. The challenges that can be experienced for different patient groups using oral medicine for treatment of different conditions can be summarised: • • • • • • • •

Accurate dose titration Difficulties swallowing Ease of use Confusion which medicines to take at what time for what disease Avoidance of misuse and or abuse Diversion and use by others than the intended patient Compliance and monitoring Integration with other sources of health data and information.

Several efforts looking for improvement of these challenges have been developed or are in development. For example, compliance-supporting measures such as a pill incorporating a mini-transmitter, digital-calendarised pill boxes, extended release formulations, a capsule which once swallowed can dispense medication for a week; help with swallowing difficulties such as oral disintegrating tablets, powder formulations; enabling dose titration 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Treatment of ADHD

using mini-tablets in a syringe for paediatrics or a self-fill digital container. However, most of these ideas focus on one or two of the challenges and not the whole solution. One product in development integrates oral prescription medicine with intelligent dosing in a handheld digital device. It is a prescribed regimen consisting of two parts: a re-usable control unit and a disposable prefilled cartridge with active medicine. One development treatment area is ADHD. For these medications the control unit would last for 12 months or more whilst the cartridge would last for one month’s prescription. New cartridges are attached by the patient each month. Attention-deficit hyperactivity disorder (ADHD) is a common, neurobehavioural disorder, with onset in childhood, that can result in inappropriate inattentiveness, increased impulsivity and hyperactivity, affecting multiple areas of life. Prevalence of ADHD has been estimated to be 11% in children and 4% in adults1. Stimulants (methylphenidates and amphetamines) are the best-known and most widelyused ADHD medications, despite concerns about their adverse effects and potential for abuse. These drugs are highly effective in reducing core ADHD symptoms, and help patients to concentrate better, be less impulsive,

feel calmer, and learn and practise new skills. In clinical practice, however, stimulants require substantial efforts in fine-tuning and titration of doses for the maximum patient benefit without adverse effects. This is especially true during treatment beginnings but can also remain an issue as patient grows 2. Moreover, there is a growing concern over misuse, abuse and diversion of stimulant drugs. ADHD medicines are controlled substances, yet one in eight teenagers has misused or abused them, which increases to one in five among college students3. An investigation which tracked calls to the American Association of Poison Control Centres from 1998 to 2005 observed a 76% increase in calls related to teenaged victims of prescription ADHD drug abuse over that eight-year span4. A further challenge for treatment of ADHD and many other diseases is the difficulty in swallowing pills which can subsequently impact compliance. This is observed frequently in children but also in 10 to 40% of the adult population 5,6. Eventually treatment success depends on compliance and adherence to medication. This has been found to be a key challenge for children, even when treated by caregivers, adolescents and adults with ADHD7,8. Summer 2019 Volume 11 Issue 2


Drug Discovery, Development & Delivery Personalisation Through Formulation The company formulates the oral medication as small granules or micro-units (less than 1000 µm). This supports patients who do not like to swallow pills or find difficulty swallowing pills. The granules can be administered directly orally or taken together with liquid or soft food. Depending on medication, the company can utilise taste-masking (if needed) to solve palatability. The use of small granules or mini-units also helps with more accurate and individualised dose titration. Often titration of medication is needed due to a drug narrow therapeutic range, dosing based on the weight of the patient, and dose adjustment to optimise effect and minimise side-effects7. However, the use of small pellets or granules can present a technological challenge for product development. The ability to dose titrate accurately within regulatory guidelines can vary depending on the API used, loading of the API in each granule and physical characteristics of the formulated granule (such as surface properties, shape, size and hardness). In addition, the optimal approach is to use a mechanical dispensing technology rather than dispensing being dependent on gravity. The company has developed a proprietary technology to achieve these goals. Therefore, setting the dose and adjusting the dose and dispensing the dose on the ADHD prototype is achieved through a simple D-pad on the control unit showing the chosen dose on an LED display. The Potential of Digitalisation Product design to develop an improved approach to dosing oral medicines relies on designing the mechanical, software and hardware systems as well as the user interface. Digitalisation provides several advantages compared to conventional pills in a bottle. The pre-filled cartridge (for ADHD, a one-month prescription) has an integrated circuit board chip which communicates relevant information to the control unit. The cartridge enables the control unit to set the dose, prevent from taking more than the maximum dose, allow titration, ensure notification of tampering, and record drug dispensing. The information available immediately provides opportunities to support compliance. Such information www.ipimediaworld.com

in an anonymised form could also be used in the future provide useful information on treatment. The control unit of the device itself can provide dose reminders and a log of the previous dose taken. Further personalisation through connectivity, using Bluetooth and a companion application on a smartphone, opens the possibility to provide an accurate log of drug dispensing over time. Opportunities exist for self (caregiver)reporting of symptoms. With ADHD these could include level of concentration, hyperactivity, behaviour, schoolwork etcetera, which can further support treatment outcomes9,10. For caregivers, access to information in a companion application will help provide reassurance regarding compliance and treatment effect10. Whilst many separate smartphone applications exist, the possibility to directly link to the device dispensing medication, showing both dose and time the dose was taken, adds an additional dimension to the data collected, especially when aligned with self-reported symptom monitoring. The product could be linked to existing applications or a dedicated application. Connectivity also opens opportunities enabling the device and companion application to be developed to link to other units, relevant to a disease area, such as wearables monitoring activity. Personalisation Through User ID With controlled substances the risk of misuse and abuse are key concerns and has more recently been the target of policy-makers. The company has an interest in the pain area with the aim to provide reassurance of correct medication use. Similar user identification can be important with ADHD medications which are controlled substances. This was observed as a positive product attribute by physicians, patients, caregivers and payers in market research focused on ADHD treatment which the company conducted in the US. The advantage of integrating medicine and digitisation allows for personalisation and user identification. The control unit would enable this through use of a pin code or biometric identification. More Focus on Paediatric Formulations There is an increasing focus toward paediatric medicines which presents a

key challenge for regulatory authorities. Approximately 50–75%11,12 of drugs used in paediatric medicine, lack FDA-approved paediatric formulations, leaving approximately 40% of children worldwide at increased risk of adverse events such as suboptimal dosing, lack of adherence to medication regimens, and reduced access to novel treatments13. This gap has resulted in a global effort towards an improvement of paediatric formulations and their delivery13,14,15. Different groups and consortiums such as the European Paediatric Formulation Initiative (EuPFI) are focused on this important area. Areas of interest are age-appropriate formulations, taste-masking, and use of excipients, as well as devices to dose accurately to support paediatric patients. Product development by the company recognises that this is an area where their granule-dispensing technology could be useful. A qualitative investigation on how children received their medication highlighted that adult tablets are broken into smaller pieces, then crushed and added to food or liquid and often, parents resort to hiding or forcing administration, or discontinue treatment completely after unsuccessful attempts16. Liquid or syrup formulations can offer a suitable alternative but not all drugs can be formulated as such: the volume/dose ratio of liquid medicines can be impacted by solubility of the medicine, which may require additional excipients17. Product stability may require addition of other compounds such as antioxidants and preservatives, whereas taste-masking may require sweeteners and flavours. Other challenges associated with liquid delivery form include the need to shake the suspension, transport and storage of liquid medicines (often requiring refrigeration), and an accurate measuring device (spoons, cups and others are not always accurate and/or are hard to read). The WHO specifically recommends a ‘flexible solid oral dosage’ design as the optimal formulation for oral paediatric medicines18. Product development using small granules will facilitate concerns of children and caregivers regarding swallowing conventional pills. Such formulation technology can be designed with taste-masking if needed to support palatability. Dose titration using the INTERNATIONAL PHARMACEUTICAL INDUSTRY 31


Drug Discovery, Development & Delivery

8.

9. 10.

11. 12. 13. 14.

15.

same technology to accurately dispense pellets can be used. Depending on the course of treatment or treatment regimen, however, digitisation may be less critical and as such, compliance monitoring could be achieved mechanically on the device. Individualisation and Personalisation with Oral Medicine Oral medication for ADHD, pain management and paediatrics can be improved to support the needs of patients, caregivers and healthcare professionals. Different conditions and patient groups present many challenges which conventional oral medications do not currently meet. Treatment outcomes in other treatment areas can also benefit from improvements of integrating oral formulations with digital technology. Titration and compliance are critical for post-organ-transplant patients treated with immunosuppression drugs. Geriatric patient groups present issues with swallowing difficulties, compliance monitoring and dexterity issues with current tamper-proof packaging. Several product development initiatives to improve aspects for oral medication address one or two of the issues being experienced. Through 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

integrating medicine, intelligent dosing in a handheld digital device, the company hope to address the challenges experienced and therefore support improvements in treatment outcomes. REFERENCES 1.

2.

3.

4.

5.

6. 7.

Simon V et al. Prevalence and correlates of adult attention-deficit hyperactivity disorder: meta-analysis. Br J Psychiatry 2009; 194: 204–211. Brown K et al. Pharmacologic management of attention deficit hyperactivity disorder in children and adolescents: a review for practitioners. Transl Pediatr. 2018 Jan; 7(1): 36–47. Cleamow DB and Walker DJ. The potential for misuse and abuse of medications in ADHD: a review. Postgrad Med. 2014; 126(5):64-81. Setlik J, Bond GR, Ho M. Adolescent prescription ADHD medication abuse is rising along with prescriptions for these medications. Pediatrics. 2009; 124:875880. Sefidani Forough A et al A spoonful of sugar helps the medicine go down? A review of strategies for making pills easier to swallow, Patient Prefer Adherence. 2018; 12: 1337–1346 Patel A et al. Effectiveness of paediatric pill swallowing interventions: a systematic review 2015; 135(5): 2014-2114 ADHD: Clinical Practice Guideline for the

16.

17. 18.

Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents Pediatrics November 2011, VOLUME 128 / ISSUE 5 From the American Academy of Pediatrics Clinical Practice Guideline https://www.additudemag.com/ adhd-treatment-options-caregiversadults-survey-results/ visited on 27 March 2019 https://www.addrc.org/importance-adhdtreatment-monitoring/ visited 27 March 2019 Powell L et al, ADHD: Is There an App for That? A Suitability Assessment of Apps for the Parents of Children and Young People With ADHD, JMIR Mhealth Uhealth. 2017 Oct; 5(10): e149. Published online 2017 Oct 13. doi: 10.2196/mhealth.7941 https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC3772669/ visited March 27, 2019 https://www.ncbi.nlm.nih.gov/ pubmed/12928467 visited March 27, 2019 https://www.ncbi.nlm.nih.gov/ pubmed/19108801 visited 27, March 2019 van Riet-Nales DA et al., Methods of administering oral formulations and child acceptability. International Journal of Pharmaceutics. Volume 491, Issues 1–2, 1 August 2015, Pages 261-267 Revised WHO Classification and Treatment of Pneumonia in Children at Health Facilities: Evidence Summaries. Geneva: World Health Organization; 2014. Bergene, E. H., Rø, T. B. & Steinsbekk, A. Strategies parents use to give children oral medicine: a qualitative study of online discussion forums. Scand. J. Prim. Health Care 35, 221–228 (2017). Nunn, T. & Williams, J. Formulation of medicines for children. Br. J. Clin. Pharmacol. 59, 674–6 (2005). Newell, M.-L. & Cambridge, M. J. E. series; 958. The selection and use of essential medicines: report of the WHO Expert Committee. Bull. World Health Organ. 81, 1969–1987 (2007).

Martin Olovsson Martin Olovsson has over 25 years in the life science industry. He has had senior roles within the pharmaceutical industry across commercial and development at local, regional and global level. Martin has a past as global lead for the Respiratory franchise in AstraZeneca and as CEO of AstraZeneca Nordic-Baltic. Martin cofounded OnDosis in 2017 based on a concept from AstraZeneca. Email: m.olovsson@ondosis.com

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Drug Discovery, Development & Delivery

Biologic Medicines and Patient-centricity – A New Phase of Hope The global pharmaceutical industry has entered an exciting new era of drug development, bringing new hope to patients around the world. It is estimated that close to 40 per cent of all medicines in pipeline development are biologic in nature. The world’s top-selling commercial biologic medicines cover a broad range of diseases – including autoimmune challenges such as various forms of arthritis and psoriasis, Crohn’s disease, ankylosing spondylitis, ulcerative colitis, as well as other conditions such as multiple sclerosis and macular degeneration – bringing hope to many long-suffering patients.

Biologic medicines have also transformed treatment and personal care for a significant portion of the diabetes patient population. Furthermore, biologics have provided breakthrough therapies in the advanced treatment for various forms of cancer, where more than 70 new therapies have entered the market within the past five years, many of which are biologic in nature. Within the last few years, favourable incentives have also encouraged the use of biologics to treat rare and orphan diseases, bringing much-needed hope to a significantly under-served population. In the US, the FDA has approved record numbers of new drug approvals in the consecutive years 2016 and 2017, as well as keeping pace in the first half of 2018. Drugs with special designation including orphan, breakthrough, etc. have comprised approximately 40 per cent of new FDA drug approvals over this 30-month period1. It is also noteworthy that approximately 25 per cent of these new drugs represent cancer therapies1. It is also worth noting that biologics represent big business potential for drug developers. The top ten biologic medicines comprise therapies with annual global revenues in excess of $71 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

billion2. Biologics represent seven out of the top ten best-selling medicines across all therapeutic categories3. There are currently more than 45 biologic medicines on the market that have reached blockbuster status (selling more than $1bn annually) and ten biologic medicines yield sales in excess of $5bn globally. The total biologic market is expected to reach $390bn by 20204. The rise of biosimilars, or generic biologics, represents another attractive growth opportunity for the pharmaceutical industry – and is a perceived win for the patient population by way of reduced access and decreased cost through market competition. Biologic medicines facing patent expiration represent noteworthy biosimilar market opportunity for a multitude of developers. By 2020, biosimilars have the potential to enter the market for brand biologics currently representing more than $45bn in global sales4. Changes in Drug Delivery Bring New Freedoms The advent of biologic medicines brings considerably different forms of drug delivery compared to traditional oral solid-dose medications. In the early days of introducing biologic medicines to the healthcare market, drug products were commonly delivered in traditional glass vials requiring ancillary components for administration – such as syringes or needles of various gauges depending on drug and patient tolerance, potentially paired with safety applicators or other devices. These medicines may have been self-administered by appropriately trained patients, but more commonly they were administered by healthcare professionals in clinical settings. The implications of this method of delivery require frequent visits to healthcare facilities by patients to seek treatment, which – for some diseases – could be multiple times per week. This continues to be a common platform for many institutionally administered medications.

With the progressively competitive landscape and the healthcare industry’s initiative to become more customerfocused, or ‘patient-centric’ – coupled with the payer community’s desire to limit patients being onsite in clinical settings to reduce the cost burden – more focus and resource has been placed on advancing drug delivery forms to allow easier routes of administration for patients. In some instances, this is driving development of better methodologies for drug delivery in the clinical setting, but increasingly the focus has been to provide safe, reliable and convenient forms of drug delivery for patients to self-administer, with the goal of minimising the impact to their everyday lifestyle and providing more freedom from the burden of receiving their medication in a formal healthcare setting. Diabetes care is one great demonstration of the popularity of this developing technology, with multi-use – and often refillable – injectible insulin pens spreading past developed markets in North America and Europe, rapidly progressing now into developing and third world countries. This transition has generated new paradigms for patients, providing more freedoms but also shifting the burden of responsibility for safe and accurate dosing from the clinical environment to the patient. This raises the stakes considerably for the pharmaceutical company, which needs to ensure that the patient is best positioned for success. In fact, even the best and most effective medication would fail to garner FDA approval without the execution

Summer 2019 Volume 11 Issue 2


Drug Delivery Devices Innovative developments Customized solutions GMP contract manufacturing

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

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 35


Drug Discovery, Development & Delivery

and successful demonstration of comprehensive human factor study analysis; that this has been performed and has shown that the average patient can administer the therapy easily, effectively, and repeatably. The Impact of the Transition for Injectibles The popularity of prefilled syringes has grown considerably over the past few decades; the current global market is estimated to be between three and four billion syringes annually, with projected growth of between eight to ten per cent, year-on-year, fuelled largely by the burgeoning Asian market5. The familiarity and growth in the diabetes market has provided significant economies of scale in the syringe market, as well as provided the platform for advancing syringe material and delivery technologies. As the market has progressed to consideration of safety and ease of use, exciting new developments have been introduced to both aid the injection process for patients, and to provide safety measures to reduce potential for accidental needle sticks or other concerns. Innovative approaches have been taken to engineer solutions for sheathing needles with protective covers, triggered by use, or retracting needles into the housing of the prefilled syringe system. Likewise, patient comfort has been better addressed in advanced delivery systems with refined needle technologies, particularly impactful for large-volume injections. Such advanced prefilled syringe delivery and added safety features bring increased complexity in assembly and handling. Precise multi-part integrated assemblies with precision-moulded plastics and spring-based systems demand expert automated solutions, complete with multi-stage in-process inspection to ensure the accuracy 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

of each sequential assembly. This systematic and sequential approach to assembly provides consistency in mitigating risk and maximising safety, ensuring reliable delivery in every dose. Failure in accuracy for any individual assembly would likely result in a failure of the intended feature. PCI’s investments in cutting-edge technologies have focused on robust multi-level inspections to ensure that safety and accuracy are consistently and reliably achieved for these complex assemblies. Pens and Autoinjectors – the Next Generation of Convenience The success of products such as Enbrel, Avonex and Lantus has paved the path for the advancement of autoinjector and pen technologies, rapidly progressing this as an important growth category for the biotech market. The sheer scale of the market has made investment attractive for the category. Whereas initial pioneers in the autoinjector and pen markets were once forced to create and engineer their own technologies, leading providers – such as Ypsomed, SHL Group, Beckton Dickinson, West and others – have now created portfolios of ‘off the shelf’ proprietary innovative delivery systems built on standardised syringe or cartridge deliveries from sterile manufacturers. These solutions provide standardised volumetric-based platforms, taking into account other critical factors such as product viscosity. Advancing medicines are pushing the envelope for longerlasting medicines; reducing frequency of injection, but often requiring larger volumes of liquid-based delivery. This has pushed the industry to develop larger-volume injection systems, sometimes pushing wearables as a more optimal solution when autoinjectors may not be conducive to the duration of administration for patients.

Neulasta’s new wearable delivery is a great example of how this can transform patient care and truly deliver freedom for patients. Innovative dual-chamber technologies also provide for simple reconstitution for marrying lyophilised drug products with sterile water for injection, simplifying preparation and administration of these drug forms – further providing freedoms for patients looking to self-administer and minimise trips to the clinic. Injectible Devices and Tertiary Packaging for Delivery – a Comprehensive Approach With the market developing and furthering exciting new delivery technologies, consideration must also be made in packaging forms to deliver the drug device to the end user. The push towards patientcentric solutions and enabling freedom from the healthcare setting for product administration creates a dynamic where it is vitally important that pharmaceutical companies put considerable thought and preparation into the packaging by which the device is delivered. Furthermore, the premium nature of the medication warrants careful consideration to ensure successful navigation of the supply chain, as well as providing a user experience consistent with their expectations for a premium product. Secondary packaging plays a vital role in ensuring the product navigates the complex supply chain safely and securely, and in the considerations for end delivery to the patient. Product protection is paramount. Sophisticated drug delivery devices are often designed around combinations of glass, plastic and other elastopolymers that are susceptible to breakage if mishandled. Furthermore, the complexity of these advanced drug delivery systems demands appropriate protections from the elemental forces of shock and vibration in the distribution system, coupled – and sometimes exacerbated by – refrigerated or frozen conditions in the required cold chain environment. Protective packaging must be both useful in its intended form, as well as elegant and sophisticated, marrying the advanced device with its other critical components in a cohesive and functional system. Summer 2019 Volume 11 Issue 2


Drug Discovery, Development & Delivery parts of the delivery, as well as a rotational approach to the use and administration of these tools, to ensure the sophisticated strategy in staying ahead of criminal elements that may look to counterfeit or divert premium drug products.

Packaging must also be communicative. Through the process of human factor analysis, careful and detailed analysis identifies the key graphic elements and tools that form the basis for communicating key factors for success – instructions for patient use and administration, as well as conditions for safe storage or other drug protections, potential side-effects, and many others. Given the high value and critical nature of this category of medicines, compliance and adherence is vitally important for successful health outcomes. Leading pharmaceutical companies leverage the packaging system as an opportunity to address compliance and adherence by incorporating valuable patient support tools. In addition to well-prepared packaging graphics, it is common to include patient support tools such as brochures, leaflets and other included media that provide a platform for patient education, support programme enrolment, prescription discount or reimbursement, or other tools to address common factors for non-adherence. Given the high value of the drug product and the inherent attractive nature of the drug category for counterfeiters or other bad actors in the supply chain, thorough preparation must also be given to a robust serialisation and anti-counterfeiting strategy. Taking a comprehensive approach in both the drug delivery device as well as the secondary packaging in a systems-based architecture provides an opportunity to orchestrate a multi-layered and nuanced strategy in ensuring ultimate product safety and authenticity, vital in today’s global pharmaceutical market. This may require incorporating anti-counterfeiting elements in various www.ipimediaworld.com

Connectivity – the Next Frontier As we transition between the era of the IoT and the advancing AI world, there is tremendous excitement in the world of connected health. Communication tools such as Bluetooth or NFC are simply the first stages in the ability of injectible devices being able to communicate proactively and reactively – both data gathering and transmitting for patient information, as well as inbound prompting and communicating – generating valuable new opportunities for interactivity in patient health. Benefits of such real-time connectivity include the ability to intervene when adherence issues begin to present themselves, as well as to deliver positive reminders and patient support in advance of bad habits being formed. Medication devices can be interconnected with other health monitors, related diagnostic devices, doctor and healthcare systems, and other touch points in the connected supportive healthcare ecosystem. In Conclusion – a Bright Future for Amazing New Drugs The industry has embarked on an exciting new journey, developing amazing new drugs for frustrating and long-term health issues such as diabetes, cancer and autoimmune conditions, demonstrating breakthroughs in combatting these afflictions and improving quality of life for those who suffer with the daily struggles of their diagnosis. Furthermore, incentives have provided a pathway for development of treatment for rare and orphan diseases, giving optimism to patients who may have otherwise felt lost and without hope of effective treatment, yet may now have therapy options that they never had before. There is optimism that biosimilars will level the playing field for a broad population of patients seeking impactful and affordable treatments. Innovative new drug device technologies are making drug delivery increasingly safer and more effective,

and are providing patients with new freedoms to live their lives – giving them more control and independence, without being bound by the requirement to constantly visit their healthcare provider for frequent treatment. Such advanced technologies allow them to live more normal and predictable lives. Even further advancing technologies may soon allow them to maintain a very connected health relationship with their providers without needing to be face-to-face. The advances in biotech medicine have transformed therapy and should provide hope and optimism to us all. REFERENCES 1. 2.

3. 4. 5.

https://decisionresourcesgroup. com/drg-blog/fda-roll-drugapprovals-h1-2018/ https://www.marketresearchreports. com/la-merie-publishing/blockbusterbiologics-2017-sales-recombinanttherapeutic-antibodies-proteins https://www.genengnews.com/lists/ the-top-15-best-selling-drugs-of-2017/ IMS Institute Biosimilar Brief – March 2016 https://www.360marketupdates.com/ enquiry/pre-order-enquiry/10886202

Justin Schroeder Justin Schroeder is Senior Executive Director of Global Marketing and Design at PCI Pharma Services, responsible for global marketing, creative package design and new account development, with a focus on the development and commercialisation of new products. Justin has over 20 years’ experience in outsourced pharma services in various roles, including engineering, project management, marketing and development. He holds a Bachelor of Science from the School of Packaging at Michigan State University, US, and an MBA in marketing from Northern Illinois University, US. Justin is a certified Packaging Professional from the Institute of Packaging Professionals, US, and is Vice Chairman of the US Healthcare Compliance Packaging Council. Email: justin.schroeder@pciservices.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 37


Drug Discovery, Development & Delivery

The Correlations Between Viscosity, Needle Diameter, Flow Rate and Dose Accuracy in a Patch Pump Therapy Patch pump therapy is a convenient way of drug administration. The devices can be worn directly on the body, no tubing has to be attached, and the cannula or needle is inserted automatically. They are often equipped with programmable delivery patterns, which allow high flexibility and rational adjustment to the patient’s needs. In turn, the patch pumps must fulfill the highest criteria in dosage accuracy and safety. The fluidic path through the whole device, including body resistance at the injection site, combined with the physical properties of the drug, define the pressure loss that the pump needs to overcome. Since smaller needles are more comfortable and therefore preferred, they often represent the bottleneck of the system. The dependencies thereof are depicted hereafter.

Viscosity Range of Suitable Medication Many common drugs for patch pump therapy are aqueous solutions in the range of 1 cP to 30 cP. Fluids with higher agent concentration or larger molecules might reach up to 50 cP or even higher. This often requires large needle diameters or significantly lower flowrates.

Needle Limitations To limit pain at needle insertion, small needle diameters are a preferred option. Typical needle diameters for patch pump therapy range from 27G up to 31G. While thinner needles are desired, the pressure loss over the needle increases with smaller inner diameter, higher viscosity and flow rate. Depending on the available maximum pressure of the 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

patch pump and the drug viscosity, a 31G needle might be preferred and suitable for low flowrates but may not be suitable for high viscosities. Penetration depth and insertion angle define the needle length, which linearly scales up the pressure loss. A common range for subcutaneous injection is 8 mm to 13 mm.

Limitations of Flowrate If for certain therapies, pharmaceutical companies desire shorter dose delivery durations and therefore, higher flowrates, this can result in pressure variations and therefore in possible dosage deviations. Choosing adequate pump size, internal tubing and needle is key for high dosage accuracy. The chosen needle usually defines the

maximum flow rate. In this study, maximum flow rate is assumed to be in continuous delivery mode (worst case). Lower flow rates can always be achieved by delivery patterns with certain pauses or slower motor rotation. The selected pump size defines the minimum partial dosage increment that can be delivered and results in a possible limitation of the maximum flow rate. Influence of Total Fluidic Resistance on Delivery Volume Accuracy (DVA) Each fluidic part in the up- and downstream fluidic path (bends, tubes, transitions, etc.) adds to the total fluidic resistance of the system, resulting in higher pressure loss and potentially lower DVA. Flexibility in the fluidic connection between pump and needle allows the dampening down of pressure peaks and acts as fluidic buffer, enhancing the pump’s functional zone. However, in most applications, the flow situation inside the needle primarily dominates the pressure loss of the complete fluidic system. Correlation of Needle Diameter and Viscosity at Different Flow Rates In the following figures, calculated pressure losses for several needle Summer 2019 Volume 11 Issue 2


Drug Discovery, Development & Delivery

Table 1: Pump characteristic for a 2 μl pump (left) and a 10 μl pump (right) at different flowrates (pump rotational speeds). The lines indicate the calculated pressure loss for different needle diameters with needle length 12.7 mm (calculated length 22 mm). Density assumed 0.997 g/cm3. To achieve a desired accuracy (DVA) of ±5%, the needle pressure loss needs to be in the green area.

the presented limitations. The results were verified at different flowrates, viscosities and needle combinations.

Sensile Micropump

diameters and a range of viscosities are correlated to measured delivery accuracy of two Sensile micro pumps (2 μl and 10 μl volumetric pumps). The green and yellow areas represent the pumps’ pressure capability at ±5% and ±10% DVA in continuous delivery mode for tested viscosities. The maximum feasible operation points at ±5% DVA (intersection points of needle pressure loss curves and green area border) are extracted and plotted in the figures below. These graphs can

be used to predict needle limitations for flowrate and viscosity combinations. For example, for a 31G needle, a liquid with 10 cP would flow well up to 0.5 ml/min but could not be delivered at higher flow rates with a DVA of ±5%. For scenarios resulting in operation points above the green area, a reduction of flow rate is the best option. For this study, all assumptions were chosen conservatively so that sufficient performance is probably reached even when choosing points somewhat over

Table 2: Flow rate vs dynamic viscosity for Sensile 2 μl pump (left) and 10 μl pump (right). The green areas’ shadings represent the ±5% DVA functional zone for several needle diameters. (Needle length 12.7 mm, fluid density 0.997 g/cm3.) www.ipimediaworld.com

Conclusion The correlation between flow rate, viscosity and needle diameter delivers a horizontal and vertical asymptotic pattern. Delivering viscosities greater than 50 cP can still be managed with large needle diameters and very low flow rates to meet dosage accuracy targets. On the other end of the scale, flow rate is limited by the fluid’s viscosity and the mechanical limitations of the pump. Here, the larger 10 μl pump’s limit is at 12 ml/min where viscosities up to 2 cP can be delivered with a 27G needle. The performance scales linearly with the needle length.

Michael Girschweiler Michael Girschweiler has worked for Sensile Medical since 2017. He is technical project leader in the field of micropump development and expert in the company’s pump core technology. He has a bachelor’s degree in mechanical engineering and worked as research assistant at the institute of Thermal-and Fluid Engineering at the University of Northwestern Switzerland, mainly in FEM and CFD simulations of thermomechanical projects.

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Clinical and Medical Research

A Clever Combination: Calcium Plus Vitamins

One of the largest demographics in the bone and joint market is the aging population. For these people, maintaining bone health and preventing osteoporosis for as long as possible is vital. According to the World Health Organization, in 2010, approximately 22 million women and 5.5 million men aged between 50 and 84 years were estimated to have osteoporosis in the EU. Due to changes in population demography, the total number of people affected is expected to increase to 33.9 million by 20251. Considering this demographic evolution and lifestyle trends such as dietary habits, a preventive strategy is key to mitigating the future healthcare burden.

Bone Health Concepts In order to prevent osteoporosis and to keep bone mass stable, sufficient mineralisation from an early age is of vital importance. A regular dietary intake of calcium is therefore essential, but can be difficult to achieve – particularly for people with dietary restrictions, due to food intolerances or nutritional preferences. On the other hand, even a calcium-rich diet might not suffice when the requirement is at its highest, for example during adolescence. Postmenopausal women and men over the age of 70 also require more calcium to slow down bone loss. Calcium supplements can be helpful to ensure that the recommended daily allowance (RDA) for each life stage is reached. However, it is not only calcium which is vital for bone health – vitamins D3 and K2 are also essential for optimal calcium absorption and correct deposition. Vitamin K2 acts as an activator of the protein osteocalcin, which is responsible for calcium utilisation in the body. Activated osteocalcin can bind calcium ions and store them in the bones. Vitamin D3, meanwhile, supports the absorption of calcium in the small intestine and helps to regulate calcium and phosphate homeostasis. Studies have shown that combined calcium and vitamin D supplementation can reduce 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the rate of bone loss in elderly women2, and reduce hip fracture rates3. Therefore, several concepts have been developed which combine the health benefits of calcium carbonate, vitamin D3 and vitamin K2. Together with a balanced diet, supplements based on these concepts contribute to the RDA for calcium, according to EU specifications. One such concept is a chewable tablet: natural calcium carbonate is granulated in a fluidised bed using process parameters that improve the compactability of the mineral and generate low-density granules that are ideal for a chewable dosage form. Combined with vitamins D3 and K2, flavours and sweeteners, this formulation makes calcium supplementation a pleasant experience, increasing patient compliance. Table 1 shows the content of active ingredients in this formulation.

the formulation includes a novel, co-processed multifunctional mineral excipient made of calcium carbonate and tribasic calcium phosphate. For manufacturers looking to develop bone health supplements in the form of tablets, this mineral excipient offers superior technological properties. Table 2 shows the content of active ingredients in this formulation. The innovative excipient has an external lamellar structure that encloses a core of interconnected pores, allowing it to facilitate the production of tablets that uniquely feature both high porosity and maximum levels of hardness (Image 1). Because of their excellent mechanical strength, among other benefits the resulting tablets can be filled in conventional packaging, thus reducing costs. The excipient’s direct compressibility into granules without the use of a binder and its high porosity allow for faster water uptake,

Table 1: Content of active ingredients (Omya)

When Compliance is the Key Target Certain population groups have difficulties swallowing or even chewing large tablets, which is usually the case with calcium supplements. As a result, compliance is a major challenge for oral dosage forms targeting those patient groups suffering from a loss of bone mass and strength. In order to address the aforementioned challenge, a second concept was developed. In the proposed formulation, natural calcium carbonate is used to deliver 40% bioavailable calcium together with vitamins K2 and D3. Additionally,

which leads to a short disintegration time. In a study conducted in 2017, scientists confirmed the ability of the mineral excipient to formulate orally disintegrating tablets (ODTs) with enhanced mouthfeel, and examined their acceptability among healthy volunteers4. Mouthfeel was assessed using a 10-step visual analogue scale (VAS), where 0 represented the most positive answer. In addition, eight different questions concerning the mouthfeel and taste were asked. If

Table 2: Content of active ingredients (Omya) Summer 2019 Volume 11 Issue 2


Clinical and Medical Research

2.

3.

4.

Copyright: Omya

report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Arch Osteoporos 8:136 (2013). Chapuy MC et al.: Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 327:1637 (1992). Chapuy MC et al.: Combined calcium and vitamin D3 supplementation in elderly women: confirmation of reversal of secondary hyperparathyroidism and hip fracture risk. Osteoporos Int 13:257 (2002). Wagner-Hattler L et al.: In vitro characterization and mouthfeel study

the water uptake phase of an ODT is too quick, it is often associated with drying of the mouth, which may create discomfort for the patient. The best sensation is when the disintegration starts quickly upon contact with a small amount of saliva and lasts less than 30 seconds. In this study, the tablets with the innovative mineral excipient were well accepted. There were no negative descriptions given by any of the volunteers. Additionally, despite the good mechanical stability of the tablets, the high porosity required to absorb the liquid necessary for disintegration was preserved. These findings led to the conclusion that the mineral excipient is suitable for ODT dosage forms and can also impart a pleasant mouthfeel. Aging Well Starts Young Today’s consumers understand the benefits of preventing rather than curing

Copyright: Heike Rau (Fotolia)

disease. They are looking for nutritional all-in-one solutions, so it makes perfect sense to offer functional combinations that meet their needs. As has recently been announced by Mintel, a leading market intelligence agency, healthy aging continues to be on the industry’s radar. Consumers are striving for a longer and healthier life by prioritising health and wellness in their daily routine. Specific to the world’s diverse senior populations, these needs can be addressed through pharmaceuticals, foods and drinks for medical purposes, as well as via products designed for prevention, with formulations that are nutritious and easy to consume, such as bone health tablets combining calcium and vitamins. REFERENCES 1.

Copyright: andresr (Shutterstock) www.ipimediaworld.com

Hernlund E et al.: Osteoporosis in the European Union: Medical Management, Epidemiology and Economic Burden. A

of functionalized calcium carbonate in orally disintegrating tablets. Int J Pharm. 534(1-2):50-59 (2017).

Dr Carolina Diaz Quijano Dr Carolina Diaz Quijano is Head of Technical Services for consumer goods at Omya. She joined the mineral company in 2013. Dr Diaz Quijano has worked as Senior Scientist for Mineral Surface Chemistry and as Manager for Technical Services and Innovation. Previously, she 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.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 41


Clinical and Medical Research

Understanding the Challenges Experienced in the Investigator Initiated Study Supply Chain Investigator initiated studies (IIS) are an integral part of the investigational drug development process and are increasing gradually, year on year, on a global scale. Phase II IIS studies grew 5 per cent between 2015 and 2017, with Phase I IIS studies also recording an annual growth trajectory within the same time period.1

These types of trials can play an important role in helping pharmaceutical companies better understand their drugs, along with appropriate application. Typically, smaller and less complex in nature IIS studies, usually initiated and managed by non-pharmaceutical company researchers or collaborative groups, have the potential to improve patient care and contribute towards future therapeutic breakthroughs by generating drug safety and efficacy data in a real-world environment. For pharmaceutical companies, IIS can be an excellent tool to help drive internal product development strategies. They can also explore new indications for products already on the market or simply be used to conduct medical research. From the investigator’s point of view, the motivation to conduct these studies may be to investigate and broaden the use of new treatments for rare diseases or new treatments for underrepresented patient populations. There is also a drive for investigators to publish new findings and gain recognition for their research. However, it is not enough to only acknowledge the potential benefit these programmes can deliver. To enable patient enrolment and maximise the opportunity for positive outcomes, it is necessary to scrutinise the indisputable additional challenges these studies can bring. It is then crucial to develop effective strategies to overcome them. The clinical supply chain contains several risk hot spots for IIS trial managers with multiple functions 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to organise – from contracts to logistics, kit design and labelling, to inventory management and regulatory compliance. Without clearly defined roles and responsibilities, effective planning and communication, and a clear view of trial data, the potential benefit of IIS programmes can be lost. So, what are the key considerations when managing investigational medicinal product (IMP) supplies for IIS programmes? And how should clinical supply chains be approached and managed to reduce risk and ensure continuous patient resupply throughout the lifetime of the trial? Operating at a Disadvantage Developing and securing approval for a new drug is estimated to cost pharmaceutical companies $2.6 billion, according to the Tufts Center for the Study of Drug Development2. In company-sponsored studies, pharmaceutical organisations rely on their Goliathan resource and budget to employ specialist teams. Experienced clinical teams create the clinical trial protocol and manage associated sites. Data management experts utilise the latest technology to generate reports and conduct statistical analysis to identify trends, anticipate risk and continuously harmonise recruitment predictions with supply forecasts. Compliance is managed with regulatory submissions from specialists. Supplies – the coordination of bulk material, as well as clinical packaging and labelling functions – are managed by a highly skilled team of people. Finally, vendor

managers liaise between departments and third parties to proactively seek out opportunities for continuous process improvement. Despite these resources, on occasion, challenges can occur. Unpredictable events can influence enrolment, which in turn can quickly lead to overage and waste, or a shortfall in supply, negatively impacting the patient. Equally, unavoidable mid-study protocol changes can lead to delays and require prompt and accurate mitigation. However, with experience, technology and specialist vendors in place, situations can be managed, and disaster averted. In contrast, IIS programmes have little resource to harness therefore operate at an immediate disadvantage in comparison. Investigators are required to assume responsibility for all the pre-mentioned functions and the myriad of tasks associated with them. In doing so, they can spread themselves thinly over a vast remit which, in turn, can compromise the study’s ability to provide the right drug, to the right patient, at the right time. As such, IIS trials tend to progress at a slower pace than company-sponsored trials while investigators essentially ‘learn on the job’. Although some IIS models benefit from extensive involvement from the pharmaceutical company, the majority operate in relative isolation. Breaking Down the Challenges The benefits of running IIS trials are often offset by the multiple challenges synonymous with physician-led Summer 2019 Volume 11 Issue 2


Clinical and Medical Research programmes3. The three core supply chain challenges evident in IIS trials relate to roles and responsibilities, inexperience in managing clinical trials and a lack of data visibility. Clinical trials management usually has not formed part of an investigator’s remit prior to embarking upon an IIS programme. They are key opinion leaders in their own field but may not have had the exposure to all aspects of running a clinical trial. The level of support offered to them, when their proposal for an IIS is approved by the pharma company, will vary from company to company. With just the one clinical site to cater for, at face value the process of ordering IMP from the pharmaceutical company and dosing patients at site can seem straightforward. It isn’t. It is a live, reactive, multifaceted entity where one overlooked element can cause a ripple effect, introducing unnecessary risk and lengthening timelines. Through in-depth research, peer support and holistic and strategic planning at the earliest opportunity prior to the study’s inception, this challenge can be met. Using standardised templates for contracts and agreements between investigators and pharma companies or CMOs will help to determine roles and responsibilities. They will ensure thorough understanding of processes creating greater agility and flexibility which, in turn, helps to reduce study start-up time, costs and risks. This lack of awareness of roles and responsibilities is understandable and stems from a general inexperience in managing clinical trials. From a clinical

supplies perspective this can, at times, translate into too much inventory being ordered, which can lead to waste due to IMP expiry. Additionally, requests for supplies can often be left to the last minute, due to a lack of understanding of the tasks and timelines involved. Effective clinical trials management is also reliant upon clear visibility of trial data. Although the scale is smaller, the principles remain the same. However, IIS trials rarely have access to a centralised data capture system. This can make it more difficult to see where patients are in the trial, which can impact forecasting activities. Investigators can over-estimate the recruitment rate for the trial which can result in an extension in the trial timelines. This significantly impacts the supply chain when considering product expiries and the knock-on effect of additional packaging activities. Centralising the IMP management of IIS programmes with a single group to focus expertise and streamline processes will help to generate a reliable forecast and help to set achievable

milestones. Replacing manual ordering and drug assignment with randomisation and trial management systems such as interactive response technology (IRT) will give the investigator full visibility of patient activity and IMP usage in order to help them make clear, informed decisions. It is also worth noting that many vendors offer simplified systems for randomisation and / or inventory management. These systems may have less functionality than a full IRT; however, they can be a much more cost-effective solution and may be especially suited to IIS programmes. If the technology is set up and maintained in conjunction with an experienced supplies manager, it offers greater reassurance that inventory management at site is taken care of. Building the Strategy for a Patientfocused IMP Supply Chain Haven taken a look at the challenges that can come with an IIS trial, there are several core areas within the IMP supply chain for IIS trial managers to focus on in order to design an effective and patient-focused strategy. Where contracts are concerned, physicians need to be aware of what they are accountable for. Not only do physicians need to dedicate time to understanding their responsibilities, they also need to familiarise themselves with contract templates and identify what activities need to be outsourced. The importance of kit design is something which can easily be overlooked. To reduce the likelihood of getting it wrong, physicians should contemplate the multiple factors that influence design far in advance of production. Factors such as visit duration, dose per visit, visit windows,

www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 43


Clinical and Medical Research

the end user, compliance and product stability all need to be considered to produce an end product that is fit for purpose. The same is true of clinical labelling, which becomes even more complex for IIS trial managers running multi-country trials. Despite limited exposure to the intricacies of clinical labelling or knowledge of the lengthy timelines involved, physicians will need to bring the CRO/CMO on board to assist with Master English Label Text (MELT) generation, regulatory review and translations. Documents needed for quality release can be either study- or productspecific – something which the physician may not have had exposure to. Similar to contracts, uncertainty here can cause serious delays, if the physician is unaware of who to request this information from and fails to do so in a timely manner. It is possible for IIS trials to co-ordinate forecasting and inventory

44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

management independently. However, this is a vital component which demands time and strategic planning to get right. Physicians have a choice to either contract this activity out to CMOs or dedicate significant time and resource to analysing data – relating to expiries, bulk availability and recruitment rates – to determine accurate supply. The same is true of logistics. It’s not enough to understand the timelines and specific country requirements relating to import and export, the physician will need to demonstrate full traceability for the drug from production to storage and distribution through to returns and destruction. This requires comprehending the associated processes and access to systems to gather the necessary data. In practice, however, very few physicians have previous experience of these systems, such as interactive response technology (IRT), and in addition, there often isn’t the budget available to purchase them.

Conclusion To keep patients, their safety and experience at the heart of IIS trials, investigators need to define the IMP supply strategy at the earliest opportunity. By establishing which activities need to take place, and by understanding the interlinked nature of supply and demand, IIS trial managers would be better placed to identify risk and make informed decisions about what they can and cannot manage. They will also gain a clearer idea of what should be outsourced to expert vendors with access to the people, processes and technology needed to deliver a successful IMP supply chain operation. By championing clear and consistent communication with these vendors, and providing regular updates on study status and changes, all challenges can be managed, and a streamlined, cost-effective, patient-focused IMP supply chain successfully established. REFERENCES 1.

2.

3.

Source: GlobalData: Total Investigator Initiated Clinical Trials from 2015 forwards across all geographies; includes ongoing and planned studies by phase of development. https://www.policymed.com/2014/12/atough-road-cost-to-develop-one-newdrug-is-26-billion-approval-rate-fordrugs-entering-clinical-de.html https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC6176691/

Victoria Maguire Victoria Maguire, Project Group Manager – Supply Chain Management Vicki Maguire graduated from Aberdeen University, Scotland, with a MSc in Sports Nutrition. Vicki Joined Almac in 2007 as an IRT Project Manager and has been a member of the Supply Chain Management team since 2010. The team are responsible for forecasting, production planning and inventory management of clinical trial material. Vicki has over 15 years’ experience in the Clinical Research Industry, including roles in Clinical Study Management and Clinical Pharmacy and has a thorough working knowledge of GMP, GCP and GDP.

Summer 2019 Volume 11 Issue 2


Volume 9 Issue 1 - Spring - 2017

Volume 9 Issue 1

Peer Reviewed

International Pharmaceutical Industry

Supporting the industry through communication

IPI – International Pharmaceutical Industry

INSIGHT / KNOWLEDGE / FORESIGHT

MALDI Mass Spectrometry in Drug Discovery Gaining A Deeper Understanding

Three Ways to Mitigate the Risk of

Late-Stage Failure in CNS Drug Development

Data

The Foundation of Clinical Trials www.ipimediaworld.com

Temperature Management Keep Your Cool

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SUPER PUBLICATIONS FOR SUPER PHARMACEUTICALS

IPI

Peer Reviewed, IPI looks into the best practice in outsourcing management for the Pharmaceutical and Bio Pharmaceutical industry.

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JCS

Peer Reviewed, JCS provides you with the best practice guidelines for conducting global Clinical Trials. JCS is the specialist journal providing you with relevant articles which will help you to navigate emerging markets.

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Volume 4 Issue 1 Volume 4 - Issue 1 Supporting the Development of Veterinary Drugs, Veterinary Devices & Animal Feed

PEER REVIEWED

Applying Game Theory to One Health Modelling Veterinary Healthcare Delivery International Animal Health Journal - Supporting the Development of Veterinary Drugs, Veterinary Devices & Animal Feed

Mastitis due to Mycoplasma bovis Insights Pet Obesity Prevention is Better than Cure Leadership Skills of Extraordinarily Successful Executives

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Official Supporting Associations -

Sponsor Companies -

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25/02/2017 13:37:17

IAHJ

Peer Reviewed, IAHJ looks into the entire outsourcing management of the Veterinary Drug, Veterinary Devices & Animal Food Development Industry.

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Peer reviewed, IBI provides the biopharmaceutical industry with practical advice on managing bioprocessing and technology, upstream and downstream processing, manufacturing, regulations, formulation, scale-up/technology transfer, drug delivery, analytical testing and more.

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 45


Clinical and Medical Research

A Novel Valuation Model for Medical Intervention Development All stakeholders involved in the development, licensing and market access of healthcare technologies use a stage-specific valuation match that integrates risks and outcomes to inform their decision-making. A stage-specific valuation method, based on defining future cash flows for a product that are success-rate probability adjusted prior to being discounted with a risk rate, is termed risk-adjusted net present value (rNPV). Values from these calculations can be highly variable depending on the data used to generate the calculation, and in light of the estimated $2.6bn in capitalised costs that is necessary to move an innovation to market, without any guarantee of product reimbursement, the financial risk is very high. Recent return on investment (ROI) numbers for life science investment are significantly lower than the weightadjusted cost of capital, implying healthcare research and development (R&D) is economically unattractive. The outcome is that the objectives of modern intervention R&D are more linked to moving risk off the books or downstream to larger companies, that at face value seem better positioned to develop the products further, when in fact a complete reconfiguration of approaches, models and realistic actions and strategies are likely to generate more value. As rNPV calculations are only as good as the data used to generate them, and both accurate and comprehensive values ideally should be used, based on real market dynamic, the latest clinical success rates and considering the latest reimbursement approaches (such as health technology assessments [HTAs]), we reassessed valuation approaches. To do this, we integrated the reality of later-stage clinical validation, product reimbursement based on payer perspectives, and downstream costs to generate a whole value-chain calculation. The outcomes led us to develop an alternative risk rate model based on dynamic changes that occur throughout the R&D process. While modelled for medical intervention development, the outcomes of this work can also be applied for diagnostics and medical devices. Our work has the potential to identify

46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and address gaps in the development programmes of medical interventions (pharmaceuticals, devices and diagnostics) to improve them and thus increase the ROI significantly beyond the current rate of return. This article is the first in a series which describes the market problem, and our solutions and commercial offerings.

not only carries significant financial risk but also fundamentally diminishes the value of the money being engaged. There are several possible sources of this problem: •

Keywords: Innovation management, valuation modelling, full economic cost, inverse modelling, alternative risk rates, reimbursement

For any entrepreneurial venture, a positive net present value (NPV) calculation on any product in development is a good indication that upon market release, the financial return will exceed the cumulative life cycle costs of research, development, market validation, market access, market release, manufacture and sales and therefore potentially justify the initial outlay; this is summarised as return on investment (ROI). In healthcare, and particularly therapeutic intervention, development takes a long time of typically over 14 years (FDA 2016; Stewart et al. 2018), and is costly (up to $2.6bn, (DiMasi et al. 2016)) which means that significant risk has to be carried for a long duration before knowing if the product was worth the investment. This significant risk has led to the establishment and now standard usage of an rNPV (Villiger n.d.; Booth 2011; Booth 2014; Dillon 2015; Drummond 2013) for life science investments, in which the risk rate is typically the company-specific internal rate of return (IRR) (Gallo 2016). At present, the ROI on pharmaceutical R&D is reported to be dropping below an estimated 2% for 2018 (in 2017 it was 3.2% (Terry and Lesser 2017), and in 2010 over 10%), while the weight-adjusted cost of capital is presently at an industry average of 8.13% (Stern communication 2017). This means that to perform R&D

• •

First, the definition of the terminal market value in the rNPV equation, in which global or total accessible market (TAM) values are used, yet launching a healthcare innovation in different ‘regulatory’ trading blocks (North America, Europe, Asia-Pacific, Mercosur, and potential further geographic distinctions) cannot occur without satisfying the local clinical requirements which cannot be geographically transferred (Shenoy P 2016; Ndebele P et al. 2015; Van Norman G 2016; Dunlop et al. 2016; Allen et al. 2017; Angelis et al. 2018); Second, the pertinence of HTAs which often (in over 120 countries) include cost-effectiveness analyses comparing the new intervention to existing standards of care to define where and at what price the intervention will be reimbursed and that, while valuations simplify global market values, the geographic diversity of HTA and if, how and for what decisions are made means local geography valuations have to be integrated; Third, the complexity and volume of clinical data that needs to be generated, managed and continually collected to generate a high-quality reimbursement argument with associated costs; Fourth, the indication-specific probability of clinical transition of a therapeutic; and Fifth, the perception that total indicated sales represents the terminal market value to be used, ignoring the reality that nearly two-thirds of the sales costs are used to manufacture and sell the final product.

As rNPV is the de facto valuation model used throughout the industry, Summer 2019 Volume 11 Issue 2


Clinical and Medical Research the previous studies indicated above and several recent articles in the past year reported on updated clinical trial success and our own experiences. We investigated the impact of indication specific success rates, the relevance of HTA determined SAM/SOM values and full economic costing on rNPV valuations in healthcare. This work then prompted us to develop a de novo valuation model. Methods We used the industry standardised valuation model and equations for performing rNPV calculations (Villiger n.d.; Dillon 2015; Svennebring and Wikberg 2013; Stewart et al. 2018). We started by integrating full development costs into the rNPV calculation, followed by indicationspecific success rates obtained from recent analysis (Wong, Siah & Lo 2018), published market size values for the complete drug development lifecycle. Differing terminal market values were based upon level of market penetrance of existing standards of care for the different conditions, against which any new intervention would be compared for reimbursement purposes. This enabled us to model stage of development-specific rNPV calculations as a level of ‘arguable competitiveness to existing standard of care’ of the product. Further in-depth analysis can only be performed comparing original proprietary interventions being developed to the mechanisms of action and agreed reimbursement usage of the existing standards of care, which can only be calculated using individual companies’ proprietary information. Sensitivity analysis was performed at multiple levels: different market penetrations, generalised vs latest indication specific success rates, and highest vs lowest potential costing. rNPV model validation was performed using four different possible interventions in two different indications, while real-world model validation was performed using three interventions presently on the market with significant revenues. www.ipimediaworld.com

Results Modelling the rNPV We first set out to determine the impact on output valuations when the full economic cost (FEC) or the abbreviated cost of development were used in the SAM. Using just the USA as the SAM market example, the high costs were compared to the low costs using generic success rates for four potential interventions; biologics treatment for cardiacrelated disease, biologics treatment for diabetic-linked diseases, chemical entity-based treatment for cardiacrelated disease, and chemical entitybased treatment for diabetic-linked diseases.

Much of this forms part of pricing and reimbursement decision-making through procedures like HTAs, which can therefore influence the pricing. HTAs are nowadays well established not only in traditional HTA markets like the United Kingdom, but also elsewhere like other European markets and in the United States, Canada and Asia, and it is gaining further global momentum. Whilst processes and methods may differ from one jurisdiction to another, the basic principles of the data used being relevant and meaningful to decision-makers and the value proposition being robust and able to be substantiated remains across jurisdictions.

Independent of the disease indication or application, using FEC resulted in a reduced rNPV value along the value chain. On average and independent of clinical phase, rNPVs were $49 million dollars higher between abbreviated low costs and FEC low costs, and $71 million dollars higher between abbreviated high costs and FEC high costs.

Therefore, we have researched these aspects and reflected them against our own experience conducting and advising on HTAs in these jurisdictions to inform our analyses.

When comparing phase by phase, rNPVs for abbreviated costs were on average $10.5 million higher for both Phases II and III compared to the FEC, while Phase I rNPVs for abbreviated costs were $36 million higher, implying that increasing the cost-effectiveness of the early-stage R&D will have a greater impact on longer-term value. When we integrated into the rNPV calculations the latest indication-specific success rates, the impact was more dramatic. The next simulation was to integrate in level of local market penetrance, or SOM. In healthcare interventions, SOM is determined by the existing standard of care, the outcomes of the clinical trials and specifically payer-relevant outcomes, how convincing the clinical data is compared to the null hypothesis and the potential pricing. For example, generating a fifth in class (but not generic) me-too intervention and obtaining reimbursement can often entail offering significant price reductions to the paying body to ensure market penetrance, while mechanism of action, off-target effects and drug-drug interactions can further influence the paying bodies’ willingness to consider the intervention.

For this we considered published sources as well as our own experience. As the work we present in this article is a novel approach and has not been done before, we firmly believe this to be a robust approach to this decision analysis. In rNPV calculations, the success rates inputted typically correspond to the success rate of transition into the next phase, not the cumulative success rate of the intervention at that specific phase, going all the way to market. We therefore repeated the rNPV calculations this time using the indication-specific cumulative success rates. Changing the Risk Rate Despite rNPV valuations increasing with clinical phase success and success rates increasing, if the ROI is decreasing, the implication is that the risk rate being used in the rNPV calculation is incorrect or illogical. We therefore decided to model a formula for a risk rate that would be based on financial risk and a successful movement to market dynamic. We used the phase-specific cumulative success rates to generate the failure or progress risk rate, and multiplied the baseline risk rate by this value to generate the phase-specific risk rate. INTERNATIONAL PHARMACEUTICAL INDUSTRY 47


Clinical and Medical Research When a progress-dependent dynamic risk rate (pd-DRR) is used in combination with market penetration SOM values, significantly lower valuations are obtained compared to using the IRR, but earlier-stage innovations still retain value. This may be disappointing news for investors in life science, but it corresponds more to the market reality. Testing the Model To compare and test the models, we looked at three interventions that had been launched onto the market: Ramipril (chemical entity – cardio), Reopro (biological / cardio) and Dapagliflozin (chemical entity – non-insulin), obtaining total global sales volumes for each one as the terminal market value. These analyses confirmed the validity, robustness and meaningfulness of our research and modelling. Discussion It has been argued that “the only thing you can guarantee about any valuation is that it is wrong” (Dillon 2015), which prompted us to leverage our experiences in working from the early stages of R&D to mid-stage clinical validation, and from mid-stage clinical validation to marketing authorisation, reimbursement, market access and sales planning to identify potential reasons for holistic solutions to address the issue. No recent studies have been based on actual indicationspecific clinical success rates and based on our observations and the accessibility of 15 years of up-to-date information (Thomas n.d.; Wong, Siah and Lo 2018), this has an enormous impact on value calculations. It was also important to perform complementary simulations using well-known and peer-reviewed sources of costs of development and historical success rates matched with the figures from the latest research to break down the components and figures that go into valuations to see where possible optimisations could be performed. The aim being to make valuations somewhat closer to reality. The outcomes of the simulations clearly indicated three key findings: • First, that every stakeholder in the development of novel interventions 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

needs to be fully integrated, and communicating costs with each other, so that each one understands the full cost of development and how this impacts the stage-specific valuation; Second is the importance of indication-specific success rates, which in simulations reduced values by up to $500 million, and using real-world data $200 million; Third, that from a small company perspective working typically within one regulatory and HTA-specific geography, their own innovations should have their valuations performed using terminal market values defined by not only a regulatory licensing but also a value for money (as determined by HTA organisations and payers) assessment of their innovation, vs. the standard of care in the given jurisdiction to determine ranges of possible market penetration. As already stated above, payer and HTA requirements, methods and processes may vary across jurisdictions. However, certain characteristics overlap across those jurisdictions, i.e. robustness of evidence / data, its meaningfulness and relevance to decision-makers. We took these into account for our work based on published evidence and our own experience conducting and advising on HTAs and payer discussions for recent healthcare technologies. We have further taken into account developments of payer and HA-specific early scientific advice services offered by payers and HTA organisations, both official and unofficial procedures (e.g. NICE scientific advice, EMA-HTA scientific advice, advisory boards, etc.) to further substantiate our work.

The rNPV outcomes obtained by using the full economic costs of the development that would be incurred by either one stakeholder performing everything in-house, or through multiple stakeholders transferring the technology upstream to a more relevant stakeholder versus abbreviated costs were dramatic, and if based on using accepted ‘generic’ values go some way to explaining why the ROI on drug development is so low. Drugs reach the market where competing

products drastically diminish the value of the innovation’s applicability. This was further impacted by geographic separation into SAMs and further still when the simulation included real-world market penetration of interventions, in which there are multiple reimbursable interventions available. This would mean that all portfolios would need to be re-evaluated to assess true value, and then tied into the company’s logistical capacities, implementation approaches and strategies, and partnering possibilities to try to maximise value. The use of a harmonised risk value inside the calculation would go a long way to informing all stakeholders, and while the IRR is standard, because its estimation is company-specific, this can change significantly. We have proposed one alternative; it is clearly more realistic than existing risk rates when put into the context of real-world data but further modelling using many different real-world examples, including from licensing deals, would inform the utility of its application. There are limitations our research presented here: • First, costing of development. While there was an impact on rNPV for the small company or business unit, they already know they are working within a high-risk endeavour and, to a certain extent, given the long timeframes, all possible opportunities from an innovation may not be apparent at the start of development. However, opportunistic costs of capital cannot be ignored; an investor wants to make a return and therefore prioritises investment based on this. • Second, the real costs of development; these can balloon and decrease during early stages very easily, while the reported costs of clinical studies, we feel are an underestimate. In all costing models, only direct costs to the clinical centre are mentioned; the typical 100 to 120% indirect cost charged to a large company is not included, nor are the company-related costs for the clinical trial such as their own staff and intervention manufacture, which can run into millions of dollars. • Third, related to clinical trial design: we are fortunate to have access to 15 years of modern clinical Summer 2019 Volume 11 Issue 2


Clinical and Medical Research trial data success rates, but in many cases, progression, primary outcome achievement and eventual reimbursement definition is defined by the clinical trial design, whether it is randomised, non-randomised, cross-over, matched pair and so forth. It would be interesting to know within the different levels of success for each stage for each indication, whether there was a bias towards a clinical trial design that favoured successful outcome. Conclusion We believe we have identified a risk rate model that corresponds to the dynamics of medical intervention development, which relies less on hidden figures and is based upon a common understanding of investment decisions. While early-stage innovators and investors may not like the reduced valuation, the alternative is for them to invest and be told after a lot of money has been spent that there is no chance of a license or gaining reimbursement and thus uptake and sales, while if a more realistic valuation is performed, they may find a more amenable and also long-term R&D partner in the purchaser. This may be uncomfortable for many investors and small companies, but the risk and future costs being carried by the entities responsible for actually converting the innovation into a commercial product is significantly greater than is presently being calculated. However, our work also has the potential to identify and address gaps in the development programmes of medical interventions (pharmaceuticals, devices and diagnostics) to improve them and thus increase the ROI significantly beyond the current rate of return.

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123–152. Booth, B. (2014). A Billion Here, A Billion There: The Cost Of Making A Drug Revisited. Retrieved from https://lifescivc. com/2014/11/a-billion-here-a-billionthere-the-cost-of-making-a-drugrevisited Dillon, J. (2015). Valuation and Deal Structuring. Retrieved from https://www. bio.org/sites/default/files/Valuation%20 and%20Deals%20Structuring%20 Concepts%20and%20Trends_ Joe%20Dilion.pdf DiMasi, J.A., Grabowski, H.G. and Hansen, R.W. (2016). Innovation in the pharmaceutical industry: New estimates of R&D costs. Journal of Health Economics (47), p20-33 Drummond, M. (2013). Twenty years of using economic evaluations for drug reimbursement decisions: what has been achieved? J Health Polit Policy Law. (38) p1081-1102 Dunlop, W.C.N., Daniel-Mullins, C., Pirk, O., Goeree, R., Postmaa, M.J., Enstone, A. and Heron, L. (2016). BEACON: A Summary Framework to Overcome Potential Reimbursement Hurdles. Pharmacoeconomics. 2016 ; 34(10): 1051–1065. F.D.A. (2016). The drug development and approval process. Retrieved from http://www.fdareview.org/03_drug_ development.php Gallo, A. (2016). A refresher on the Internal Rate of Return. Harvard Business Review, March 17, 2016. Ndebele, P., Blanchard-Horan, C., Shahkolahi, A. and Sanne, I. (2014). Regulatory challenges associated with conducting multicountry clinical trials in resource-limited settings. Journal of acquired immune deficiency syndromes (1999), 65 Suppl 1(0 1), S29-31. Shenoy, P. (2016) Multi-regional clinical trials and global drug development. Perspect Clin Res. 2016 Apr-Jun; 7(2): 62–67. Stern Communication (2017). Costs of capital by sector. Retrieved from http:// people.stern.nyu.edu/adamodar/New_ Home_Page/datafile/wacc.htm Stewart, J.J., Allison, P.N. and Johnson, R.S. (2018). Putting a price on biotechnology. Nature Biotechnology Bioentrepreneur. Retrieved from https://www.nature.com/ bioent/2003/030101/full/nbt0901-813.html doi:10.1038/nbt0901-813 Svennebring, A.M. and Wikberg, J.E.S. (2013). Net present value approaches for drug discovery. SpringerPlus 20132:140 https://doi.org/10.1186/2193-1801-2-140 Terry, C. and Lesser, N. (2017). A new future for R&D? Measuring the return from pharmaceutical innovation 2017. Deloitte Centre for Health Solutions. Retrieved from https://www2.deloitte.com/ content/dam/Deloitte/uk/Documents/ life-sciences-health-care/deloitte-ukmeasuring-roi-pharma.pdf Thomas, D.W., Burns, J., Audette, J., Carroll, A., Dow-Hygelund, C. and Hay, M. (n.d.). Clinical development success

17.

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rates 2006- 2015. Retrieved from https://www.bio.org/sites/default/files/ Clinical%20Development%20Success%20 Rates%202006-2015%20-%20BIO,%20 Biomedtracker,%20Amplion%202016.pdf Van Norman, G.A. (2016). Drugs and Devices: Comparison of European and U.S. Approval Processes. JACC: Basic to Translational Science Volume 1, Issue 5, August 2016, Pages 399-412 https://doi. org/10.1016/j.jacbts.2016.06.003 Villiger, R. (no date given). NPV vs rNPV – valuation in life sciences. Retrieved from http://www.avance.ch/newsletter/docs/ avance_on_NPV_vs_rNPV.pdf Villiger, R. and Bogdan, B. (2006). Pitfalls of valuation in biotech. Journal of Commercial Biotechnology. Vol 12. No 3. 175–181. Wong, C.H., Siah, K.W. and Lo, A.W. (2018). Estimation of clinical trial success rates and related parameters. Biostatistics, kxx069, https://doi.org/10.1093/biostatistics/kxx069

Dr Jonathan Dando Jonathan is an International Portfolio/ Contract Manager with 22 years’ global experience, working in early-stage design and development. He has managed over €600 million in R&D funding in global healthcare projects, and co-founded several start-ups and consultancy firms. He also runs Echino Ltd, an innovation management company specialising in international partnering, development and ecosystem design. Email: jdando@aestimo.ie

Maximilian Lebmeier Maximilian is a health economist with over a decade’s experience in the pharmaceutical industry. He has worked on a wide range of disease areas from very common to very rare conditions, including some of the world’s largest-selling pharmaceutical products. He has worked on over 150 HTAs. He also runs Athena Market Access Solutions Ltd., providing pricing and market access solutions to organisations in the life sciences industry. Email: mlebmeier@aestimo.ie

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Labs

Filtration – The Forgotten Process

Introduction Across all industrial sectors, there is a requirement for some form of solid‐ liquid separation. Regardless of scale or whether the solids are a valuable product or an unwanted waste stream, precision separation of the solid and liquid streams is usually a critical step in the process. It is therefore curious that during development of new processes, this step is largely overlooked and can become a major obstacle in scaling up new processes from the lab to commercial plant. Development of filtration technology has also typically been driven by vendors responding to specific market opportunities. This results in technology that tends to be limited by scale, industry sector or process duty, with little/no research into application outside of these constraints. Consequently, the scale‐up of filtration processes is typically limited to catalogue engineering, reusing the same technology already prevalent within the sector, often creating bottlenecks and inefficiencies that could be removed through application of better technology. Through my own experiences of scaling up processes or trying to solve difficult process issues post scale‐up, I feel there are great opportunities for better process development to define filtration parameters for scale‐up, and better technology development to transcend sector and scale boundaries. This will allow selection of the right filtration technology at an early stage when the overall process design can still be adapted to maximise the efficiency and robustness of the process.

Process Development Challenges Too often during process development, filtration is just a proof of concept with a Buchner funnel and vacuum. The solids are separated and washed to determine yield data and little additional data is ever generated. Typically, if filtration takes a long time, an oversized funnel will be used to get it done quicker, but this vital piece of information is rarely documented to trigger additional studies. If one were 50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to do the experiments with scale‐up in mind, it would be obvious that to achieve the plant throughput, the filter would be infeasibly large or there would need to be multiple parallel units to achieve the same filtration area. A different approach to process development is needed if we are to develop robust filtration processes at commercial scale. Vendors can generally do trials and specify equipment from their range of technologies, but the downside with this approach is that the knowledge lies with the vendor, and the selected equipment may not be the optimum technology for the process. To retain control of the process development, it is recommended that in‐house data is generated using a simple set of targeted laboratory-scale experiments. These experiments require relatively inexpensive equipment, and the data generated can be used to develop empirical models to predict the filtration performance at commercial scale. Most process engineers are familiar with line sizing calculations where they determine the pressure drop in a pipe based on the flow, length of pipe, number of fittings, etc. Using the same principles but turning the formula around to predict flow is what is needed to scientifically scale up filtration processes. Equation 1 provides a qualitative model for the prediction of flow.

Equation 1

In the case of filtration, the model can be made independent of scale (Equation 2) by introducing the concept of flux, which is the flow rate per unit of filtration area.

Equation 2

The driving force is provided by the differential pressure, and the resistance is provided by the filter cake and the filter media. In many filtrations, the resistance provided by the filter media can be largely ignored because it is negligible compared to the resistance from the cake. The model can therefore be further simplified by Equation 3, where A, B & C are constants specific to the characteristics of the material.

Equation 3

Using basic fluid flow theory, flow would be proportional to the sqrt of differential pressure and the resistance to flow would be linear with the cake thickness, so B = 0.5 and C = 1. These two values would represent what could be considered as ideal behaviour, which can be represented by Equation 4. This simple approach can be used to develop empirical models from the lab data, which then allows prediction of the throughput from a filter during scale‐up.

Equation 4

Whilst Equation 4 represents the ideal behaviour, experience shows that excessive pressure can compress the cake or blind the filter media, resulting in increased resistance. Similarly, some materials may present a non‐linear relationship between cake thickness and flow. In these cases, the filtration rates will deviate from the ideal behaviour presented by Equation 4, so reverting to Equation 3 would be more appropriate. It is still possible to develop usable empirical models based on Equation 3, but the data analysis becomes more involved to determine the values of B & C that best fit the data. An example data set has been provided in Figure 1 to visualise the output achievable from this form of analysis. Summer 2019 Volume 11 Issue 2


Labs analysis to fit the data to the models. The key to successful development of the models is to accept that they are empirical and need to be tailored to the material being filtered, and the results can be key to the successful scale�up to commercial operation.

Figure 1: Example Experimental Results

A further development of the models is possible if you consider how the slurry concentration may affect the filtration performance. The products in Figure 1 were actually two different concentrations of the same material, and it was found that the plots would overlap as shown in Figure 2 with a simple adjustment for the concentration as per Equation 5.

Equation 5

In this revised model, S is the ratio of solids to filtrate, and for this dataset it was found that D = 1, though it is suggested that this is likely to be specific to the material being filtered.

Whilst the data provided here is limited, it demonstrates that sensible correlations can be achieved to allow modelling of filtration performance. These models are independent of scale and can be applied to both batch and continuous filtration processes, allowing you to quickly assess the optimum balance between cake thickness, pressure drop, slurry concentration and throughput for a given process material. I have applied this development approach to different materials in different industry sectors. Some of the materials I have worked with exhibited ideal behaviour across a wide range of conditions, whilst others, such as the data provided here, required a little more

Technology Challenges Knowing the characteristics of the filtration is only half the battle; the second element is finding a suitable technical solution. Giving due consideration of the commercialscale filtration operation during early-stage process development is critical to ensuring there is a suitable technology for your process duty, and it may identify that the original process concept should be adapted to match the available filtration technology. There are many elements to consider before selecting a technology, such as whether the product is the solid or liquid stream; what losses are acceptable and does the cake need to be washed; what is the intended scale of the commercial operation; is the intended commercial operation batch or continuous, manual or automated, etc. Once these questions have been answered and the mass balances around the filter have been established, the filtrations models will help do a first pass sizing of the filtration area that will be required. For many filtrations processes, the choice of filter for scale�up will be a relatively straightforward catalogue engineering exercise. However, for slow filtering materials the choices become more difficult, because the technology solutions may not yet be developed. From the models described in the previous section, there are two ways to improve the filtration rate: 1. increase the driving force (pressure) 2. reduce the resistance (cake thickness)

Figure 1: Example Experimental Results www.ipimediaworld.com

Typically, a fourfold increase in pressure will be required to double the rate, and very high pressures are generally undesirable because of the potential to compress the cake, so the most potential for improvement will lie with reducing the cake thickness. INTERNATIONAL PHARMACEUTICAL INDUSTRY 51


Labs

For batch filters, thinner cakes mean larger filtration area to achieve the same batch size. This is the usual solution in a lab during development, but as you scale up, the filters get infeasibly large or you end up having many filters in parallel to achieve the surface area. Both options become very expensive, so alternative approaches are required, such as continuous filters or self‐cleaning filters. Continuous Filtration As you scale up, continuous filtration has a number of advantages over batch filtration, such as smaller footprint, lower costs, and greater opportunities for process control. These filters can do filtration, cake washing, cake drying and in some cases cloth cleaning simultaneously, and you get instant feedback on the cake / filtrate properties, so parameters can be adjusted in real time instead of waiting for a batch to complete. The filter speed, vacuum/ pressure setpoint, feed rates, wash rates, drying air, etc. are all adjustable to adapt to the characteristics of the material being filtered, and ensure the desired product quality can be achieved. The historical limitation with this technology has been scale, because they were originally designed for larger-scale operations, and it was difficult to find suitable options for smaller-scale duties. Consequently, it is not uncommon to find batch filters used in semi‐continuous mode to allow thin cake filtration, with two or more filters in parallel and buffer 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

volumes built in either side of the filters to allow continuous operation in the rest of the process. The result of this is a compromised process that is less efficient, more complex and thus more expensive than necessary. Fortunately, some of these historical gaps are being filled as a much broader range of continuous filtration technologies are being developed, which will hopefully eliminate the need to compromise the process design with semi-continuous solutions. Both pilot-scale and micro‐ scale continuous filters are now being marketed to meet the needs of smaller‐ scale operations, including disposable rotary drum filters for single-use applications in the pharmaceutical industry. If the limitation of scale has gone away and the technology has even become disposable, there are greater opportunities than ever before to ensure the optimum technology is selected during process development. Self-cleaning Filters Self‐cleaning filters have been developed for the water industries where there are very high liquid throughputs and minimum pressure drop is critical, so it is undesirable to allow even a thin cake to build up. These filters typically scrape the filter surface preventing a build‐up of solids and ensuring the liquid is presented to a clean filtration surface with minimal resistance. These filters are typically designed for removal of unwanted solids from a liquid stream

rather than collecting a solid product, and there are currently limitations in the particle size that can be removed because the filters usually use wedge wire media, but with a little imagination I believe the concepts could be easily developed for much broader application. For example, it would be a very simple modification of the technology to swap a wedge wire filter cartridge with a sintered metal or ceramic filter cartridge, both of which have smooth surfaces to work effectively with a wiper blade, and both of which are capable of filtering to significantly finer particle size ranges than a wedge wire filter. This would allow application in processes with very fine particles where the liquid throughput is lower, or the pressure drop is less critical. I’m sure it should also be feasible to scale down the filters with smaller casings / filter cartridges to minimise hold‐up volumes and losses when the solids are discharged. There are lead times involved in developing bespoke solutions, but these developments seem relatively minor, so I believe that if vendors are engaged early enough in the process development cycle, there is great potential to employ these filters outside of the traditional sectors. There is no suggestion that continuous or self‐cleaning filters will be the answer to all difficult filtration problems, but there is a very wide selection of filtration technologies on the market and it is important to explore the technology space to understand all the options. As described above, most of the technologies have been developed Summer 2019 Volume 11 Issue 2


Labs to meet specific needs within specific industries, but with some creative thinking, these technologies can be easily adapted to cross over sector and scale boundaries. R&D / engineering teams are encouraged to explore the technology options outside their specific company / sector experience and engage with vendors early to develop innovative solutions to difficult problems. Summary In many processes, filtration is a key unit operation, yet the development of this process is generally overlooked, with little experimentation done to understand or optimise the filtration parameters. There is also a tendency for R&D / engineering teams to repeatedly employ the same technology even if it is suboptimal, either because they are unaware of alternatives or because the alternatives have not been fully developed to suit their application. In either case, the consequence is usually a compromised process resulting in operational and/or quality issues that are only identified when it is too late or too expensive to change the technology.

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These issues can be avoided with some simple experiments and empirical modelling to allow a data-driven approach to scale�up. The key is to generate sufficient data across a broad range of parameters to allow reliable fitting of the data to the model. Accept that the models are empirical, they will be unique to the material being filtered, and use the simplest approach to get the greatest benefit with the least effort. Th e re a re a l s o s i g n i f i c a n t opportunities for R&D / engineering teams to engage with vendors to get a broader understanding of the different technologies available and then select the technology that best suits the process requirements, rather than copy what has been done before. In some cases, an innovative approach may be required to tailor the selected technology to the specific requirements of the process, but if this occurs early enough in the process development cycle, there is likely to be sufficient time to develop the filter technology with the vendor.

Filtration is generally a quality critical step and can cause significant operational and quality issues if not developed properly. Time spent developing models and researching technology will reap rewards with a commercial process that operates efficiently with the desired capacity, yields and product quality.

Noel Quigley Noel Quigley is managing director of BPE, one of the UK’s leaders in process engineering design. Noel is a chartered chemical engineer and Fellow of IChemE, with vast experience of senior management and project leadership. As managing director of BPE, he leads the team and helps to define the technical strategy of client projects. Having held process engineering roles with Procter & Gamble and GlaxoSmithKline, he truly understands clients’ challenges and needs.

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Technology

Overall Equipment Effectiveness: A Crucial Component in Process Performance Improvement By the end of 2019, more than 75% of the world’s prescription medications will be considered under different legislations.1 The development of regulations to safeguard the pharmaceutical supply chain is evidence of the fact that the pharmaceutical world has woken up to the problems of counterfeit medicines.

It is crucial that organisations implement robust serialisation processes to curtail counterfeiting. Currently, pharmaceutical manufacturers are investing considerable efforts into complying with government and industry standards for quality, traceability, and safety. Various serialisation machines are being employed to ensure the traceability of products from the manufacturer to the end customer. However, alongside this investment in traceability and the challenges that counterfeit medicines present, companies must strive to maintain effective machinery and equipment for timely production and quality products. With the increased demand for pharmaceutical equipment and machinery, decision-makers have become careful when it comes to capital investments and purchasing decisions in order to achieve cost-optimisation. Overall equipment effectiveness (OEE) is one of the most fundamental factors that should be considered while making key purchase decisions, such as the acquisition of pharmaceutical inspection machines. OEE, a term coined by Seiichi Nakajima in the 1960s, determines the effective utilisation of equipment in a manufacturing environment. This article provides an overview of the various components that are involved in measuring the OEE of pharmaceutical products. In addition to OEE, validation, verification, and routine performance monitoring are reviewed to ensure 54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

that a piece of equipment conforms to regulatory requirements during its lifecycle. These measures are elaborated below. Validation and Verification Numerous organisations have defined validation and verification. In the pharma purview, according to the 21 Code of Federal Regulations Part 820 – Quality System Regulations of the Food and Drug Administration (FDA), “validation means confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use can be consistently fulfilled”,2 and “verification means confirmation by examination and provision of objective evidence that specified requirements have been fulfilled”.2 The meaning of validation is restricted to the demonstration of the suitability of a method or process for its intended purpose. On the other hand, verification involves the determination of whether the previously validated method is suitable for use in the given specific experimental conditions. Validation is performed to confirm whether the equipment conforms to the design specification, and if the right equipment has been selected. However, the on-site validation is performed only once – at the time of installation of the equipment, or whenever the equipment undergoes modification (revalidation). Conversely, verification is conducted annually to confirm if the equipment is functioning in accordance with the expected specification or has enhanced specification requirements. The internal quality assurance (QA) team of a company plays a critical role in coordinating this activity, alongside an external independent third party. Routine Performance Monitoring Routine performance monitoring involves a series of performance verification checks completed at frequent and regular intervals. Operators and production executives evaluate

whether the equipment is operating within the set limits using various tests. The internal QA or production team regularly perform these tests during production, or before and after product changeover. The frequency of these tests varies. OEE The International Society for Pharmaceutical Engineering document states the following: “Levels of OEE performance are highly variable, and it is important to set expectations accordingly. A continuous processing plant in oil or chemicals will often have OEE rates of 90% or more. A multi-product, sterile pharmaceutical packaging line will often have OEE rates of less than 10%. It is, therefore, important to recognise realistic and achievable target levels for the equipment in question.”3 OEE is calculated using the following formula:4 OEE (%) = Availability rate × Performance rate × Quality rate. •

Availability rate4 (the percentage of time in which a machine is ready to produce, works correctly, and is not in the process of changeovers or adjustments). It is a measure of how often a system is up and running. It is often referred to as uptime, which is calculated as the ratio of actual, versus planned, production time.

Performance rate4 (the ratio of output compared to an output standard). It is a measure of the maximum output achieved when compared to the designed output and can be described as performance. Performance is the ratio of net runtime to runtime.

Quality rate4 (the ratio of the good output compared to the actual output). The manufacturing industry sometimes refers to this as the first pass yield, which is a computation of the good units Summer 2019 Volume 11 Issue 2


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Technology produced as a percentage of the total units produced, or the ratio of the good count to the total count produced. OEE Parameters When it comes to the benefits of using inspection equipment, executives should consider these factors: •

Availability Contributes to the reduction of rework. Timely identification and rejection of defective products can prevent damage to equipment, and thus prevent unscheduled downtime. Performance Contributes towards the quick set up of production equipment and informing the production team of scheduling downtime.

Quality Contributes toward the timely identification of a deviation in process parameters and setting the course of corrective action. Hence, this parameter helps in reducing start-up and production reject rates.

Considering the above, we can surmise that OEE is most effective when utilised to determine the scope and steps of process performance improvement, rather than the output of an individual machine or component. Closing the Performance Gap Tablets/capsules manufactured by the pharma industry are packaged into a blister using a blister-packing machine. Because these tablets/capsules are manually fed into the hopper of a packaging machine, there are chances

of errors/defects. These errors/defects may include: 1. 2. 3. 4. 5. 6. 7. 8.

Incorrect products Foreign particles Broken products Duplicate products Crushed/cracked products Only body/cap in capsule Changes in shape, size, and form Spots or discolourations

Extensive data collected (by interviewing customers) on the number of extra hours spent to correct/address the errors/defects. We found that during a typical eight-hour shift, almost 1.5 h was spent on the rework process as defective products were being packed. Actual completion time of one shift – 8 h (480 min) Rework time in one shift – 1.5 h (90 min) Quality = Actual time / (Rework time + Actual time) = 480 / (90+480) = 0.8421 = 84.21% i.e., one day per week of production was lost due to rework. This translates to 48 days lost per year of annual production. The solution was to reduce manual intervention and install a camera-based inspection system on the blisterpacking machine. This ensures that no defective product is packed, ultimately reducing the amount of lost time (due to rework). Solution – Cutting Out Manual Intervention An inspection system on a blisterpacking machine is positioned right after the tablets/capsules are dropped from the hopper into the cavities of the base foil. A reference image of correct packaging of the tablets/capsules is used as the benchmark. A camera continuously takes images, and software-based image algorithms compare these images with the reference image. Any defects or rogue products cause the camera to provide a reject signal, and the defective blister gets rejected at the end of the line. Thus, all the defective blisters are automatically collected in a separate rejection bin without any manual intervention. This eliminates

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Technology the time-consuming process of manual visual inspection. Another set of interviews conducted with customers (from the same set as earlier) who installed an inspection system on their blister-packing machine. It was observed that the installation of inspection system resulted in approximately 15 mins of rework per shift. The calculations mentioned below are self-explanatory which increased the quality of outcomes. Actual completion time of one shift – 8 h (480 min) Rework time in one shift – 15 min Quality = Actual time / (Rework time + Actual time) = 480 / (15+480) = 0.9696 = 96.96% i.e., one day in each month of production is lost, which translates to only 12 days lost per year of annual production. Therefore, a straight 36 days of production gain was achieved. Result By reducing manual intervention and installing an inspection system on their blister-packing machine, our customers were able to reduce error rates, which ultimately led to the improvement of the production process. This can translate to increased availability and performance rates of the machine, which may eventually improve the OEE of the blister-packing machine. As we know, measurement of perfor-mance is essential, because it identifies performance gaps between current and desired performance and provides an indication of progress towards closing the gap. By using OEE, we can work on reducing this gap up to a certain level. Despite the emphasis laid on process control and consistency by the FDA guidelines, inconsistencies are often observed in many facilities. These inconsistencies mean non-compliance to the current good manufacturing practices, and this non-compliance can lead to process inefficiency and loss of productivity. Conclusion OEE is an essential factor that helps www.ipimediaworld.com

to ensure effective purchase decisionmaking. The OEE concept, however, only scratches the surface of the process involved when choosing appropriate pharmaceutical inspection equipment to improve production cost-effectively. It is imperative that buyers expand their knowledge on this subject. Vision inspection systems help the industry to minimise the production downtime and higher reject rate due to false rejection. Therefore, it is evident that quality and, consequently, the OEE can be improved substantially. This, in turn, can considerably contribute towards enhancing production and revenue. These systems can ensure that all the products are inspected and adhere to standards. Simultaneously, these systems can identify and remove non-conforming products. The capabilities of vision inspection can vary from fundamental to complex systems. The latest vision inspection technologies not only inspect each label in real-time, but also track foreign objects such as plastic, bolts, and washers on the tablet counting machine. Such capabilities help companies to avoid unnecessary product recalls and their associated costs. Apart from the detection of defective products, inspection equipment can help achieve better runtime data. Buyers can achieve superior OEE if they can determine the causes of potential defects and take preventive actions accordingly. The OEE of a plant is usually compared to the world-class OEE. Typically, OEE can be benchmarked at 60%; this score indicates a substantial scope for improvement and a possible target. However, a score of 100% is considered a perfect production, under which, only good units are produced in the shortest time and without any stoppages. Thus, the monitoring of OEE is highly beneficial; it is a vital aspect of the quality control process that increases efficiency and profitability, and enhances production processes. REFERENCES 1.

Packaging digest. Serialization: Why manufacturers and packagers must prepare now [internet]. 2017 [cited 2018

2.

3.

4. 5.

27 Sep]. Available from: http://www. packagingdigest.com/serialization/ pmp-serialization-why-manufacturerspackagers-must-prepare-now-151104. CFR - Code of Federal Regulations Title 21 [internet]. 2018 [cited 2018 27 Sep] Available from: https:// www.accessdata.fda.gov/scripts/ cdrh/cfdocs/cfcfr/CFRSearch. cfm?CFRPart=820&showFR=1. Overall Equipment Effectiveness (OEE) and its Application in Pharma/Biopharma Manufacturing. Available from: https:// www.ispe.org/omcop/oee-oct2010-oeebasic-philosophy-definitions-part1-4. pdf Calculate OEE. Available from: http:// www.oee.com/calculating-oee.html. Lean Production. OEE (Overall Equipment Effectiveness) [internet] [cited 2018 28 Sep] Available from https://www.leanproduction.com/oee. html.

Ettore Cucchetti Ettore Cucchetti is the CEO of ACG Inspection Systems Pvt. Ltd., which includes ACG ValueLinks LLP and ACG Pharma Agents LLP. As a CEO, he deals efficiently with ACG’s business challenges and has the ability to work with diverse cultures and domains for designing and executing strategies for high-tech markets and products. Developing and deploying the technical, operational, and relational aspects through various ad hoc solutions, including the use of innovative tools and methodologies, has always been his “cup of tea” (although he actually prefers coffee). Organisational set-ups, management, sales and marketing, business development, product branding, lobbying, and networking are like second nature for him. Having held key executive positions in public and private companies previously and now as an integral part of the Board Committee, Ettore ensures that the ACG leadership is constantly attuned to the changing market, the competitive environment, new industry possibilities, and expansion opportunities around the globe. Ettore has an extensive background in account management with some of the top Fortune 500 companies, which has helped him gain experience across different sectors.

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Technology

Monitor and Support Patient Medication Adherence through Connected Health Healthcare is increasingly digital, from wearable medical devices to remote patient monitoring to telemedicine. Yet most big drug makers have been slow to join the m-health revolution. In fact, medication is one glaring example of the critical health data components that remain outside the digital environment or struggle to integrate effectively into electronic health records.

The High Cost of Poor Adherence Medicine is vital to our understanding of disease management and progression. The ability to measure medication effectiveness – and patient adherence – plays an important role in managing and improving patient health, especially as healthcare systems in the United States and globally start to implement outcome-based reimbursement. However, little actual data exists that pinpoints when, or even if, patients take their medication. A range of research has demonstrated, though, that nearly 50 per cent of all medicines are not taken as prescribed.1 Even for patients with chronic conditions, adherence is only 50 to 60 per cent.2 It is estimated that this poor medication adherence is responsible for $290 billion in avoidable healthcare costs in the United States – approximately 13% of total US healthcare spending.3

of new prescription drug development can be as high as $2.6 billion.6 But despite this investment, when patients walk out of the pharmacy after filling their prescription, whether or not they actually take the medication as prescribed is anybody’s guess. Connected health solutions can help fill that void. Getting Connected to Meet Growing Demand Only a few connected health solutions tied directly to medication have made it to market so far. These pioneering systems indicate that connected health solutions are going to become more prevalent in monitoring, measuring and supporting patient adherence to prescribed medications. Integrating connectivity into innovatively designed, patient-centric drug delivery devices offers promising opportunities for pharmaceutical companies to improve the patient and provider experience. It also helps them to support increased adherence by making it easier and simpler for people to take their medication on-time and as prescribed. Connectivity provides an efficient way to monitor patients’ adherence

and condition, as well as to share both real-time and historical data with patients, clinical researchers, healthcare providers, caregivers and payers. The connected health ecosystem includes three primary components: connected devices, such as inhalers and injectors; digital interfaces, including patient and caregiver apps, and dashboards for healthcare professionals; and a cloud platform, enabling data integration with multiple sources including diagnostic devices, IoT sensors and EHRs in order to generate insightful analytics. To be successful, a connected health solution needs to be built on the right technology, incorporate a deep understanding of key business drivers and focus on serving patient needs. In order to create a positive patient experience that supports improved adherence, a connected system should include simple, intuitive mobile apps and reminders that support and motivate users. It has to be easy for patients to load apps, connect to devices and record data. It should also enable pharmaceutical

In addition to their negative impact on patients, desired outcomes, emergency department admissions and healthcare costs, the poor adherence rates also reduce the potential income of pharmaceutical companies, accounting for approximately $188 billion in lost revenue.4 Adherence rates ranging from 31 to 66 per cent for popular respiratory, diabetes and autoimmune drugs can leave between $1 billion and $10 billion dollars “on the table” in any given year.5 However, even as little as a three per cent increase in adherence can generate more than $1 to $3 billion in additional revenue for these popular drugs over a five-year period, according to our estimates. This is significant, especially given the cost 58 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2019 Volume 11 Issue 2


POWER UP YOUR PRODUCTION Be part of the UK’s largest event in processing and packaging machinery, including robotics and industrial vision See the latest innovations to help you increase your production line efficiencies, enhance business performance and profitability

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Technology on a connected health platform include: •

companies to motivate and instruct patients on treatment information and medication administration, further supporting adherence. Four years ago, the first connected health system was approved by the FDA for a specific drug. In the time since the product was released to the market, interest in connected health has flourished. The number and popularity of connected health pilots is growing, but pharmaceutical companies sometimes struggle with how to scale the model, and extract and quantify the value created, which can impede additional investment. While the cost of developing connected technology is significant, so is the potential for supporting increased adherence, facilitating improved outcomes, and potentially generating additional revenue for the drug manufacturers. Recognising the increased interest and demonstrable benefits connected systems provide, we decided to invest in developing a highly scalable platform to service the expanding market, rather than developing and maintaining one-off, application-specific solutions for each new project. Best Practices and Benefits of a Connected Health Platform The result was a connected health platform. This cloud-based connected health platform provides a scalable medical device data system (MDDS) for pharmaceutical companies and platform drug delivery device customers. The opportunity to build drug delivery devices on an existing connected health platform helps pharmaceutical companies and drug delivery device developers on several fronts. It reduces the risk, time and cost associated with developing connected health solutions. This, in turn, helps accelerate time to market. Additional benefits of building solutions 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Comprehensive informationsharing and analytics capabilities. A connected health platform supplies the digital tools needed to extract powerful health and market insights. It provides a medical device data system (MDDS) that connects pharma companies, clinical researchers, providers, patients and payers, sharing and displaying information from connected drug delivery devices, biosensors and regulated mobile medical applications (SaMD/MMA). Advanced analytics capabilities that span the care continuum allow researchers and other users to quickly generate 360-degree views of data, and also to create a data presentation layer for use by the analytics engine, providing deep insight into how medication is taken. Dashboards can be changed or fine-tuned quickly and easily at any point – not only during the core software development phase, as has previously been the case. This capability saves time and money, adds high-value flexibility and streamlines connection with other supported external analytic systems. A connected health platform can also integrate medication, diagnostic and therapeutic data from multiple sources using an enterprise master patient index as well as support global comparisons by normalising data across geographies. As a result, American patients with asthma, for example, can be compared with patients in France or the United Kingdom. Data can easily be anonymised or pseudonymised to support clinical research. It can also be made actionable, enabling patients to be added to specific care pathways and monitored accordingly. Robust cybersecurity. Data security and privacy must always be a top priority. Connected health solutions can be deployed in a secure private cloud with a credible legacy of health data security, in a cloud hosting option selected by the pharmaceutical company, or in the company’s own data centre. Those

offered as Platform as a Service (PaaS) relieve customers from responsibility for data management and storage, whether they count patients in the thousands or hundreds of millions. They also free pharmaceutical companies and drug device developers to focus on their primary objective: connected health solutions that provide better patient experiences and facilitate improved patient outcomes. In addition, cost-effective and secure collaborative environments are available for situations where cross-industry partners want the ability to share data. •

Streamlined regulatory documentation. Connected health platforms that come complete with full regulatory documentation services to support premarket submissions for 510(K), combination products and CE mark help lower project costs and speed time to clinical trial, regulatory approval and market – ahead of the competition.

Modular approach. Working with a manufacturing partner who can deliver connected health solutions that incorporate devices with electronics and sensors already embedded also speeds the development process and keeps costs low, for both reusable and disposable drug delivery devices. Connected health platforms that come with a software development toolkit and defined, extensible API, allow any device to be connected to the system. As a result, pharmaceutical companies can deploy a single solution across all therapy areas for each product and drug compound if desired, rather than having to utilise different companies’ platforms for each product and device type. Pairing a configurable app with the connected health platform and deploying it across multiple products using a standard Bluetooth interface further supports a rapid, low-cost path to clinical trial and market.

Massive scalability. Building infrastructure for a connected health solution on a flexible, scalable platform rather than Summer 2019 Volume 11 Issue 2


Technology starting from scratch for each new drug makes it highly cost-efficient to add or refine infrastructure for future projects. Because the price per user declines as the patient population increases, the costs for integrating connectivity for medications used to treat common chronic conditions also decrease. •

Post-market surveillance and updating. Connected health solutions need to keep pace with the constantly changing mobile technology industry. Drug device developers and pharmaceutical companies not only need to invest in the service and support required to deploy and maintain the systems, but also need to proactively test new mobile operating system releases and smartphone models against the connected health platform and apps. A drug delivery device built on a platform that is continually updated and modified as needed ensures a seamless patient experience, which is always a primary focus.

Connected Health in Practice: A Case Study This case study demonstrates the value a connected health solution can add for both patients and pharmaceutical companies. A leading pharmaceutical company recognised the need to update its current drug injection device in order to retain existing patients and attract new ones. The company's drug had established safety and efficacy, but its injection device lagged in user-friendliness. The company sought to use electronics to improve the injection experience but also wanted to help patients better manage their disease by offering seamless integration between the device and a patient app that could track injections and remind patients when and where to take them. An innovative electromechanical

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autoinjector connected to the cloud was launched in just two-and-a-half years, using customisable technology accelerator building blocks that eliminated the need for lengthy and costly R&D processes. The new connected autoinjector system featured: • Ergonomic design with a button in the middle of the device, operated with one hand and light pressure, making for a gentle experience; • Secondary control functions hidden on the inside, so they don’t interfere with the day-to-day operation of the device; • A dashboard for healthcare professionals to easily monitor patients and determine who needs support; • Bluetooth connectivity that ensures data on injection time, volume and body location are synced with the patient app and dashboard; • Personalised, localised messages and reminders for patients on their device and in the app. The integrated system was introduced in countries worldwide after its initial launch in Europe. It has made injections more intuitive for patients, made it easier for caregivers and healthcare providers to coordinate and follow up on treatment and helped the company retain its market position. Summary The learning curve for connected health solutions remains steep, but the pace of development continues to accelerate as pharmaceutical companies and drug device developers seek to meet market needs by capitalising on emerging technologies. Unlocking the value in connected health offers promising potential for creating a more positive patient experience that can help improve adherence and facilitate better outcomes. The opportunity to develop innovative, connected health solutions

using a secure, cloud-based platform that provides a safe and scalable medical device data system helps pharmaceutical companies and drug delivery device developers reduce risk, cost and time to market. At the same time, by demonstrating a clear pathway to value creation, these cost models can bridge the gap between pilot and programme and encourage additional investment in connected health by pharmaceutical companies. REFERENCES 1. 2. 3. 4.

5.

6.

Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005 Aug 4;353(5):487-497. Philipson, Tomas. Non-Adherence in Health Care. Forbes. May 8, 2015. Philipson, Tomas. Non-Adherence in Health Care. Forbes. May 8, 2015. Capgemini Consulting HealthPrize Technologies. Estimated Annual Pharmaceutical Revenue Loss Due to Medication Non-Adherence. 2012, reprint 2016. Capgemini Consulting HealthPrize Technologies. Estimated Annual Pharmaceutical Revenue Loss Due to Medication Non-Adherence. 2012, reprint 2016. Sullivan, Thomas. A Tough Road: Cost to Develop One New Drug is $2.6 Billion; Approval Rate for Drugs Entering Clinical Development is Less Than 12%. Policy & Medicine. March 21, 2019.

Kevin Deane Kevin Deane is Vice-President, Innovation at Phillips-Medisize. With over 25 years of experience developing new products, Kevin has supported a broad range of drug delivery and medical devices to market. He leads an early-stage development team and co-ordinates large-scale developments in connected health, from devices to data, pulling together the deep capabilities across PhillipsMedisize and Molex. Kevin moved from the US to Cambridge UK in 1994 and worked for PA Consulting as a Partner in the Technology Group. He has led a number of drug delivery and connected health projects for pharmaceutical clients across Europe, Asia Pacific and the US, supporting strategic assessment through to full system implementations.

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Technology

Tracking Devices: Lessons from Big Pharma as Medical Device Manufacturers Prepare for New Reporting Obligations Big Pharma has long had to contend with rigorous electronic reporting standards, designed to protect patients. Now, it’s the turn of medical device manufacturers, which have so far escaped the same transparency measures. So what does best practice data management and reporting look like? AMPLEXOR’s Elvis Paćelat distils some tips from the pharmaceutical industry’s experiences

Substantial new controls are coming to medical device manufacture, as part of new moves to make companies more accountable for their products once they have been released into the real world. First Europe, then almost certainly other regions around the world, is demanding that device producers comply with new tracking and reporting requirements.

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The shift presents some fundamental challenges which have strong echoes of where pharmaceutical companies were some 14 years ago – when EMA and other regional authorities started to roll out new information submission standards and keep closer tabs on medicines. After significant pain and cost over the last decade or more, drugs companies have come a long way – their most recent effort being to create a more definitive, consistent and reliable picture of their products from a regulatory perspective, in anticipation of new ISO IDMP requirements. Until now, medical device manufacturers have been largely exempt from such controls. But this is now changing, in the run-up to the

European Commission’s new medical device regulation (MDR), applicable from May 2020, and the equivalent in vitro diagnostic medical device regulation (IVDR), due for introduction in May 2022. Staying Accountable for Patient Safety One of the most critical areas of focus of the new regulations is post-marketing surveillance and follow-up research and feedback, once medical devices are being used by patients. Once the new regulations are live, it will be incumbent on device manufacturers to formally monitor the long-term safety of their products – watching out for signs of leaking implants, metal release from hip replacements, and so on. They will be expected to provide evidence of their follow-up findings in periodic safety update reports.

Summer 2019 Volume 11 Issue 2


Technology Clearly, then, companies need to be able to capture post-market safety data. MDR demands a detailed summary of safety and clinical performance information, which must be updated and reported at regular intervals with post-market clinic follow-up findings – a combination of formal studies, incoming feedback from patients and GPs, and potentially commentary captured via public online patient forums and social media platforms. While some forms of follow-up will have been taking place routinely with life-and-death devices such as pacemakers, the new post-market surveillance requirements will apply to every category of medical device, creating a lot of work for manufacturers. The implications of falling short of authorities’ expectations could be significant, ranging from multi-milliondollar fines and products being taken off the market, to lasting reputational damage. The increased rigour is expected to be replicated globally, too. It is estimated that, in the US, more than 1.7 million injuries and almost 83,000 deaths may have been linked to medical devices, based on reports to the FDA over a 10-year period, due to inadequate checks into manufacturers’ safety claims. And, significantly, the International Medical Device Regulators Forum (IMDRF) has a keen interest in MDR and IVDR, which could result in countries in Asia, and South as well as North America, adopting their own variations on the requirements in the coming years. IMDRF’s remit is to accelerate international medical device regulatory harmonisation and convergence much as the International Council for Harmonisation (ICH) does in the global pharmaceutical industry. Learning from the Early Adopters With little more than a year to go until the first new requirements come into force in Europe, there is a growing sense of urgency for medical device manufacturers to put in place strategies, processes and systems for managing all of their new reporting responsibilities. So, what can they learn from their counterparts in the pharmaceutical sector, to save them repeating early mistakes? www.ipimediaworld.com

The first takeaway is not to see the coming changes as a single event that manufacturers can plan for with a definitive, one-stop project. If pharma has learnt one lesson above all, it is that the global regulatory climate is continuously evolving, so trying to pin down all requirements up front, or waiting until all the final variables are known before getting going, is not a practical approach. Similarly, regulators’ hunger for information is seemingly insatiable, so selecting a series of best-of-breed applications that each handle a finite set of parameters, has been found to be a false economy. When pharma companies did this, many ended up with between 20 and 40 different systems from different vendors, all of which needed to be supported and updated, and many of which did not integrate and share data very easily with each other. This caused firms to fall back on manual processes and spreadsheets for managing all of the contributing information, reintroducing inefficiency and undermining their considerable investments. Over time, pharma companies have realised that it is far more practical to create a more fluid, end-to-end information management capability which can be adapted to a range of different needs. The ideal many firms are now working towards is the creation of a single, complete, master set of data about their products and their evolving status – one that spans R&D, approvals, and post-marketing follow-up, and which can be applied as needed for each different use case. Having a clear line of sight across a definitive single set of complete information offers companies all sorts of advantages, not least the scope to reduce repetitive data re-entry or document creation, and the opportunity to automate preliminary information checking and content-building processes. In pharma, companies have been able to do away with huge teams of temporary staff who had been drafted in to review and edit regulatory documents ad infinitum. With strong, authenticated master data to draw on in support of multiple use cases, they were able to automate much of this work.

Exploiting New Product Visibility Looking for broader efficiency gains will also serve medical device manufacturers well as they are required to provide better information directly to patients – for instance, online advice about the lifespan of a product, or guidelines about airport safety for users of pacemakers. That’s aside from the immediate benefits of being able to call up a product’s status information in a couple of clicks, to verify where it is currently approved, or what has been the latest correspondence with a particular authority. Working towards a comprehensive, global master resource of product regulatory data offers medical device manufacturers a host of potential advantages, and a chance to skip to the point that many pharmaceutical companies are only just getting to now. With the first deadlines for the new regulatory compliance bearing down, medical device manufacturers need to press on. One of the first discussions may need to be about moving extended product data management off the shop floor into a regulatory lifecycle/regulatory information management (RIM) environment, overseen by those tasked with matters of safety and compliance. Certainly, as postmarketing surveillance activities grow in prominence, regulatory affairs teams will see their role and status grow, with the likelihood that relevant skills will be in high demand. It is yet another reason why manufacturers must not delay their planning.

Elvis Paćelat Elvis Paćelat, Executive VicePresident for Life Sciences at AMPLEXOR, has more than two decades of international experience in the life sciences market and is a specialist in end-to-end content management, regulatory compliance and business impact analysis. Email: elvis.pacelat@amplexor.com

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Logistics & Supply Chain Management

Digitalisation, Quality & Efficiency in Pharmaceutical Distribution Why are digital technologies rising in importance in pharmaceutical cold chain logistics? The reasons are intertwined and not easily separated. In this article, we’ll discuss some of them, namely the increase in biological medicines, the convergence of mutually supporting technologies, and the way in which regulations and pharmaceutical quality practices affect each other. We will also discuss the potential of both current and upcoming digital technologies to enhance the efficiency and safety of pharmaceutical logistics with a focus on IoT. We will additionally touch on the benefits of implementing these technologies into use in pharmaceutical distribution.

The Rise of Biopharmaceuticals We have for some time now seen the rising impact of biopharmaceuticals on the pharmaceutical logistics field. In just a few recent months there have been several announcements about plans to increase production capabilities and about investments into new product development. These lead directly to the increase of biopharmaceuticals in the pipeline and the volume of marketable products leaving manufacturing sites. It is also a well-known fact that many of these products are more susceptible to temperature fluctuations than small-molecule pharmaceuticals. And while biopharmaceuticals represent a smaller overall volume than small-molecule drugs in the pharmaceutical market, biologicals tend to be, pound for pound, much more expensive. Thus, they play a larger part in the overall scheme of things than their production volume would suggest. For distribution, these facts together mean that there will be an increasing demand for cold chain and other kinds of temperature-controlled logistics. Cold chain needs for biopharma products are accordingly predicted 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to increase at over double the rate compared to non-cold chain products1. Regulation and Digitalisation A parallel trend to the increase in cold chain demand in pharma logistics, digital monitoring and control technologies are starting to increasingly enter the cold chain logistics field. The reasons for this are many, but a definite factor is the convergence of technological advancements in electronics and communication technologies, new pharmaceutical innovation, and the pharmaceutical sector’s recognition of the importance of holistic end-toend data. The regulatory environment also plays a part. In evolving along with the innovations and technologies, it must take into consideration not only the minimum standards of what needs to be done, but also the possibilities of what can be done. Thus, we have GDP guidelines that accept digital technologies as a natural part of the pharmaceutical cold chain. There is also an interesting relationship between the regulators and the regulated. We can see this in the way in which regulation recognises the ways in which the frontrunners of digital technologies use new digital means to improve on their processes. As soon as these practices are codified in regulation, the latecomers

on the regulated side implement such measures as they find in the regulatory documents and guidelines. In short, we expect that many of the new technologies and practices being tested in the field will inevitably drift down to first GDP guidelines and then industry-wide use. These technologies include IoT (arguably the foremost of current tech generation), blockchain, AI and machine learning, and predictive and prescriptive analytics Risk Management and GDP But what makes pharmaceutical cold chain operations a worthwhile focus for these kinds of digital technologies? To answer this, we’ll briefly touch on quality management systems (QMS) and quality risk management in the context of (mainly EU) GDP.2 In the GDP guidelines, a quality system is the method of ensuring that everything relating to the distribution of pharmaceutical products is geared towards pharmaceutical products maintaining their quality and integrity. This includes creating standard operating procedures (SOPs) to ensure that a sustainable level of quality is maintained. Furthermore, when creating SOPs, it is essential to employ a quality risk management approach in order to identify hazardous situations which may come up in distribution activities. Summer 2019 Volume 11 Issue 2


Logistics & Supply Chain Management The way to achieve this means, for example, temperature mapping of storage areas, vehicles and packaging used to hold pharmaceutical products. It also includes drawing up appropriate CAPAs (corrective and preventive actions) to either prevent the risks altogether or at least minimise the harm to pharmaceutical quality. As discussed earlier, biopharmaceuticals are often particularly susceptible to temperature deviations and thus experience more risk in the supply chain when compared to small molecule drugs. This also means that an even more thorough risk assessment will be required for those modes and routes in the cold chain which are employed to transport these medications. This doesn’t need to mean a whole lot of extra work, however. Both risk assessment and eventual management can be much more easily implemented with the help of digital technologies. In particular, IoT, in the form of wireless, often highly mobile sensors, provides easy tools for temperature mapping activities. These systems can also be repurposed for use in continuous monitoring in the distribution activities themselves. Another example technology would be machine learning or comparable analysis algorithms which can be used for identifying risks through data analysis. Of course, while digital systems are useful for assessing risks in the logistics chain, where they really come into their own is as a part of

the wider QMS environment, mainly in monitoring and control tasks.

such data on spreadsheets or on paper.

Why Go Digital? So how can all these new digital technologies help in managing pharmaceutical quality in a systematic way beyond mere risk assessments? For each of these technologies, the answer naturally depends on both the capabilities and requirements of the tech in question. However, they all create their main benefits by expediting the interaction between data and real world, which is a major cause of inefficiencies and actual risks in the analogue way of handling quality management.

There would be an established temperature monitoring method for the trip based on the risk assessment of the lane and packaging options. Let’s say this would be an indicator, as the trip is quite short and they foresee no great harm coming to the vaccines in such a short time.

For clarity’s sake, it might be easiest to consider the difference through two hypothetical examples, which will show what a manual quality system would look like when compared to a digitally assisted one. Thus, let’s imagine a vaccine distribution exercise from a manufacturing site in Austria to a distribution facility in Netherlands. Geographically, this would be a fairly short and simple undertaking, and with both parties holding a marketing authorisation there would be no extra legal burdens to consider. But when, despite the relatively short journey, the shipment experiences a freezing event due to a malfunctioning AC unit, what are the results? Case A: Manual In the traditional, manual way of doing things, the manufacturer’s staff would start by recording all the required chain of custody information, such as batch numbers and other

Now the driver picks up and records the necessary information to take custody of the shipment. There is no undue trouble at border crossings, and the trip from Austria through Germany and finally to the Netherlands is swift and uneventful. However, at the receiving location, the staff notice some of the indicators showing that there has been a freezing event, and thus they are not willing to accept the shipment. With the information from the indicator, the RP for the manufacturer must make the decision to scrap the affected vaccines, because at this point, they are potentially unviable for human use. We can also substitute data loggers for the indicators, in which case after the data is downloaded and the deviation flagged, the manufacturer ought to start a deviation inspection. Ultimately, though, the affected vaccines still need to be destroyed. This kind of destroying affected products is probably the most common method of dealing with deviations in pharmaceutical logistics. After all, there are next to no alternatives when deviations are discovered after the fact. So, what would the same situation be if we assumed a fully digitalised cold chain? Case B: Digital This time at the manufacturer’s site, the staff have linked their ERP systems and TMS systems together, so that recording chain of custody and other end-to-end product data can be done with a few clicks. This information is recorded on a blockchain in real time, and an automatic transaction is logged by both parties and verified by other members of the particular blockchain system.

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 65


Logistics & Supply Chain Management Once the shipment is loaded onto a truck, IoT-based temperature sensors in the shipment establish a connection with relevant vehicle systems and record the shipment as picked up. The sensors also start sending real-time temperature data into an online database. There it can be accessed either in a dedicated platform or integrated directly to both trading parties’ quality management systems.

QMSs, or by sharing data from any of these to a common blockchain, is still to be seen. However, it seems certain that with increased visibility into operation, stakeholder cooperation becomes not only easier, but also increasingly probable. And then maybe that previously mentioned stakeholder can at last easily tell what has happened to an individual medicine, wherever it may have been.

The trip starts just as uneventfully as before, but when the temperature starts to fall, the sensors alert the quality management personnel or a relevant system directly. An analysis algorithm projects that the most probable cause is that the AC has been set too low for the vaccines. The driver is alerted and advised to raise the temperature a bit. This is promptly done, and the driver logs the action in the online QMS database. The distributor receives the shipment without any complaints because complete sensor data means that product quality is validated immediately on arrival. Additionally, a confirmation is sent to the blockchain that the transaction has been successfully completed.

All this not only makes the Responsible Person’s job easier by providing them with all the data they need in order to effectively ensure compliance. It also actively helps prevent those mishaps that can easily tie up much of quality management’s time. Eventually this will prove to be profitable, not only in the form of decreased waste, but also in the saved time that would be required by manually accomplishing monitoring, validation and waste management activities.

Are We There Yet? Of course, the second scenario is somewhat more advanced than what we can reasonably expect to be in use today. For example, currently it is extremely rare that even an individual stakeholder in a pharmaceutical multipoint supply chain could with absolute certainty say what kinds of environmental conditions an individual medicine has experienced along the way to its destination. Or at least not without an impractical amount of work. But even with the kind of digital technologies we have access to now, just the fact that all that data can be recorded in relative real time makes it possible to have access to unprecedented amounts of visibility within a relevant timeframe. With increasing amounts of IoT implementation, realising the dream of end-to-end visibility and transparency requires only connecting these real-time systems together. Whether this will eventually be achieved by connecting ERPs, TMSs or 66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

First Steps We began by discussing biopharmaceuticals and how they are going to be a rising influence in cold chain operations, continued to expand on GDP, QMS and risk managements, and finished on the potential of digital technologies to support all these efforts. Now it’s only just that we end this article by drawing all our threads together. As we’ve demonstrated, digital technologies are highly likely to become ubiquitous in the pharmaceutical logistics field because of the way they can support and make monitoring and, to an extent, control tasks easier, while building stakeholder trust by increasing transparency to distribution operation. However, while many studies show there is widespread interest throughout the industry for how these technologies could help, and plans for implementation are on the rise, we’re quite clearly still in the first part of the process where the forerunners are only just taking their first steps on the road to fully digitalised cold chain distribution operations. It’ll be interesting to see how fast the forerunners’ enthusiasm will reach the regulators and start affecting GDP guidelines, and eventually the rest of the industry.

For our part, we’re expecting that implementing digital technologies like IoT, blockchain and machine learning will very soon prove to be overpoweringly efficient in preventing wasted time, money and pharmaceutical products – and by virtue of that, enter into codified practice. REFERENCES 1.

2.

https://pharmaceuticalcommerce.com/ cold-chain-focus/global-biopharmacold-chain-logistics-will-hit-15-7billion-in-2019/ Visited on 2 May 2019 European Commission Guidelines of 5 November 2013 on Good Distribution Practice of medicinal products for human use (2013/C 343/01)

JP Asikainen Jukkapekka (Jp) Asikainen is the founder and CEO at Sensire Ltd. He is a leading expert on the cold supply chain and an accomplished innovator of market-leading wireless monitoring solutions. Jp is a highly successful serial entrepreneur with over 30 years in executive management, marketing and sales. As a long-time specialist in environmental monitoring systems, Jp is exceedingly experienced at providing customers with real-life solutions to real-world challenges. Email: jp.asikainen@sensire.com

Ossi Laakkonen Ossi Laakkonen is Technical Director at Sensire Ltd. He is an expert in cold supply chain technology design and accomplished in designing robust and comprehensive environmental monitoring systems for a wide variety of applications. Ossi’s specialty is the Internet of Things and he has over 10 years of experience with working on wireless sensor network research and development. He also holds several groundbreaking patents on these technologies. Email: ossi.laakkonen@sensire.com

Summer 2019 Volume 11 Issue 2


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Logistics & Supply Chain Management

Evaluating a Verification Router Service: Four Key Questions to Consider In November 2019, the Drug Supply Chain Security Act (DSCSA) Saleable Returns Verification requirement phases in, requiring wholesale distributors to verify saleable returned products before they can be placed back into inventory and resold.

This requirement introduces enormous challenges for not just wholesale distributors, but pharmaceutical manufacturers as well, as wholesale distributors will need fast, secure access to manufacturers’ product data in order to minimise operational impact and ensure that saleable products are returned into the supply chain as quickly as possible. Time is running out before everyone in the drug distribution supply chain will have to routinely verify the serialised product identifiers for any saleable products that have been returned before they can be restocked and resold. In this article, Dan Walles, general manager of track & trace and compliance at TraceLink discusses the considerations to take into account when evaluating a verification router service (VRS) and offers guidance on how to select a comprehensive solution. Saleable Returns and the 2019 DSCSA Deadline Saleable returns are estimated to represent approximately 2% gross sales* for wholesale distributors. A survey by the Healthcare Distribution Alliance (HDA) revealed that nearly 60 million units are returned annually. The present volume of annual saleable returns, the study found, is largely due to the industry’s propensity to over-, rather than under-stock drug inventories to ensure supply covers demand. With an estimated worth of $10 billion, resold product is critical to helping manage overall supply more effectively and efficiently. Spanning 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

gaps in production and other shortages, stocks of returned medicines help distributors meet spikes in demand, manage sudden shortages and help replenish depleted stocks. This has become a valuable market segment as resold product is critical to meeting variations in product demand. November Deadline is Looming By November 2019, manufacturers will be tasked with responding to hundreds or thousands of verification requests each day from both direct and indirect trading partners. As wholesalers enter 2020, they will be required to verify the GTIN, serial number, lot and expiration date on returned products before re-selling. Failure to respond quickly risks action by the FDA. The combination of the return volume as well as the number of products the typical wholesaler manages – which could be as high as 20,000 stock keeping units (SKUs) – creates a difficult data management challenge for wholesalers. Although the requirement is the responsibility of the wholesaler, participation from the manufacturer is necessary for compliance. Wholesalers and manufacturers will need to work together to ensure wholesalers have access to information from the manufacturer in a timely manner. It is critical that this new requirement does not slow down the receiving and return receipt process for wholesalers. A Viable Approach to Meeting the Deadline: VRS To help distributors and manufacturers minimise the impact of saleable returns on their operations, the HDA Returns Task Force has defined the verification router service (VRS) model to automate verification requests and achieve near real-time request/ response performance. For manufacturers, a VRS automates responses to verification requests from primary wholesalers that do not choose to “self-verify” against an

internal serial number repository, as well as from secondary wholesalers and dispensers that may not have a direct relationship with the manufacturer. For wholesalers, a VRS ensures that returned products can be verified if a manufacturer is not providing EPCIS data with its shipments or if the status of the product has changed since the original shipment was received, either by a recall, withdrawal, or suspect product investigation. With a VRS, product verification remains with the manufacturer, eliminating the potential liability of self-verifying against an internal serial number repository. While the HDA VRS task force has established a set of technical guidelines to ensure industry-wide adoption, not all VRS solutions offer equivalent functionality and utility. It’s critical that wholesalers and manufacturers discuss their returns verification requirements with each other, and ask these key questions as they consider a VRS solution: 1. Is the VRS based on open, interoperable standards? A wholesaler may publish a verification request using one VRS, but the responding manufacturer may use another. The process relies on the lookup directory, which operates as a phone book that is synchronised across VRSs. Any VRS based on closed, proprietary technologies puts companies at risk of ending up on an island: no other VRS will be able to publish information to or from their lookup directory. 2. Does the VRS integrate product master data access? With serialisation, the National Drug Code (NDC) number that was previously used to identify a product will be replaced by an encoded Global Trade Item Number (GTIN). With many wholesalers managing in excess of 20,000 prescription drug SKUs, they need up-to-date product master data from manufacturers to ensure Summer 2019 Volume 11 Issue 2


Logistics & Supply Chain Management GTINs are correct to avoid verification failures. The VRS should provide the ability to integrate master data sharing so manufacturers can distribute up-to-date master data to their trade partners. Wholesalers should look for the capability to access product master data directly from their suppliers and use an automated solution to ensure their product master data remains up-to-date. 3. Can the VRS meet sub-second performance requirements? The HDA task force has specified that wholesalers need near real-time responses to verification requests to minimise any disruptions to warehouse operations. A VRS that offers a scalable architecture and partner connectivity is critical to deliver the performance requirements of the HDA VRS model. 4. Can the VRS work with ERP and WMS systems? Separating saleable returns verification – including partner connectivity, serialised data exchange, and request routing – from everyday business operations is an important benefit of a VRS. But it’s also important that a VRS can integrate with your existing business systems and warehouse scanning solutions to track the status and location of returned products. In asking these questions, both manufacturers and wholesalers should be able to determine which VRS solution will give them a fast track to DSCSA compliance, while providing robust performance with master data sharing for uninterrupted business efficiency. Preparedness Forecast: Partly Confident with Considerable Concerns A recent TraceLink poll during its Saleable Returns Webinar series revealed that companies that partner with a solution provider and exchange data over a trusted network say they feel more prepared – and confident – in their ability to meet the November deadline. While 40% of respondents considered the 2019 requirements to be at least as complex as past DSCSA lot-level and serialization requirements, 60% cited the fact that their companies can count on the expertise and technical foundation provided by their track-and-trace www.ipimediaworld.com

solution provider to reduce the complexity of saleable returns verification. Despite preparations and confidence in solution providers, respondents still have considerable concerns related to saleable returns. By far, the greatest concern was being cited by the FDA for non-compliance, with 62% of attendees noting anxiety about regulatory scrutiny. Other concerns include impact on operational efficiency, unauthorized access to product data, being overwhelmed by verification requests and network performance and reliability. Time for Industry to Work Toward Alignment and Collaboration As manufacturers, wholesale distributors and other parties examine their operational requirements to meet saleable returns verification mandates, they should work toward aligning systems to meet both business and compliance priorities. Solutions that support real-time data exchange through

digital information platforms based on open, interoperable standards will inherently be more effective and ensure uninterrupted flow across the supply chain under the DSCSA’s requirements.

Dan Walles Dan Walles is General Manager, Track &Trace and Compliance at TraceLink, where he brings to his role more than 20 years ofexperience in product marketing, sales and service delivery. He has focused exclusively on the needs of the life sciences industry for the past 15 years. Since joining TraceLink in 2010, Walles has been instrumental in educating customers on how to drive business value and better patient outcomes through information sharing and collaboration. @dwalles @TraceLink

INTERNATIONAL PHARMACEUTICAL INDUSTRY 69


Manufacturing

In-house ‘SWAT team’ helped lower PMI

Rising industry concerns about environmental footprints and the global need for cleaner and greener initiatives are driving the pharmaceutical industry towards adopting newer process improvements. Globally, patients are becoming more aware, and pharma is increasingly trying to improve its corporate citizenship and, where possible, reduce its environmental impact. In fact, historically pharma has prioritized reaching patients in need faster with as few regulatory challenges as possible, over reducing waste for a product or process. To give a brief history of green chemistry initiatives, they were born out of the Pollution Prevention Act of 1990, which marked a policy change from pollution control to pollution prevention – for example looking at the amount of waste a product produced. This concept was adopted to give the 12 Principles of Green Chemistry, which provided a framework for learning about green chemistry and designing or improving materials, products, processes and systems. However, trying to manage something is impossible without a way of measuring it. One of the primary metrics to measure how efficient manufacturing processes are is the process mass intensity (PMI). PMI measures the mass of raw materials as a fraction of the mass of desired product output and is used for benchmarking and as a basis for objective comparison. Compared to the typical PMI of other chemical industries, such as oil refining where the average PMI is approximately just 1.1, the pharma industry has a surprisingly high PMI, typically ranging from 26 to well over 100, and in many cases over 500 for earlier phase projects. This is perhaps understandable considering the chief focus on rapid product launches to address unmet medical needs and safety, which puts constraints on the development time for a product. In 70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

addition, the scale of individual drugs is much smaller than the oil industry, so the cost incentives seen in other industries are not the primary drivers of processes optimization. Yet reducing the PMI does bring many benefits to CDMOs. In particular, a lower PMI reduces the raw material usage and uses less production cycle time. The direct result of this is a lower cost and less waste generated, reducing the impact on the environment. A lower PMI process is therefore not only ‘greener’, but also allows the client’s product to have a larger profit margin. Phase of Process R&D A company looking to reduce its PMI must consider the trade-off between efficiency and getting a client’s product to market fast, but in our view, these don’t need to be mutually exclusive anymore. The most important consideration is to bring PMI principles in early, not as an afterthought later in development. Yet it is also up to the CDMO to cooperate with its customers on the long-term benefits and reassure on route scouting timelines. Understandably, if running a large development pipeline, customers will very often balk at investing any additional amount of time or effort in identifying a green solution for the early stage pipeline – since, in reality, the majority of pipeline products fail (and we all know clients are keen to fail as fast and inexpensively as possible). Fundamental to any green chemistry approach to manufacturing the API, is an efficient synthetic route. Greener synthesis minimises the number of steps while maximising the atom economy. Maximising the atom economy reduces the formation of waste by-products so there is less of a burden on the environment and in turn, is more cost effective as less reagents are required. Technologies such as continuous processing, catalysis and recycling of waste all contribute to boosting efficiency.

Another consideration is that route scouting and process development is usually done at phase I of the clinical trial and it can be challenging to change the process once it has been validated. If the change is likely to impact the filing regulation document the client and plant QA can both refuse to change the validated process. Therefore, the process R&D of an API must be well developed before the PPQ (Process Performance Qualification) campaign is initiated. For example, in some hazardous reactions, a switch to flow chemistry methods to replace the traditional batch chemistry technique ultimately should be developed early. Batch processing usually requires the construction of large facilities to deliver high volume products. Due to these large-scale operations, the type of processes that can be performed are often greatly restricted by safety constraints. Continuous flow chemistry is inherently safer and faster and requires lower material usage so can proceed using smaller facilities. It also allows less hazardous intermediates to be formed than in batch processes, and reactions can be easily scaled-up. Economy of Solvents Solvents are the largest contributors to pharmaceutical waste and emissions. Reducing the volume of solvents used or choosing greener solvents will have a large effect on PMI. ‘Using 10 volume of solvent for reaction, extracted with 5 volume of solvent by three times, washed with 5 volume of water by three times. Process descriptions like these are very common when we get the process from a pre-clinic project. How to minimize the usage of solvent with the fewest experiments is a very important capability for a CDMO since meeting the timeline is the major driver for early project. In some cases, we often just require 2-3 experiments to get not only better process parameters, but also minimize usage the solvent. Using the same solvents at more steps, telescoping more than 2 steps reaction, one-pot reactions, etc. These principles are very helpful to reduce Summer 2019 Volume 11 Issue 2


Manufacturing the solvents usage and reduce the PMI. Reusing or recycling solvent is also a good approach to reduce PMI when the production demand ramps up to the commercialization stage. But it can be a huge challenge to wait to introduce this approach at the commercialization stage. Hence, a process which could reuse or recycle the solvents for late phase project before the PPQ campaign was developed in order to ensure that recycling greener solvent process will be a part of to-be-validated process. Enabling Technologies Contribute to Greener Production Catalysis is at the heart of sustainable chemistry. Transition metals are widely used in the pharmaceutical industry, but these are often expensive, in short supply, potentially toxic or their extraction and isolation significantly impacts for example the environment. Whilst palladium catalysis is the most common, cheaper and more sustainable metals such as nickel and iron, are recently being deployed. The evolution of enzyme technologies has seen replacement of more traditional reactions mediated by transition metal catalysts with those facilitated by biocatalysts- a trend that is likely to continue. Reactions involving biocatalysis are considered to be greener than using metal catalysis due to the consumption of fewer resources and production of less waste. As a result, switching to using biocatalysts would reduce PMI of a process. Additionally, because the enzymes are produced from living organisms, procedures are usually more energy efficient as temperatures necessary are usually around room temperature. The majority of enzymatic processes also have low toxicity so less hazardous waste is produced, therefore the PMI is lower. As an added bonus, reactions involving biocatalysis usually occur in water, reducing their environmental impact. The key reason why biocatalysis has become increasingly popular is due to the availability of enzyme engineering technologies. Advancements in genetics, including genomic databases and next-generation sequencing as well as robotics and computational modelling has enabled the development of novel biocatalysts optimised for the manufacture of complex APIs. It is estimated by pharma companies that anywhere from 25–75% of drug www.ipimediaworld.com

pipelines can benefit from biocatalytic methods.1 Using biocatalysts in more than 60 projects has made a large contribution to our reduction of PMI, and we have developed a large in-house library including 1000+ enzymes from commercially available sources enabling rapid screening. The biggest factor behind success? Simply, a long-term commitment to PMI as well as a sizable cultural commitment amongst scientists. But on a more practical level, a three-point plan could be ran. Firstly, PMI data is collected from thousands of production batches. The practices from R&D teams with the lowest PMI values are thoroughly examined, and the learnings deployed to other teams – essentially an in-house SWAT team for PMI. Teams with the lowest PMI or most improved PMI will be recognized, which would continue to drive forward progress. Additionally, introducing PMI reduction as a KPI to all process development teams and setting standard targets for different processes would largely contribute to success. The increasing pressure to move towards a more sustainable industry will push more CDMOs to focus on PMI reduction. As such, it is up to the industry itself to force the tides of change. But we do expect to possibly see global agencies like the EPA (Environment Protection Agency) pushing for tighter regulations and greener chemistries in the near future as well. Additionally, products are often being scrutinised by shareholders and stakeholders alike in terms of green credentials. A transformation towards sustainability may also be attractive to conscious pharma customers and could set more responsible companies apart. Taking a wider look at the industry, there are many other incentives for a company to reduce its waste. In particular, waste products released from antibiotic manufacturing is a driver for antibiotic resistance. Currently, a lot of efforts in this industry are focused on treating the waste itself to remove the antimicrobial contaminants. However, making process improvements are becoming more popular. For example, using greener fermentative and enzymatic process for antibiotic intermediates, in turn minimizes the release of anti-

microbial active ingredients into the environment and reduces PMI in the process. In moving towards a more sustainable industry, we need to embrace new science and technology. Yet improving existing processes and updating equipment aren’t the only ways we can progress. It is vital for training and education to be available, not only for current staff, but also the next generation of employees; students. Everyone should be engaged in this greener manufacturing movement. Additionally, the link between the industry and academia must be strengthened. Too often we see an exciting new biocatalyst be developed only to find to that it will only work in a solvent completely unusable in manufacturing. We need to come up with more efficient ways to translate new discoveries to a point where they can be quickly adopted by the industry, to make sure scaling up is on the agenda from the beginning. The key to accelerating green chemistry in pharmaceutical manufacturing is collaboration. While collaboration with biotechs and academia are more common, surprisingly collaboration between industry competitors is increasing to find greener manufacturing strategies. Though this can be difficult due to pharma’s propriety culture. However, joining forces on sustainability initiatives can consequently open the door for effective collaboration on large scale R&D projects and development of new licensing pathways. But most importantly from top to bottom of industry to implement green culture, just like when implementing QBD, standards must be present throughout the business. REFERENCES 1.

http://www.pharmtech.com/goinggreen-biocatalysis

Joshua Zhang Joshua Zhang is the Head of Jinshan site at STA Pharmaceutical, a WuXi AppTec company.

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Manufacturing

100 years of Kahle Automation

Let us start will a brief history of Kahle Automation. What is your organizations role in the industry? What are your core offerings? Celebrating our 100th Anniversary, Kahle is a worldwide supplier of high-speed automation and process equipment for the Medical Device, Pharmaceutical and Healthcare Industries. Kahle designs and builds machines for the assembly and inspection of all types of medical devices, drug delivery and diagnostic products. Kahle’s services include custom equipment design, system integration, parts feeding, material and package handling, and equipment validation, along with the documentation to meet the unique requirements of all types of manufacturing applications. Kahle is a true turnkey solution provider that has been meeting the demands of the marketplace since 1920. Kahle dedicates 182,500 engineering hours per year designing automation and has the most comprehensive portfolio of technology in the industry.

What are your future plans? What will be your core offering for the rest of 2019, and on to 2020? Kahle looks forward to continuing our tradition of “Innovation through Technology” and providing our customers technical solutions to meet are there complex manufacturing needs. What is your opinion on the current political system? How do you foresee growth patterns in the Pharmaceutical Industry? It is such an exciting time to be working with the Pharmaceutical Industry and Drug Delivery products. Technology is changing so fast, there are some many new things being developed to aid the medical community to care for their patients and for patients to care for themselves. 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

years. Working with our customers to partner with them to manufacture both their new drug delivery products and there traditional products, with the cost efficient, high capacity, validated automation equipment that meet the challenges of today’s complex manufacturing and quality requirements.

Kahle is excited with the opportunities and the challenges that the future brings to partner with the industry and provide them with robust, innovative, high speed manufacturing solutions to meet their current and future requirements. Can you tell me about the new challenges and opportunities presented in pharmaceutical production? We are finding at Kahle that as products are getting smaller and tolerances are getting tighter, this puts pressure not only on the automation suppliers but also on the component suppliers to produce high volume components at much tighter tolerances than before. These Micro-Assemblies and associated Micro-Components are crucial to the functionality of today’s complex drug delivery and diagnostic devices. Kahle designs and builds automation equipment for Micro-Assemblies with production outputs ranging from 10ppm to 630ppm. Our expertise includes the feeding and assembly of molded components, tubing, and cannula as small as 6mm long and 32G. Our equipment can integrate micro dispensing, vision and leak testing, punching filters and diagnostic mediums, welding, and cannula bending.

What are your opinions on the implications of Artificial Intelligence in the Pharmaceutical Manufacturing Industry? We find the area of Artificial Intelligence to be very interesting and as a parent of a handicapped child I can appreciate all the doors it opens to help individuals be more independent and function in society, however Kahle to date has not had the opportunity to work on any projects that involved Artificial Intelligence. We welcome the opportunity. Considering this is your 100th Year Anniversary, what special celebrations do you have planned to commemorate this milestone? In preparation for our 100th Year Anniversary we have recently launched a new website, with special attention to our History, documenting the significant milestones and technology developments that are a part of Kahle’s legacy as well as some fun showing of how Kahle advertising has evolved over time. In additional we plan to celebrate with our Customers and Industry partners at the Trade Shows and Conferences throughout 2020. Invitations will be coming!

Where does your organization intend to be in the next 5 years time? Kahle plans to continue to do exactly what we are doing today and what we have been doing for the last 100 Summer 2019 Volume 11 Issue 2


Always thinking. Our solutions don’t come in a box. Why would our ideas? Kahle® is dedicated to providing custom automation machinery solutions for the Medical Device, Pharmaceutical, and Healthcare Industries.

Visit www.KahleAutomation.com or contact Kahle@KahleAutomation.com www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 73


Packaging

How Packaging Suppliers in the Drug Delivery Industry Contribute to a Healthier Tomorrow The challenges to the healthcare industry are constantly changing, causing industry leaders to adapt their offerings to meet varying customer needs and technological advancements. To compete in today’s highly-demanding healthcare market, pharmaceutical and medical manufacturers must not only rely on their own expertise in drug development, but also cooperate with partners in the industry with a deep understanding of the challenges and requirements being faced today – especially when it comes to parenteral packaging.

In the ever-evolving pharma market, companies have to provide the appropriate solutions to meet their clients’ needs. This includes the development and processing of drugs, introducing new treatment methods, and understanding how to best guarantee drug safety. In order to give primary focus to these issues, it is imperative that drug developers rely on the industry’s leading packaging providers to be a strategic partner in developing the safest and most effective parenteral packaging solutions.

packaging must be pure, prevent drug product contamination, and be easy to use over an extended period of time. These reasons alone make it necessary for drug manufacturers to choose a packaging supplier with an expertise on which they can rely. High-quality Packaging Solutions Suppliers must not only offer a strong product portfolio, but must be a solid partner for developing the ideal packaging solution for each and every drug. The cooperation begins during the first steps of product development and lasts through commercial distribution. During these stages, the drug must be filled, stored, delivered, and administered in the best packaging to remain 100 per cent effective and delivered safely.

In order to meet the packaging requirements for various drugs, suppliers must offer a wide portfolio of drug delivery solutions. The preferred methods of drug delivery in the industry are via vial, prefilled syringe, and cartridge applications. Below, each delivery system will be examined and the ideal packaging solutions for each will be explored.

No matter how high-quality the drug, without the appropriate packaging, it will not meet the increasing regulations and standards existing in the market. By combining the knowledge and experience of drug developers with the expertise of packaging partners, companies are able to meet the challenges of the pharmaceutical market now and in the future, and thereby, help to make the world a healthier place. Strong Partnerships for Reliable Drug Packaging Each existing and newly developed drug has its own unique composition, which makes selecting the right packaging particularly important. As packaging solutions are immediately in contact with the drug product itself, it must be assured that the two products will be compatible. The drug 74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 2: Vial stoppers and aluminum-plastic seals ensure drug and packaging stability. Source: Datwyler Sealing Solutions

The High-performance Solution – Vials Vial systems are known as one of the most preferred primary containers used for pharmaceuticals. While using this kind of sterile container, it is especially important to use high-quality sealing materials so that the vial applications can effectively protect the drugs they contain.

Figure 1: Prefilled syringes, vials and cartridges are the preferred methods of drug delivery in the market. Source: Datwyler Sealing Solutions

Elastomeric stoppers are the highest-quality sealing solution for vials. Packaging suppliers use material science and processing technology to develop complex and unique elastomeric compounds and coatings to safely and securely package sensitive drugs without compromising their efficacy. For highly-sensitive drugs, such as biologics, a fluoropolymer Summer 2019 Volume 11 Issue 2


Packaging coating can be applied to the elastomer to eliminate the need for siliconisation, which is a known cause of visible and subvisible particles. In addition to being a silicone-free solution, these coatings provide an additional barrier between the elastomer and the drug product.

seal the prefilled syringes, while also ensuring the system integrity. Similar to cartridge plungers, prefilled syringe plungers must also play a dual role: providing a reliable seal to external contaminants and dispensing the drug product safely and precisely. To dispense smoothly, a fluoropolymer coating can be applied to the plunger to guarantee excellent manufacturability and provide a protective barrier for highly-sensitive drugs.

To ensure absolute integrity of the drug product, an aluminum-plastic seal is crimped onto the vial, providing an additional level of sealing assurance. Developed using the highest-quality alloy and plastic polymers, these seals guarantee the highest level of quality and reliability. Cartridges for Parenteral Drug Delivery Cartridges are used in a variety of pharmaceutical and biotech therapies, such as for dental treatments and insulin management. Cartridge delivery requires two packaging solutions: a plunger to dispense the drug product and a combiseal to contain the drug. Both packaging solutions need to be of the highest quality in order to properly and safely deliver the drug. Plungers are an essential feature of cartridge delivery systems. Used to both seal the container and dispense the drug, the plunger must perform a variety of functions. Made from a specialised butyl-based formulation, plungers provide all of the physical, chemical, and mechanical properties essential for the safe and easy

Figure 3: Plungers and combiseals meet the multiple challenges of cartridge sealing. Source: Datwyler Sealing Solutions www.ipimediaworld.com

Protecting the needle from external forces is also an important aspect when it comes to injectables. Needle shields and tip caps have to guarantee safe and effective processing during production and handling.

Figure 4: Plungers, needle shields, and tip caps are used to seal prefilled syringes. Source: Datwyler Sealing Solutions

administration of the drug product. For highly-sensitive drugs, the components can be coated with the same fluoropolymer technology as used for vial stoppers. The coating prevents any unwanted interactions with the drug, while also allowing for the same smooth delivery that would be achieved using a siliconised plunger. As the plunger seals one end of the cartridge, a combiseal is used to seal the other. In combination with a plunger, these rubber-lined aluminum seals ensure the system integrity of the cartridge. Adding a protective laminate to the high-quality alloy creates a barrier against external forces and reduces the risk of abrasion during manufacturing and handling. The Safest Drug Delivery System – Prefilled Syringes The containers of choice for parenteral delivery systems are prefilled syringes. Prefilled syringe systems have become indispensable in the world of injectables as prefilled applications, in conjunction with an optimal sealing solution, guarantee greater medical safety. There is a broad range of sealing solutions for prefilled syringes. Plungers, needle shields, and tip caps are used to

Supplier Commitment to Quality and Purity for Reliable Drug Packaging The aforementioned advanced packaging solutions demonstrate the effectiveness of a reliable and sustainable partnership between a drug manufacturer and its packaging supplier. Fortunately, more and more suppliers strive to not only offer their customers basic services, but offer a deep understanding of the market for parenteral packaging. By encouraging a working synergy, new and innovative solutions can be developed to help make drug products safe and effective, while, ultimately, improving the lives of patients.

Kelly McCarry After receiving her Masters of Business Administration from Saint Joseph’s University, Kelly began her marketing career as a Promotional Marketing Manager for Coca-Cola. From there, she moved into the healthcare industry, working for medical device manufacturer, Unilife, as a Marketing Associate and then a Program Coordinator. After Unilife, Kelly moved into a Marketing Manager role at SiO2 Medical Products, before finally joining the team at Datwyler Pharma Packaging in 2018 as Marketing Manager for the Americas.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 75


Packaging

How Feasible are Sustainable Packaging Solutions  in the Pharma Sector? Packaging has never been more in the news – but right now it’s making headlines for all the wrong reasons. High-profile media coverage of ocean pollution and concerns over the impact on the planet of single-use materials have put packaging under the microscope as never before – as the most visual contributor to a global problem. 

Every business sector can expect to come under increasing pressure to address the sustainability of all areas of their practices. In the case of those shipping goods, there is and will be increased focus on the packaging solutions they choose, as public opinion reacts to the ecological warnings of the world’s scientific community. First and foremost, it is important to remember the reason for packaging. Packaging is often viewed as unnecessary, a significant and frustrating cost, a view which is further heightened in the current environmentally-conscious climate. However, packaging in many cases is vital. It is protective, informative and provides security to shipments. All of these factors are especially important within the pharmaceutical sector. Packaging will quite literally save lives by ensuring pharma products arrive fit for consumption and maintaining their integrity. But is the pharmaceutical industry, where medical and scientific protocols rightly demand the highest performance specifications of packaging, well placed to react to a shift in emphasis that protects the planet as well as healing the sick? Is this most scientific of sectors ready to react to the warnings of climate science? And is the sector ready to see the benefits sustainable packaging can bring to a business as a whole if used in the right way? In order to address these questions, it’s necessary to take a suitably scientific approach. Sustainability can be an emotive issue, and the ‘green’ scene is riddled with vague definitions, 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

differing opinions and competing ideologies. The pharmaceutical sector have to ensure that any solution used is of course the best solution – but in this current climate, ecological and sustainable considerations need to be included in decision-making, not just relying on what has been the status quo, as the status quo is rapidly shifting.   Sustainability is about protecting the environment  but it’s not just about choosing the most eco-friendly or green product, because that choice may not always be the one that gives the performance required. The pharmaceutical industry will always require certain high levels of performance from its packaging solutions, which will, understandably, take precedence over considerations of factors such as recyclability.   For example, other packaging sectors delivering perishable, fast-moving products such as food, have seen advances in packaging technology such as bioplastics that are unlikely to be accepted in pharmaceutical packaging in the near future. While it’s true that these bioplastics are being developed for use in some medical and dental procedures, they are less likely to be adopted as part of pharmaceutical packaging solutions, where the robustness and sterility of plastic is of paramount importance.

The question of contamination in pharmaceutical packaging also makes it less likely to be recycled than in other sectors, and more likely to be disposed of through a method that is counter-intuitive to ecological policies – incineration. Advice from the World Health Organisation (WHO) states that while uncontaminated waste in pharmaceutical packaging – paper, card, plastic – could be assimilated into domestic recycling processes, anything contaminated must be disposed of differently. In fact, while the WHO says the recycling of uncontaminated paper and card is ‘highly recommended’, it also describes sending these uncontaminated items to landfill or incineration as ‘recommended’. The incineration of uncontaminated plastics and rubber from pharmaceutical packaging is ‘highly recommended’ under WHO advice. This advice may seem extreme, but it reflects the added safety concerns of the pharmaceutical world. However, when international baselines are set so high, it is no surprise that the topic of sustainability is addressed differently within the sector than in others. Even the eminently sensible advice for consumers to keep the paper information leaflets inserted next to their blister packets of pills ‘for future

Woolcool IPI 1: Packaging is the globe’s most visible pollutant, an easily measurable and quantifiable problem. High-profile media reporting of issues such as climate change and ocean pollution, mean companies are becoming more open-minded about ways to mitigate their impact on the environment.  Summer 2019 Volume 11 Issue 2


Packaging increasingly efficient tracking methods to reduce product wastage – and so the challenge of bringing further focus on sustainability into the sector is not beyond them. While the easy option is to dismiss  sustainability, that these solutions cannot deliver the necessary performance or that they are too costly, a more scientific approach allows Woolcool IPI 2: The nature of pharmaceutical ecological considerations to challenge products and the need for sterility throughout the packaging and delivery process has meant questions the status quo – and it’s incumbent of sustainability are not as high on the agenda as on packaging innovators to provide in other sectors.  the quality management, performance reference’ seems counter-intuitive to graphs, assistance with testing and the the societal shift to recycling. Pharma, tailored options needed to validate quite rightly, has its own set of rules. decisions. Every cold chain is different, However, sustainability should each with its own unique challenges, surely be included as a valid factor and even more so with changes in when considering all future packaging legislation, customer habits and even protocols. The shift is already in climate. motion; the question is, is proactivity Long experience shows that more favourable than reactivity? By packaging innovators are ready to adopting this mindset, pharma can collaborate to find new or improved take a measured and timely approach, solutions. That means – before any choosing the solution that ticks all the notions of being ‘environmentally relevant boxes – but is demonstrably friendly’ – packaging manufacturers the least damaging to the environment.  must show that their products work This approach is surely better than and deliver pharma products in waiting for change to be enforced temperature and fit for use.  through legislation or taxes, which is Packaging developers and their always more costly. Taxation has long pharmaceutical clients must accept been proposed as a potential ‘remedy’ that, as a result of scientific climate for packaging waste, as part of the warnings, consumer consciousness ‘polluter pays’ principle.  is now shifting. Along with the To make this shift in mindset usual considerations of cost and possible in the case of packaging, performance, businesses of all kinds pharmaceutical companies should be should listen to the growing calls for able to turn to their packaging partners environmentally-responsible decisionfor support. They are already well making. They will only continue to grow.  versed in meeting the exacting needs Key to this change in mindset is the of a science-based sector. need to debunk myths that surround The packaging creators who serve the notion of sustainability.  the pharma sector understand the The best way to do this is through requirement for compliance, reliability the application of scientific principles. and robust evidence behind the The effectiveness of alternative, solutions they present. Pharmaceutical natural materials should face the same delivery chains need to be reliable but rigorous testing as other man-made simple, offering consistency, evidence- components. It is up to the packaging based performance data and excellent quality management systems. Above all, it is about ensuring shipments arrive within the bounds of the required temperature range. Passive packaging solutions have to be tested and proven to work, and GDP guidelines need to be adhered to. The packaging sector is already adept at collaborating with pharmaceutical clients to identify the best Woolcool IPI 3: The packaging sector has always proven to be quick to collaborate with the pharma solutions for their needs, including industry and should be ready to help customers develop and adopt more sustainable solutions. introducing reusable containers and www.ipimediaworld.com

sector to provide the evidence to show they can be viable – and preferable – alternatives. The perception of the costeffectiveness of eco-friendly solutions has been warped by 20 years of ‘organic’ overpricing. In reality, choosing the right combination of materials not only results in cost-effective packaging, but can make logistical savings elsewhere – for example through the use of fewer ice packs, smaller, lighter boxes or fewer deliveries. As with other ‘green’ sectors, such as energy generation, innovation in the field is continually driving down costs. In packaging, this often means eliminating unnecessary materials and layers while still delivering the performance expected. The development of better insulators, for example, can make packages smaller and cheaper to assemble and ship. Reusability has now become more widely accepted as feasible, again presenting a reduction in longer-term spending whilst also providing a sustainable, circular chain.  Vitally, when trying to apply a sustainable approach to pharmaceuticals, there must be a realisation that some things cannot change, that ultimately the demands of the sector, particularly one involving the health of humans, must precede questions of recycling and materials. The priority must always be to opt for the best option available for a specific product, but this must also include an open-mindedness to sustainability and an elevation of its importance in the decision-making process. That way, the challenge is then passed to packaging companies to deliver new solutions that meet all the criteria needed. However, it is important to note that any new solution being introduced into this market will need to have as minimal impact as possible logistically for the pharmaceutical customer, making them more likely to adopt sustainable practices. The facts have been out there for many years; however, it is only now, as the reality is presenting itself in visible and impactful forms, that we are accepting them. The world’s leading climate scientists recently warned there are only a dozen years left for global warming to be kept to a maximum of 1.5C, beyond which even half a degree will significantly worsen INTERNATIONAL PHARMACEUTICAL INDUSTRY 77


Packaging

Woolcool IPI 4: The distances that pharma products travel can also have an environmental impact in terms of carbon footprint. More sustainable solutions can reduce this by creating smaller, lighter packaging.

the risks of drought, floods, extreme heat and poverty for hundreds of millions of people. The authors of the report by the UN Intergovernmental Panel on Climate Change (IPCC) say urgent and unprecedented changes are needed to reach the target. Science-based, expert warnings such as this, and high-profile media reporting of issues such as ocean pollution, mean more consumers and companies are waking up to green issues, and becoming more open-minded about ways to mitigate their impact on the environment. We must not underestimate the power of the patient in ultimately dictating the direction of an industry, whether the industry is ready or not. Packaging is the globe’s most visible pollutant, an easily-measurable and quantifiable problem. According to European Commission statistics, in 2016, 170 kg of packaging waste was generated per inhabitant in the EU (varying from 55 kg per inhabitant in Croatia and 221 kg per inhabitant in Germany). Where science perhaps once eschewed ‘natural’ materials as less reliable, it is now reconsidering them as a result of climate change research and the public’s demands. In that respect, sustainability in pharmaceutical packaging is really about being willing to look beyond the status quo.  Once we have identified data-backed systems and products that provide solutions that are as good as – if not better than – current environmentallydamaging options, it’s about looking outside of conventions about ‘manmade being better’, ‘it’s what we have always done' and opening our minds to try new things, fast tracking through the change curve.  78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Environmentally responsible or sustainable packaging can also provide the opportunity to use your packaging as an asset, as a marketing tool that champions and celebrates the positive decisions being made in the face of challenges. It’s the ultimate challenge in change management, but one that neither the pharmaceutical industry – nor the packaging sector – can afford to ignore. What does exist is a vacuum for more leaders in this field, and companies that take on this challenge head-first – from multi-nationals to innovative start-ups – can become the pace-setters in a race which we must all eventually join.  Packaging is already responding. As an industry that is well attuned to marketing and public opinion, the packaging sector is already facing the challenges of improving sustainability head-on. The Sustainable Packaging Summit in London this year will see industry leaders share their ideas and concerns. In Frankfurt, I, along with many leaders across different sectors, will be speaking at the Plastic Free World Conference and Expo, about how natural and/or sustainable materials can help replace and complement some packaging components to improve sustainability. The debates regarding how to solve these environmental  conundrums  continue to  go round in circles. Packaging  has been  one of the m a j o r fo c u s e s d u e t o i t s  visibility  and  theoretical  ‘quick fixability', from calling for full immediate  elimination  of plastic to promoting the positives of using such flexible and long lasting material, from the necessity of plastic to reduce food waste, to a complete change in the way we view consumption and how

Woolcool IPI 5: Is the pharmaceutical industry, where medical and scientific protocols rightly demand the highest performance specifications of packaging, well placed to react to a shift in emphasis that protects the planet as well as healing the sick?.

we buy. These split debates are not exclusive to packaging, however. We see arguments for switching every car to electric in the next five years to  arguments against the wider roll-out of electric cars due to the unknown impact on the electrical grid and  end of life of their batteries. Depending on where the focus of any given study is applied, every solution can be positively spun, and in the same breath, every  solution has a flipside negative. However, whether we like it or not, the environmental challenges we face in the next 50 years are a reality. One thread that always runs true though, is the power of collaboration and innovation when it comes to solving such challenges and this is not to be ignored or flippantly dismissed. With regard to the ‘quicker wins’ and opportunities these  present to the sector, the packaging sector is ready to support pharmaceutical customers as they consider the specific challenges of introducing a more sustainable approach to packaging their products. So, is sustainability in the pharmaceutical industry feasible? This is a sector built on innovation and discovery, on shaping the future, so the answer must be a resounding ‘yes’ – but in order to succeed and be the trailblazers that they are in so many areas, collaboration, open minds and the dismissal of any fear of change will be essential.

Josie Morris Josie Morris BA (Hons), MA is Managing Director of The Wool Packaging Company Limited – Woolcool. A passionate advocate for diversity and the development of strong cultures within innovative businesses, Josie is also closely involved with organisations such as the BBIA (Bio-Based Industries Association) which lobby the UK Government on the environmental problems of global packaging waste and support pioneering companies such as Woolcool, that offer genuinely sustainable alternatives to plastic materials.

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