IPI Winter 2020 by Senglobal

Volume 12 Issue 4

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The Challenge of Global Covid-19 Vaccine Distribution Demands a New Approach Designing for Success A Multi-Stakeholder Approach to Clinical Development to Optimize Patient Access Secondary Drying The Finishing Touch in Spray-Dried Dispersion Manufacturing ) Exploring Pharmaceutical Packaging’s Top 2020 Trends Sponsor Company:

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Contents 06 Editor’s Letter REGULATORY & MARKETPLACE 08 Brexit White Paper DIRECTORS: Martin Wright Mark A. Barker INTERNATIONAL MEDIA DIRECTOR: Keith Martinez-Hoareaux keith@pharmapubs.com BUSINESS DEVELOPMENT: Chloe Roberts Brown chloe@pharmapubs.com EDITORIAL: Virginia Toteva virginia@pharmapubs.com DESIGN DIRECTOR: Jana Sukenikova www.fanahshapeless.com FINANCE DEPARTMENT: Martin Wright martin@pharmapubs.com RESEARCH & CIRCULATION: Orla Brennan orla@pharmapubs.com COVER IMAGE: iStockphoto © PUBLISHED BY: Pharma Publications J101 Tower Bridge Business Complex London, SE16 4DG, United Kingdom Tel: +44 (0)20 7237 2036 Fax: +44 (0)01 480 247 5316 Email: info@pharmapubs.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 Spring 2021. 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. 2020 PHARMA PUBLICATIONS / Volume 12 issue 4 – Winter – 2020

The UK formally left the EU on 31st January 2020 and the transition period, as set out in the withdrawal agreement, will come to an end on 31st December 2020. During this transition period, the UK has continued to remain under EU pharmaceutical law. Matthew Cotton at PharmaLex explains how from 1st January 2021, the UK will be able to adopt an independent regulatory framework with the Medicines and Healthcare products Regulatory Agency (MHRA). 14 Truth Matters: Why Science Journalism Has Never Been So Important Although acknowledged as benefiting society, science is unfortunately conducted and consumed by a relatively small number of people who are often thought of as the “intellectual elite”. Lucas Riordan at Shanaviews and Henry J. Riordan at Worldwide Clinical Trials explore why science journalism has never been so important, to counteract pseudo-science beliefs. 16 Putting Translation Central to the MDR Shift When it was announced that the Medical Device Directive (MDD) would be replaced by the Medical Device Regulation (MDR) several years ago, it triggered an enormous task for healthcare providers and manufacturers. Instructions for use (IFUs) remain vital to improving hygiene and healthcare safety and standards around the world. Alan White at The Translation People explores why hundreds of thousands of existing IFUs would need to be updated in the many languages they are already written in and be made available and accessible in additional languages. 18 Clinical Requirements under EU MDR: Understanding the Changes The European Medical Device Regulation 2017/745 (MDR) entered into force on 26th May 2017, bringing together requirements from the Medical Devices Directive (MDD, 93/42/EEC), Active Implantable Medical Devices Directive (AIMDD, 90/385/EEC) and a variety of European guidance documents into a single regulation. Dr. Amie Smirthwaite at Maetrics evaluates the clinical requirements under the EU MDR while outlining the changes that have been made. DRUG DISCOVERY, DEVELOPMENT & DELIVERY 22 Optimising Device Design for New Generation Biologics New waves of biological drugs may vastly improve treatment for many diseases, but not without adapted delivery devices for effective subcutaneous administration. George I’ons at Owen Mumford Pharmaceutical Services establishes why there is a need for innovative drug delivery devices that accommodate higher viscosity and higher volume formulations, typical of new biologics. 24 The Heightened Case for IDMP in the Light of COVID-19 Once manufacturers, regulators and clinicians agree on consistent representation and description of the various attributes of a drug

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 1

Contents – the promise of ISO IDMP (Identification of Medicinal Products) data standards – it will be possible to assign globally-acceptable identifiers to drugs. Lise Stevens at Iperion Life Sciences Consultancy looks into the heightened case for IDMP in light of COVID-19. 26 Critical Challenges and Potential Solutions to Optimise Downstream Bioprocessing Production The term “optimise” is often applied to complex manufacturing, automation, and business processes. It suggests that the most efficient function of all the elements of a process — technologies, sequences, and procedures — need updating with the application of new technologies or approaches. While no method can be perfect, Nandu Deorkar and Claudia Berron at Avantor explain how new techniques and advances in technology can yield significant improvements. 30 The Rabbit and the Horseshoe Crab The LAL method, which is the industry standard for the detection of gram-negative bacterial endotoxin, was preceded by the rabbit pyrogen test by about 30 years. To understand the benefits of current testing, as well as the industry’s shift from the rabbit to Limulus polyphemus or the Atlantic horseshoe crab, it is important to follow the path through which testing has evolved. Lisa Komski at FUJIFILM Wako Chemicals U.S.A. Corporation outlines what steps need to be taken next. CLINICAL & MEDICAL RESEARCH 34 Powerful, Large-scale Analytics brings Single-cell Omics into Clinical Reality Recent advances in sample preparation, biochemistry, and informatics tools for single-cell analysis have enabled the adoption of single-cell omics in both biomedical research and, more recently, in clinical practice. Marilyn Matz and Zachary Pitluk at Paradigm4 show how empowering the development of better therapeutics and diagnostic tools has resulted in vast, ever-growing datasets. 38 The Importance of Anonymised Unstructured Data in Advancing Medical Research and Patient Outcomes Unstructured free text in electronic health records (EHR) can provide an invaluable source of information beyond structured information for medical research. Free text within EHRs may contain diagnoses, investigation results, medication side-effects, symptoms, reasons for switches in therapy and cause of death. Samir Dhalla at Cegedim and Dr. Anoop Shah at Institute of Health Informatics put forward research that shows the importance of anonymised unstructured data. 42 Designing for Success: A Multi-stakeholder Approach to Clinical Development to Optimise Patient Access Developing new drug therapies is complex, taking many years to move from proof of concept to final data read out from the Phase III pivotal trial. After years of substantial investment, the end goal is to bring the therapy to patients in need. Dr. Clive Whitcher and Dr. Stuart Bell at Inceptua Group discuss how a multi-stakeholder approach to clinical development will optimise patient access. 2 INTERNATIONAL PHARMACEUTICAL INDUSTRY

TECHNOLOGY 46 What Is Preventing the Industry from Providing Electronic Product Information? In 2017, the European Commission published a report regarding the possible improvements for product information texts used for human medicinal products. The improvements aim to facilitate safe and effective use of medicinal products. Klaus Menges, Stan van Belkum, Jennie May and Peter Leister at PharmaLex show that as a result of the report, the European Medicines Agency (EMA) and the national heads of medicines agencies (HMAs) have agreed on a project to implement structured electronic ePI. 54 Completing the Puzzle: Technology in Decentralised Clinical Trials COVID-19 has pushed decentralised clinical trials (DCTs) to the forefront of clinical research. From telemedicine and wearable sensors to home health visits and direct-to-patient drug shipments, Kieran Connolly, Rosamund Round and Nick Darwall-Smith at Parexel show why the new capabilities afforded by home-based DCTs have been embraced by patients, sites and sponsors alike. MANUFACTURING 58 Secondary Drying: The Finishing Touch in Spray-Dried Dispersion Manufacturing Approximately 70% of new drug candidates fall into Class II of the Biopharmaceutical Classification System (BCS), indicating poor bioavailability due to low solubility. To increase the bioavailability of this class of compounds, formulators are increasingly turning to amorphous spray-dried dispersions. Kim Shepard at Lonza discusses how secondary drying is the finishing touch in manufacturing. 64 Preserving the Parenterals of Tomorrow Amid the evolution of the pharmaceutical industry, and more recently catalysed by the coronavirus (COVID-19) and its implications on drug demand, delivery and the supply chain, parenteral drugs are experiencing increased demand. Glenn Thorpe at Datwyler explains why parenterals allow for a controlled release — either gradual or instantaneous — that oral medication cannot always provide. 68 Managing the Mass-Production of Tablets with Efficient Processes The growing demand for increased tablet quantities and the goal of reducing time to market is putting pressure on tablet manufacturers. To keep up with this requirement, innovative processes and systems need to be adopted to improve production efficiency. Marianna D’Onghia at I Holland looks at the importance of tool management systems and online training in the quest to produce high quantities of quality tablets. 72 HPMC and the Value of Vegetarian Hard Capsules Oral solid dose (OSD) products continue to be the preferred drug delivery form for active pharmaceutical ingredients (APIs) for drug developers, due to their cost-effectiveness, comparative ease of manufacturing, and availability of patient-friendly dosing options. Winter 2020 Volume 12 Issue 4

NEXT GENERATION IS HERE

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Contents Julien Lamps at Lonza Capsules and Health Ingredients discusses the alternatives that meet consumer demand for vegetarianfriendly medicines. 74 Causes of Punch Tip Wear and How to Avoid Them Punch tip wear is a commonly overlooked aspect of many tooling inspection procedures. Tip wear is typical and can be influenced by many different sources. Bill Turner and Kevin Queensen at Natoli show how this includes poor tablet and tool design, granulation characteristics, improper steel selection for the application, and improper press setup. PACKAGING 78 Exploring Pharmaceutical Packaging’s Top 2020 Trends The introduction of new technologies has paved the way for companies to explore more innovative solutions to this market demand, as well as discovering new ways to improve their operations and drive efficiencies across the supply chain. In this article, Marcelo Cruz at Tjoapack discusses the current market landscape and the key benefits of building strategic partnerships with specialised contract packaging organisations (CPOs). 80 In Highly Regulated Industries your Labelling must Speak for your Product – Compliance is Non-negotiable!

UK lockdown has rekindled memories of the ‘blitz spirit’. News conferences speak about ‘defeating’ the infection as if it is a physical opponent, with some going so far as to label the virus as an ‘invisible enemy’. Josie Morris at Woolcool outlines how the vital work being done to defeat COVID-19 is driving change, by looking at the pharma packaging sector both in terms of method of delivery and sustainability. 94 The Challenge of Global COVID-19 Vaccine Distribution Demands a New Approach Safely and expeditiously supplying COVID-19 vaccines to the majority of the world’s adult population of more than 5 billion will be the most formidable logistics challenge ever tackled in peacetime. Alan Kennedy at Poseidon and Umit Kartoglu at Extensio et Progressio discuss if the world is ready to take on this mammoth challenge. 100 How Modular Passive Pharma Packaging Systems Enable Strategically Refined COVID-19 Vaccine Shipping Regimes What policies and processes should be adopted for the optimal cold chain management of vaccines. This task is more immense, complex and time-critical than ever before. The world is waiting for the safe, reliable and rapid distribution of the approved vaccines designed to combat the COVID-19 pandemic. In our discussion with Sven Rölle of eutecma, we will find out what contribution the company can make towards this logistical tour de force.

Validation of computerised systems is a non-negotiable requirement enforced by regulators such as the FDA in the U.S., EMA in Europe, TGA in Australia, and HS-SC in Canada. Beth Peckover at Kallik pinpoints the three areas businesses need to get right to ensure computerised systems used for labelling meet all GxP requirements set out by industry regulators. LOGISTICS & SUPPLY CHAIN MANAGEMENT 84 Working Together to Beat the Drug Counterfeiters While potential vaccines for COVID-19 are being developed, there is a very real issue that we all need to be aware of. It is predicted that 10% of pharma products worldwide are counterfeit. Alf Goebel at Advanco analyses how pharmaceutical serialisation providers can step up the fight against drug counterfeiting by adopting a more open and agile supply chain. 88 COVID-19 Vaccine: Unique Distribution Challenges Call for a Unique Monitoring Approach The COVID-19 vaccine will leverage new distribution approaches, so monitoring its physical integrity through the supply chain from manufacturing to point of use will also require fresh thinking. With a lot at stake for all parties involved such as regulators, pharmaceutical companies, and the general population, Vidya Subramanian at Roambee explains why the margins for error in delivering a vaccine promptly and with uncompromised efficacy have never been tighter. 90 How the War on COVID-19 is Driving Innovation in Temperature-controlled Packaging – and Beyond Talking about health professionals on the ‘front line’, in the 4 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Winter 2020 Volume 12 Issue 4

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Editor's Letter We are finally at the end of 2020. This year has already gone down in the history books because of the global pandemic of COVID; it is amazing to have seen the scientific community come together and that we have been able to achieve rolling out a vaccine, which has already been given to patients in the UK. I have been thinking recently that have we started to see the real beginning of personalised medicine in the way that the virus infected people; we saw and understood the end point to the virus and we managed to make a vaccine that is 95% effective all within a year. The regulatory process has had to speed up, and what can this mean for the future of our industry? There are obviously challenges which go with this: do we have enough resource to be able to deliver the vaccine to everyone on the planet? It is predicted that vaccinating Britain will come at a cost of £12 billion, with the NHS needing 46,000 new staff. Vidya Subramanian at Roambee talks about the unique distribution challenge for unique monitoring that will leverage new distribution approaches and create fresh thinking. Unfortunately, there are always going to be people who inevitably see an opportunity to create a counterfeit drug, and Alf Goebel at advanco analyses how pharmaceutical serialisation providers can step up the fight against drug counterfeiting by adopting a more open and agile supply-chain. Marcelo Cruz at Tjoapack talks about how the introduction of new technologies that have paved the way for companies to explore

more innovative solutions for packaging and building of strategic partnerships with specialised contract packaging organisations. The delivery solutions of the drugs that we take today can come in all forms, whether that be injections, plasters, nasal sprays or of course tablets. Marianna D’Onghia at I Holland explains that there is an increasing demand for mass production of tablets but that there is a goal of reducing time to market, which is putting pressure on tablet manufacturers. There are also challenges with the new drug candidates, of which approximately 70% fall into Class II, which have poor bioavailability due to low solubility. Kim Shepard at Lonza talks about how formulators are turning to amorphous stray-dried dispersions. Kieran Connolly, Rosamund Round and Nick Darwall-Smith at Parexel talks about how COVID-19 has pushed decentralised clinical trials (DCTs) to the forefront of clinical research from telemedicine and wearable sensors to Welcome to the last issue of IPI for 2020. What a significant and unforgettable year it has been. Within just twelve months since the COVID-19 outbreak, we have observed great changes, challenges, and scientific discoveries. From the first vaccine on the market, and another eight candidates currently in Phase II or Phase III clinical trials, the pharmaceutical industry has surpassed its own expectation. While the pharma industry is still trying to deal with the current situation, the British government announced the appearance of a new mutated variant of the coronavirus that appears to be spreading rapidly.

home health visits and direct-to-patient drug shipments. George I’ons at Owen Mumford Pharmaceutical Services has identified where there is a need for innovative drug delivery devices that accommodate higher viscosity and higher volume formulations, typical of new biologics. There are also some other major questions about how sustainable our industry is and what the beginning of the production chain looks like from bulk product right down to the delivery of the drug to the patient. Are we going to be able to reach our global goals which need to be delivered in the way of cutting our carbon footprint amongst other things? I wish you a very safe and Merry Christmas, as I am extremely excited to see what 2021 will deliver to us all on this amazing planet that we live on. Lucy Robertshaw, CEO LucyJRobertshaw Although scientists do not know much about the new strain, the fact that it appears to increase in prevalence rapidly, even during lockdown is causing serious concern among the wider community. It seems that challenges still lie ahead for the scientists and pharma industry as well as for all of us. Stay with us in 2021 to keep yourself well informed about the latest news through our articles. I wish you and your loved ones a warm and lovely Christmas and a Happy New Year!

Virginia Toteva, Editorial Manager – IPI

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

Georg Mathis Founder and Managing Director, Appletree AG

(Singapore, Shanghai) Steve Heath, Head of EMEA – Medidata Solutions, Inc

Catherine Lund, Vice Chairman, OnQ Consulting

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

Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

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

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

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

Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmacy 6 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Maha Al-Farhan, Chair of the GCC Chapter of the ACRP Stanley Tam, General Manager, Eurofins MEDINET

Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting Stefan Astrom, Founder and CEO of Astrom Research International HB T S Jaishankar, Managing Director, QUEST Life Sciences Winter 2020 Volume 12 Issue 4

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

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Regulatory & Marketplace

Brexit White Paper

Scotland and Wales) and Northern Ireland due to the Northern Ireland Protocol. The proposal for Northern Ireland will need to be agreed but the current position is that Northern Ireland will remain in compliance with EU legislation and comply with EU requirements with respect to medicinal products and medical devices. Separate guidance has been issued for inter-UK activities from 1st January 2021, where applicable. Control of Clinical Trials / Studies The MHRA guidance confirms that from 1st January 2021, clinical trial sponsors will still need to register trials in a currently established, publicly accessible register. For trials in the UK only, this can be the ISRCTN registry but for trials involving UK and EU sites, this will be recorded in the EU Clinical Trials Register. For UK-based clinical trials, the sponsor or legal representative of a clinical trial will be required in the UK or an approved country. The approved country list will include EU/EEA countries. Where a clinical trial has a rest-of-world sponsor and a UKbased legal representative but covers sites in UK and other sites within the EU/EEA, a legal representative located in the EU/ EEA should be assigned via a substantial amendment submission to the relevant competent authorities. For investigational medicinal products (IMPs) used in UK clinical trials, the supply chain may include UK or approved country (EU/EEA) release sites from 1st January 2021. Where the IMP is supplied from a EU/ EEA manufacturer, the sponsor will have 12 months from 1st January 2021 to ensure a UK MIA(IMP) holder puts in place an assurance system to confirm each batch of IMP has been certified by a QP before release to the trial. This will require a substantial amendment to be submitted to the MHRA to register the details of the UK MIA(IMP) holder performing the ‘supply chain oversight’. Clinical trials involving EU/EEA markets will require the addition of EU/EEA IMP release site to be included via a substantial amendment where this is currently performed by a UK IMP release site only.

Marketing Authorisation Holders For medicinal products registered in the EU/EEA, Article 2 of Regulation (EC) No 726/2004 will still apply that confirms the marketing authorisation holder (MAH) must be established in the EU/EEA. Therefore, an MAH currently established in the UK must be transferred to one in the EU/EEA before the end of the transition period. In the UK, marketing authorisations (MAs) that were registered via the EU centralised procedure will be transferred to a GB national licence but will remain applicable in Northern Ireland. Future EU marketing authorisations will continue to include Northern Ireland. A GB presence for MAs must be registered within 24 months after the end of the transition period. The EMA guidance confirms that at the end of the transition period, UK notified bodies will lose their status as EU notified bodies and will no longer be able to perform conformity assessment activity for medical devices. Product owners will need to apply for a new certificate from a recognised EU notified body or arrange for a file transfer from the current UK notified body to an EU notified body that will take over responsibility. In GB, the current EU medical devices legislation will be given effect in UK law from 1st January 2021. This will not include the EU Medical Devices Regulation nor the EU in vitro Diagnostic Medical Devices Legislation as they will not take effect until after the end of the transition period. Northern Ireland will be aligned with the EU. Medical devices in GB can, until June 2023, retain the CE marking and certification by EU/EEA-based notified bodies. However, all medical devices and in vitro diagnostic medical devices (IVDs) placed on the UK market will need to be registered with the MHRA within the proposed grace period post-transition. Companies that qualify for administrative and/or financial support from the EMA as a small or medium-sized enterprise (SME) must be established in the EU/EEA. Winter 2020 Volume 12 Issue 4

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Regulatory & Marketplace Companies that are UK-based will fall under guidance for non-EU countries following 1st January 2021. Oversight of Manufacturing & QP Release To EU/EEA Following the transition period, medicinal products manufactured in GB will be classed as imported products when transported into the EU/EEA. The supervisory authorities of medicinal products imported from third countries are the competent authorities of the Member State or Member States that granted the authorisation to the importer of the concerned medicinal product. The UK will no longer be able to undertake this supervisory role, so sites located in the UK and third countries that have been previously inspected may be re-inspected if the new EU supervisory authority deems it necessary to confirm or re-confirm GMP compliance. Each batch of finished product must be certified by a qualified person via an MIA within the EU/EEA. Where quality control (QC) testing sites are only located in the UK for EU/EAA products, new sites located in the EU/EEA will need to be registered before the end of the transition period. To UK Wholesale dealer’s licences issued by the MHRA will continue to be valid from 1st January 2021 for current holders. Companies currently importing medicines from the EU/ EEA into GB are required to notify the MHRA in writing within six months from 1st January 2020 of their intention to remain importing medical products from an approved country list. The approved country for import list will include EU/EEA countries. The MHRA will accept qualified person (QP) certified medicines from EU/EEA countries if checks are performed by a responsible person (import) (RPi). The RPi will be responsible for implementing a system to confirm that QP certification has been performed on imported medicinal products. Import can also be carried out by an MIA holder through their QP, but he/she must apply to be named on the RPi register and should then follow the RPi requirements. Medicines with a marketing authorisation sourced from Northern Ireland into GB will only require the presence of a responsible person (RP) and not a RPi. 10 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Approved countries for batch testing of human medicines for supply to GB will include EU/EEA countries in addition to non-EEA countries with existing mutual recognition agreements as per paragraph 14(1)(b) of Schedule 7 of the Human Medicines Regulations 2012. EU Labelling Multi-country packs intended for supply to the EU/EEA that include the UK can still be used only if the product information is exactly the same for UK and EU and the Member State has allowed additional information labelled in the ‘blue box’. Local representatives based in the UK that are nominated for an EU Member State in product information must be replaced with a local representative located in the EU/EEA before the end of the transition period. Where product information contains a UK representative for the UK only, this will become obsolete, but the advice is to amend this at the earliest opportunity after the transition period (i.e. next variation, renewal). UK Labelling Multi-country packs will be allowed by the MHRA for UK supply provided that the entirety of the information is compliant with the UK requirements. Amendments to the artworks, patient information leaflet (PIL) and Summary of Product Characteristics (SPC) due to UK MAH updates will need to be submitted to the MHRA. This will be within the 24-month grace period. Supply, Distribution and RP Responsibilities Supply chain mapping to determine Brexit exposure is vital to understanding potential challenges for movement of goods via the UK. Following the transition period, there will be additional considerations for the transport of materials to/from the UK, between GB and Northern Ireland and for goods passing through GB between the EU/EEA and Ireland. Moving goods from GB (England, Scotland and Wales) to Northern Ireland will not be straightforward. The Northern Ireland Protocol will require HM Customs to apply EU customs rules and regulatory standards to all goods entering Northern Ireland, ensuring that tariffs are not paid on trade within the UK and that goods going onward to the Republic of Ireland pay tariffs and meet regulations when required.

Stockpiling has been proposed as a solution to alleviate initial disruption to supply chains as additional border activities come into action from 1st January 2021. In Ireland, the Health Products Regulatory Authority (HPRA) issued a letter to MAHs on 3rd July 2020 to promote the closure of regulatory gaps in the event of a worst-case scenario. They advise that a minimum of eight to ten weeks’ supply of medicines should be available at primary wholesalers in Ireland on 31st December 2020 to ensure supply chain resilience posttransition. In a letter issued to medicines and medical products suppliers on 3rd August 2020, the UK Department of Health and Social Care advised that there will likely be disruption at the border for six months following the transition period. Whilst support has been offered in the form of express freight arrangements via specialist logistic providers, the advice is for companies to stockpile six weeks’ supply on UK soil to be prepared for potential delays in future stock arrival. This will provide a short-term solution and contingency planning for replenishing of stock in the event of longer-term disruption, and it is advised to enable continuity of supply. In order to minimise disruption at the border, customs requirements will need to be understood and implemented for movement of goods between the EU and UK. This will require the development of inhouse expertise or outsourcing to a customs broker. Considerations include: • • •

applicable registrations customs declarations classification codes for the respective materials

Companies looking to move goods into the EU/EEA will need to acquire an Economic Operator Registration and Identification (EORI) number. GMP Considerations Active substances manufactured in GB that are imported into the EU/EEA and Northern Ireland will need to be accompanied by written confirmation from the MHRA that confirms the manufacturing site that exported the active substance is compliant with EU good manufacturing practice and control. Winter 2020 Volume 12 Issue 4

Manufacturing & Recycling of thermal packaging Europe - USA

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Regulatory & Marketplace

Quality agreements may need to be updated depending on how GMP responsibilities are set out within current documentation. FMD The unique identifier and anti-tampering device required for EEA products as per the Falsified Medicines Directive (FMD) can be placed on the product by a UK manufacturing site. It is the responsibility of the importer to ensure compliance with the regulations and will be overseen by the QP (either directly, or via a suitable delegated party) at the EU/EEA batch release site. The EU MAH will be responsible 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

for uploading the data to the respective repository systems. The UK will not implement the Falsified Medicines Directive (FMD) safety features but the MHRA has advised that packs containing these features will be accepted in GB if they are in line with UK packaging requirements. Products entering GB, as a third country, will require decommissioning of the unique identifier at the point of exit from the EU. Therefore, moving goods to Northern Ireland from the EU/EEA via GB without an agreement may not be possible as product

entering Northern Ireland will need to have an active unique identifier as per EU regulations. This will present a challenge to existing supply chains and may need arrangements for supply via the Republic of Ireland or alternative routes. Products manufactured in GB will not have this issue as the unique identifier will only be activated at the point of entering Northern Ireland. Northern Ireland will be regulated by the MHRA but will need to remain compliant with EU/EEA regulations to have unrestricted access to the EU/EEA markets as promised in the Northern Ireland Protocol. Therefore, Winter 2020 Volume 12 Issue 4

Regulatory & Marketplace Northern Ireland manufacturers would need to arrange for future EU competent authority inspections to obtain the required GMP certificates and Northern Ireland importers and distributors would need to retain remote access to another EU27 NMVS to be able to carry out verification checks when moving from non-designated wholesalers and when decommissioning serialised prescription medicines. Medical device manufacturers located outside of the UK that are planning to supply to GB must assign a UK responsible person that is established in the UK. The UK responsible person will be required to place a device on the market, act on behalf of the manufacturer and be a point of contact for MHRA requests. Responsibilities for medical devices in Northern Ireland will depend on where the manufacturer is located: • Manufacturers in Northern Ireland will be responsible for registering medical devices with the MHRA • Manufacturers located in GB will need to designate an authorised representative: • Authorised representatives based in Northern Ireland will need to register all devices classes with the MHRA. • Authorised representatives based in the EU/EEA will register all classes except Class I devices, custom-made devices or general IVDs as these will be required to be registered in the EU. • Manufacturers in the EU/EEA will be required to designate a UK responsible person before placing a device on the market. It is the responsibility of the UK responsible person to register the device. • Manufacturers in third countries will require a UK responsible person, unless they have an authorised representative established in Northern Ireland. Northern Ireland-based manufacturers that have registered devices with the MHRA for Northern Ireland may introduce devices to GB without further registrations. CDR, Pharmacovigilance and Med info For medicinal products in the EU/EEA, the qualified person for pharmacovigilance (QPPV) must reside and carry out tasks within the EU/EEA. Where this is currently performed in the UK, the QPPV will need to relocate to the EU or a new QPPV that resides in the EU should be appointed. www.ipimediaworld.com

The Pharmacovigilance System Master File (PSMF) for EU medicinal products must be based in an EU/EEA country. The supervisory authority for pharmacovigilance is the competent authority where the PSMF is located.

•

The person responsible for CDRs must be located within the EU/EEA.

•

For UK medicinal products, the MHRA will retain responsibility for pharmacovigilance. For products authorised in GB, MAHs will be required to submit pharmacovigilance data to the MHRA via the new MHRA Gateway. Products authorised in Northern Ireland will require data to be submitted in line with EU requirements. Where a product is subject to a UK MA covering GB and Northern Ireland, data will need to be submitted in accordance with the EU and UK requirements, as applicable.

• •

After the transition period, the UK will continue to follow Good Vigilance Practices as set out in the EU guidelines. The QPPV may reside and operate in the EU/EEA or the UK. Where this is the EU/EEA, a national contact person for the UK should be nominated who resides and operates in the UK within 12 months from 1st January 2021. The PSMF for whole of the UK or Northern Ireland must be located at the site in the EU/EEA where the main pharmacovigilance activities are performed or at the site where the QPPV operates. For GB products, the PSMF must be accessible electronically at the same point in the UK from which the reports of suspected adverse reactions referred to in regulation 187 of the Human Medicines Regulations are accessible. Market Insight A survey has been conducted to obtain a snapshot of industry preparedness for Brexit. Areas where there is a positive preparedness trend include: •

• •

Supply chain mapping for Brexit exposure, stock management and future stock replenishment measures. Consideration of EU approval times. Transfer to EU-based MAHs and batch release sites for EU products.

Additional responsibilities for importer of medical devices from the UK to EU/EEA.

There was a split in client feedback for the following topics: UK-based medicine local roles, responsibilities and future product maintenance. Customs activities. QPPV readiness.

There was a negative trend for the following: • • •

Relocation of EU medicine QC testing sites to EU/EEA location. Northern Ireland Protocol impact. Medical devices notified body and authorised representative actions where this is based in the UK currently.

This feedback appears to be somewhat aligned with the availability of current guidance. As further guidance is released by the MHRA and UK Government on UK expectations and movement of goods, companies will be able to take suitable actions. Closing Statement Brexit will provide several challenges to the pharmaceutical industry that will require robust actions and swift resolution in order to remain in compliance once the transition phase ends.

Matthew Cotten Matthew Cotten is a Manager in Regulatory Affairs at PharmaLex specialising in CMC post-approval lifecycle management. His experience includes managing UK, Ireland and EU medicinal product portfolios for EU based clients and provision of global regulatory support for multinational consumer healthcare clients. Matthew joined PharmaLex in 2013 and holds a BSc (Hons) in Biochemical Sciences awarded by the University of Salford, UK. He is a member of The Organisation for Professionals in Regulatory Affairs. Email: matthew.cotten@pharmalex.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 13

Regulatory & Marketplace

Truth Matters: Why Science Journalism Has Never Been So Important Although generally acknowledged as benefiting society as a whole, science is unfortunately conducted and consumed by a relatively small number of people who are often thought of as the “intellectual elite”. Research findings are often not revealed to the general public or if publicised, are often disregarded due to a lack of science literacy or application to people's everyday lives. This lack of scientific literacy has left many lay people feeling left out of the process and wary of not only the scientific findings but how research is conducted. Furthermore, far too often the lay public consumes only the information which confirms their predisposed belief systems, despite having access to broader sources of evidence. This confirmation bias relegates misinformation/ disinformation to the 'eye of the beholder' allowing room for alternative facts. We are in a crucial time period where multiple sets of facts appear possible and where pseudo-science is confused with science, leaving many to hold false beliefs about science as a whole, as well as the ongoing pandemic and other important health issues in particular. Without knowledge of the scientific method and levels of evidence, the public are often not able to act in their own best interest, let alone that of a larger society. Confounding this is an ever-expanding access to an overwhelming amount of valid and reliable but often disparate catalogue of information in addition to explicitly disingenuous misleading information on the web and in the media. For example, the public has been provided with inconsistent messaging about COVID transmission (droplets versus aerosols), the importance of wearing masks, of various treatments such as hydroxychloroquine and convalescent plasma, and getting vaccinated against SARS-CoV-2 by various agencies such as the FDA, CDC and HHS. Without an understanding that the scientific process is iterative and continually evolving all science appears erroneous or suspect. In the past 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the citizenry relied on these same agencies to convey accurate and unbiased sciencebased recommendations but sadly this no longer appears to be the case, and it is up to science journalism to fill this trust and credibility void. Long gone are the days of dull and drone scientific reporting, as the need for true “investigative” science journalism has never been greater given the recent revelations that sound scientific evidence is often suppressed or even distorted for nonscientific “human” reasons. Whether this is to support one's personal agenda or buttress a political stance, this misinformation harms us all. Science journalists must fully identify and address this “human” element in scientific endeavours and especially the role that conflicts of interest play in a fair and balanced manner. Science journalism must also help educate the public on the simple tenets that most researchers implicitly understand and often take for granted but are considered problematic by the public at the same time. Researchers collectively understand the limits of their research and prominently display these in their manuscripts; they recognize the potential lack of generalisability and reproducibility, and importantly that negative findings are often overlooked. They appreciate the give and take of the scientific process and acknowledge that science proceeds slowly and rarely in a linear fashion. Unfortunately these same limitations are often viewed by the public as reasons not to trust science or facts at all. There is no better time than now to promote good scientific journalism, especially as a growing anti-science movement has arisen. This movement has always existed but now seems to have a remarkably robust voice. These organizations are well-organised, well-funded and have a large stage to showcase their views. It is telling that a vigorous anti-vaxxer movement for COVID-19 was already in place well before any vaccine had even been approved. Likewise, science journalists should have also been engaged long before the approval of a vaccine in order to increase vaccine acceptance and increase the chances of people actually getting a vaccine – especially

those who may need these the most, such as minority and underserved populations who often have the least trust in science. Similarly, in order to be successful, science journalism will require a sufficient platform, organisation and adequate funding on par with the anti-science movement, and this all starts with training a cohort of science journalists. Science writing should become part of every postsecondary educational system and be offered as both a major and minor at all public universities; and as part of every medical school curriculum. Ideally, national organisations such as NIH and others should fund undergraduate, graduate and postdoctoral level didactics and experiential / real-world educational opportunities such as internships for budding scientists, physicians and journalists alike, as well as for lay people who just want to gain a better understanding of the scientific process. In terms of budding careers, traditional journalism has alternately suffered and benefited from novel technologies designed to widen circulation such as blogs, podcasts, and social media. Science journalists can take advantage of these technologies in a national platform, but may be better served by taking on a more local role as “community-based science advocates”. In many regions, community engagement through the use of medical advocates or liaisons also known as “patient navigators” has been very successful in both treatment and research efforts in underserved and minority communities. These trusted navigators serve as a means of connecting medical and research professionals with diverse subject groups, and similarly science journalists could serve as scientific advocates/navigators to help the public maneuver through the complexities,

Winter 2020 Volume 12 Issue 4

Regulatory & Marketplace idiosyncrasies and inconsistencies of the scientific process and findings. In brief, science journalism is uniquely poised to identify, address and even assuage some of the unique issues affecting our society today but has to be more than simply paraphrasing existing research or merely translating complex technological developments into lay terms, and certainly has to be more than “infotainment” only addressing the human side of the equation. Science journalists have a fundamental responsibility in being accurate and unbiased but also have a social responsibility to inform, enlighten, and to serve as a bridge between the scientific establishment and the public. Science journalists must become beneficent mediators in order to help create an understandable and comprehensible stream of information for consumers to digest with the goal of humanising findings and both engaging and enticing the public toward action – even if that action is a simple acknowledgement of the truth.

Henry J. Riordan Henry J. Riordan, PhD is Chief Development Officer and co-founder at Worldwide Clinical Trials. Dr Riordan has been involved in the assessment, treatment and investigation of various neuroscience drugs and disorders in both industry and academia for the past 25 years. He has over 125 publications, including co-authoring two books focusing on innovative clinical trials methodology. Email: henry.riordan@worldwide.com

Lucas Riordan Lucas Riordan is the President/Editor in Chief, and past Editor of World News at Shanaviews, an American Scholastic Press Association award-winning newspaper for Spring 2020 at BSHS. He is a rising university student and budding science journalist. Email: lucas.riordan03@gmail.com

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 15

Regulatory & Marketplace

Putting Translation Central to the MDR Shift

When it was announced the Medical Device Directive (MDD) would be replaced by the Medical Device Regulation (MDR) several years ago, it triggered an enormous task for healthcare providers and manufacturers. Instructions for use (IFUs) remain vital to improving hygiene and healthcare safety and standards around the world. With the switch to the MDR predicted to affect more than 500,000 types of medical and in vitro diagnostic devices available on the EU market, the task was set to have a colossal impact on the sector. Hundreds of thousands of existing IFUs would not only need to be updated in the many languages they’re already written in, but they would also have to be made available and accessible in additional languages, as the MDR would widen to include all 27 EU Member States. However, earlier this year, the European Commission postponed the deadline to update IFUs to the new regulations by 12 months, to 26 May 2021, to mitigate against the situation presented by the COVID-19 pandemic. Though this allowed affected companies more time to prepare, time has accelerated, and it is now a mere matter of months before the MDR comes into play once and for all. The regulations are directly enforceable in each Member State, meaning there is little room for discrepancies in their interpretation. As such, those updating their IFUs must take all necessary steps to ensure their information is technically and medically precise. To achieve this, medical translation specialists teamed with the latest translation technology can ensure accuracy and consistency across different language versions, while making sure that future updates can also be made with ease. The Change from MDD to MDR The MDD, which came into law in 1992, was drafted before the surge in technology 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and the internet, both of which have enabled massive changes in the industry. For example, many consumers now use apps to monitor their own health, and there is increasing demand for software applications, such as the ability for doctors to view MRI scans from their smartphones. We also have a higher global population and the average age of death has increased dramatically. These social, economic and technological advances have encouraged officials to create a new set of guidance – governable by law – to improve transparency, safety and security in these areas. The MDR, which will be four times longer than the MDD, will provide more effective, consistent guidance to all 27 EU Member States, enabling them to increase quality control and hygiene across a huge range of devices. It will apply to everything from plasters, scalpels and pacemakers, to blood sugar monitoring systems, pregnancy tests and HIV blood tests. Specifically, the MDR will cover: 1. 2. 3. 4.

Coloured, non-corrective contact lenses or other items that are applied directly to the eye. Products that must be inserted into the human body through surgical means to modify anatomy or fixate body parts. Substances, or items to be used for facial or nasal cosmetic purposes. For example, dermal fillers. Equipment intended to aid in the reduction of adipose tissue. This equipment includes tools used for liposuction or lipolysis. High-intensity electromagnetic radiation-emitting equipment used on human skin, including tattoo or hair removal, skin resurfacing, or other skin treatment. Equipment used to penetrate the skull in order to modify neuronal activity using electrical currents or electromagnetic fields (transcranial magnetic stimulation).

Although the changes are now set to take effect mid-2021 – and even later for in vitro devices – companies should begin to start

action, updating and translating their IFUs, now. Translation Memory Though the MDR will primarily affect the 27 EU Member States – excluding the UK – manufacturers all over the world will have to adapt to the regulation in coming years, whether that’s in the recertification of existing products or ensuring their practices are in line with the guidance within the MDR. Issues of importance include ensuring IFUs for technical guidance, product labelling and clinical data are available and accessible in all necessary languages, meaning many manufacturers and other levels of the supply chain will come to rely on translation services in the near future. However, those working in already highly regulated industries who haven’t used translation before may worry that a translator either won’t understand their terminology, or that suitable translations into other languages aren’t available and therefore won’t make sense to the end user. It is certainly key to ensure that translations are only completed by medical specialists, however technology also has a part to play: certain translation technologies have the facility to incorporate bespoke ‘translation memories’ of a company’s most frequently used terminology and language, built by specialist medical translators to ensure that complex phrases and words are translated accurately and consistently in multiple different languages. Combining the medical knowledge of the translators with this smart technology ensures that the finalised content is fit for market, no matter which country in the world it is being used in, whilst also providing efficiencies in the process. This approach solves major challenges when it comes to approvals, time saving and cost benefits – all of which will be front and centre of mind for manufacturers worried about how much time remains to complete the switch from MDD to MDR. Translation memory software is designed to make the process of translation smarter, more automated and more precise. It stores and remembers words, phrases and even Winter 2020 Volume 12 Issue 4

Regulatory & Marketplace entire sections of text in company-specific, secure databases. When an IFU is updated with new information, if the translation of previous material is in the translation memory (which is specific to the company producing the IFU), it issues a prompt to the translator that there is bespoke information available in their language, which can be reused to speed up the process. It means the translator needs to focus solely on the new content being translated, and that the client doesn’t have to pay for applying the same translation. If parts of the previous IFU have been translated in a similar but not identical way before – such as will be the case for many MDD to MDR transitions – the translation memory will highlight this to the translator too, with the necessary changes marked, making huge efficiencies compared to translating from scratch. In one case of doing so, in a 46,451-word project, we actually only needed to translate 18,993 words, with the remainder being reused via the translation memory. Clients are delivered first-rate terminology and high-quality translations which are consistent across the board, with specialist linguists controlling the process to ensure that the technology is correctly retrieving the appropriate translations. Because, ultimately, technology on its own is not a powerful enough force. A great deal of input from both a translator and account manager is still needed in order to ensure a translation project runs smoothly, and that the desired level of quality required by the MDR is achieved. Terminology Management Though updating IFUs will be the priority as the MDR comes into play, companies must also be active in communicating they have taken the steps to do so. Whether that’s through adding new content to a website, circulating employee communications, or sharing company news on social media, consistent messaging and terminology is needed across all platforms and it will be essential that any language that’s updated as part of the MDR transition is also updated on your other communication channels. For example, it wouldn’t be savvy to translate the name of a product into different languages from around the world, if the whole company and its users or customers know it by its hero-language www.ipimediaworld.com

name. Without careful management and close communication between you and your translation provider, such inconsistencies can easily creep in. It’s essential for translators to work with clients to develop a comprehensive understanding of the terminology a business prefers to use across its product names, corporate language and for terms that might have multiple options within a local language. Consider the relatively simple examples in English of referring to a ‘fracture’ or a ‘break’; these terms describe similar concepts, but it’s vital that the correct terminology is used consistently throughout your documentation. Imagine these decisions across multiple languages and you begin to see the importance of terminology management. Ensuring accuracy and consistency across these terms and their translations maintains the brand’s values, upholds professional reputations and can more easily drive sales, whether you’re translating a website or undertaking technical translations such as those we’ll see during the switch to MDR. ‘Termbases’ are specialist software applications designed to develop glossaries, and which can give more detailed context or definition to the words used within a text. Sometimes based on a client’s own glossary of terms where available, they also highlight forbidden terms, to ensure that they’re never able to sneak into a company’s marketing material or technical documents. Available via the cloud, all relevant parties contributing to a translation project have access to the glossary to ensure that terms are pre-approved by client stakeholders. Because termbases can also be integrated with translation memory systems, the appropriate term for a specific language is suggested automatically to the translator, to eliminate any ambiguity in terminology usage that may arise. When used in partnership with translation memories, the outcome is even fewer words requiring translation, resulting in more significant time savings and cost reductions. On completion of the project, automated QA tests can be run to ensure that the translator has followed the termbase and that the terminology used in the document is as agreed. The result is consistency across all communications, a reduction in possible errors which allow for faster and more

accurate proofreading, and the ability to manage terminology and translation from one centralised location. The introduction of the MDR will lead to a greater level of scrutiny of the technical documentation used within the medical industry and will have a knock-on effect throughout the supply chain. However, by using translation technology in a variety of capacities, manufacturers can ease the burden of the transition while time continues to tick away. By putting faith in a translation services provider which combines specialist medical linguists with technology to create translation memories and glossaries that are completely in tune with the need for stringency, accuracy and compliance, this burden-like era for the medical sector will be eased, enabling businesses to get ahead of the changes, so they can focus on strengthening relationships rather than regulations.

Alan White Alan White has worked in the translation/localisation industry for over 20 years; as a translator, an account manager and in business development. Alan currently heads up the business development team at The Translation People, working with a variety of clients from different industries, advising on best practice when communicating with an international audience. As a fluent French and Spanish speaker, Alan is passionate about languages and their use in breaking down communication barriers, both in a business context and beyond. He is committed to providing companies with customised solutions that meet their requirements and allow translation budgets to be maximised, in particular those that combine the best that translation technology can offer with high-quality linguistic input from specialist translators. INTERNATIONAL PHARMACEUTICAL INDUSTRY 17

Regulatory & Marketplace

Clinical Requirements under EU MDR: Understanding the Changes The European Medical Device Regulation 2017/745 (MDR) entered into force on 26 May 2017, bringing together requirements from the Medical Devices Directive (MDD, 93/42/EEC), Active Implantable Medical Devices Directive (AIMDD, 90/385/EEC) and a variety of European guidance documents into a single Regulation. Although the date of application (the date after which all new devices must be placed on the market under the MDR rather than MDD or AIMDD) has been delayed from 26 May 2020 to 26 May 2021, allowing a transition period of four years, delays to publication of key guidance has left some manufacturers unsure of the action they need to take to achieve compliance. Although some manufacturers may have MDD or AIMDD certificates that are valid to 26 May 2024, certificates which expire between 26 May 2021 and 26 May 2024 cannot be renewed; a new application under MDR will be required. Given an evercontracting runway, businesses which have not already done so must address regulatory compliance urgently. There are many new requirements in the MDR as compared to the MDD or AIMDD, including requirements for clinical evidence, which means that additional action will be required to ensure that legacy devices can stay on the market under MDR. With the aim of providing some clarity to manufacturers, this article outlines the principal clinical requirements impacting pharmaceutical companies involved with medical devices, and offers practical advice for meeting the new clinical requirements. HOW THE EU MDR AFFECTS PHARMACEUTICAL MANUFACTURERS Although it is generally perceived that medical devices and pharmaceuticals are two separate worlds, there are some situations in which pharmaceutical manufacturers may be impacted by the MDR, for example where the pharmaceutical manufacturer: •

also manufactures medical devices, such as devices with ancillary medicinal

18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

•

substances; partners with or supplies to companies that manufacture medical devices (e.g. devices incorporating ancillary medicinal substances or drug delivery devices); manufactures a drug that is sold pre-packaged in a delivery device (Amendment to Directive 2001/83/EC).

Impact on Manufacturers of Medical Devices which Incorporate an Ancillary Medicinal Substance As for MDD, medical devices incorporating an ancillary medicinal substance are Class III under the MDR. Article 61 introduces new requirements for Class III devices, including: •

•

premarket clinical investigations required, including for legacy MDD devices if they do not meet certain criteria, including having “sufficient clinical data” to demonstrate safety, performance and benefit-risk in relation to the state of the art; annual Periodic Safety Update Reports (Article 86), summarising results and conclusions arising from evaluation of post-market surveillance data, including a rationale and description of any corrective and preventive actions; Summary of Safety and Clinical Performance (SSCP, Article 32) which is a publicly available (via EUDAMED) document which describes the clinical evidence upon which product certification is based, including an evaluation of how this compares with other possible therapy options. This also includes information on safety and residual risks, a suggested user profile and suggested training for users.

The requirement for premarket clinical investigations for Class III devices potentially poses the greatest challenge to manufacturers of Class III devices. Although there are certain exemptions for legacy devices, each of these are contingent upon the device already having “sufficient clinical data” to demonstrate safety, performance and clinical benefit. There will be no grandfathering of legacy devices, even if they have been on the market for several

decades. In addition, there are restrictions on the use of equivalence data for Class III and implantable devices, including: •

•

Data from other manufacturers’ equivalent devices cannot be used unless there is a contract in place with the OEM allowing access to all clinical and technical documentation on an ongoing basis, and the other manufacturer is in possession of an MDR certificate for the devices (the latter point is ambiguous in the MDR, but has been clarified by Commission guidance); Data from the manufacturer’s own devices can only be used if they are considered design modifications of existing devices currently certified under the AIMDD, MDD or MDR.

In both cases, there must be “sufficient clinical data” for the claimed equivalents, and there must be a post-market clinical follow-up (PMCF) plan design to confirm these conclusions with data from the subject devices. The MDR also places greater emphasis on concepts of scientific validity and statistical validation; this applies equally to the clinical evaluation as to the design of post-market surveillance activities, including PMCF. Although these requirements were not alien to the MDD and AIMDD, the progressive nature of medical device regulation in Europe (from effectively no regulation prior to the publication of the Directive, to increasing requirements over successive revisions and publication of new guidance) meant that these requirements were less likely to be applied to legacy devices which had been on the market a long time. Under MDR, it is clearer that legacy status in itself does not exempt the manufacturer from requirements for quality and quantity of clinical evidence. Although Commission guidance document MDCG 2020-6 allows that confirmation of conformity may be achieved for some lower risk legacy devices with limited direct clinical evidence, it highlights that these justifications are expected to be exceptional rather than routine. Winter 2020 Volume 12 Issue 4

Regulatory & Marketplace Impact on Manufacturers of Class III Implantable Devices and Certain Active Devices Intended to Administer or Remove Medicinal Substances In addition to the above, there is a new clinical consultation procedure for Class III implantable devices and certain active devices intended to administer or remove medicinal substances (Article 54). With a few exceptions (MDR renewals, minor design modifications to existing MDR certified devices, and cases where a Common Specification has been published which directly addresses clinical requirements and with which the device complies), all such devices will be put through an additional central European consultation procedure. This is in addition to any consultations required for the medicinal part of the device. After the notified body has confirmed the acceptability of the clinical evidence for these devices, they will send the manufacturer’s clinical evaluation report (CER), their assessment of the CER, and the PMCF plan to the Commission. The Commission will then transmit this to a clinical expert group, which may, dependent on the risk and novelty of the device, make recommendations for limited certificate duration, changes to indications, warnings or other elements of information for use, changes to the SSCP, changes to the PMCF plan, etc. The maximum duration of this consultation period is 60 days. Amendment to Directive 2001/83/EC Relating to Medicinal Products for Human Use Where a device includes an integral medicinal substance, and the action of the medicinal substance is principal and not ancillary to that of the device (e.g. implantable devices where the primary mode of action is due to an integral medicinal substance rather than due to the mechanical action of the device), the combination is regulated as a medicine and not as a device. Similarly, medicinal products which are placed on the market in a way that it forms part of a single integral product intended to administer the medicinal product (e.g. pre-loaded injector pens, pre-loaded inhalers), are also regulated as medicines. Article 117 of the MDR includes an amendment to Directive 2001/83/EC with respect to these types of medicinal products: •

in cases where the device part of the product has been certified under

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•

the MDR, the results of the notified body conformity assessment must be included in the marketing authorisation dossier; in cases where there is no MDR certificate for the device part of the product, the authority will require an opinion from a notified body designated under the MDR on conformity of the device part to the relevant general safety and performance requirements of Annex I of the MDR.

CLINICAL REQUIREMENTS UNDER THE EU MEDICAL DEVICE REGULATION Use of Post-market Clinical Follow-up in the Transition from MDD / AIMDD to MDR One of the many drivers for the publication of the MDR was the perception that many devices were relying on chains of equivalence, which when followed to their origins, led to insufficient or non-existent clinical evidence. Although MedDev 12.2/21 (MDD guidance on requirements for PMCF) indicated that the notified body shall “verify that PMCF is conducted when clinical evaluation was based exclusively on clinical data from equivalent devices for initial conformity assessment and that PMCF addresses the residual risks identified for the equivalent devices”, in practice many notified bodies either missed this requirement (and the use of the word “shall” in the guidance indicates that the Commission did indeed consider it a requirement), or put undue emphasis on the word “exclusively”, interpreting it to mean that any amount of data on the subject device, no matter how small or lacking in

scientific validity, meant that no PMCF study would be required. Although notified bodies have been under increasing pressure since the publication of MedDev 2.7/1 rev 42 (MDD guidance on clinical evaluation for medical devices), and subsequently the MDR, to ensure that manufacturers address such gaps, this conversion has not been complete and there are still some Class III and implantable devices on the market which are relying on equivalence routes which will not be accepted under the MDR. Prior to the publication of MDCG 2020-6, the prevailing opinion of the Commission has been that manufacturers should use the transition period between MDD and MDR to gather “sufficient clinical evidence” on their own devices via MDD PMCF studies, emphasising that there will be no grandfathering of legacy devices. However, a lack of direction as to what “sufficient clinical evidence” meant caused confusion. Although MedDev 2.7/1 offered a definition (“Sufficient clinical evidence: an amount and quality of clinical evidence to guarantee the scientific validity of the conclusions.”), there was no agreement with respect to how much evidence was required to guarantee scientific validity. Pragmatic considerations came into play as well: Article 61 implied that any Class III or implantable device would require a clinical investigation if it did not have “sufficient clinical data”, even the sutures, staples, pins, dental braces etc. of Article 61(6b). “Do we really have to do a PMCF clinical study on polypropylene sutures that have been on the market for INTERNATIONAL PHARMACEUTICAL INDUSTRY 19

Regulatory & Marketplace decades, to keep it on the market under MDR?” manufacturers asked. MDCG 2020-6 provides some options: 1.

2. 3. 4.

Undertake PMCF studies within the indications included under your MDD certification to address clinical evidence gaps Narrow the indications for use to those for which there is sufficient clinical data Remove device variants with insufficient clinical data For very low-risk devices meeting the definition of WET (well established technology) of MDCG 2020-6, assemble all clinical and non-clinical evidence to demonstrate unambiguously that the devices are safe and perform as intended, and back this up with an appropriate PMCF study under MDR to confirm these conclusions.

Post-market Clinical Follow-up under MDR A PMCF Plan is required for all devices under MDR. This may not be immediately obvious, as Annex III of the MDR says that the postmarket surveillance plan shall include “a PMCF plan as referred to in Part B of Annex XIV, or a justification as to why a PMCF is not applicable.” This seems to state in black and white that sometimes PMCF is not applicable. There is also wording in the conformity Annexes which indicates that PMCF is not always required. However, Annex XIV Part B provides a new definition of PMCF: “PMCF shall be understood to be a continuous process that updates the clinical evaluation” and MDCG 2020-73 (MDR guidance on PMCF) states: “A PMCF plan shall specify the methods and procedures set up by the manufacturer, to proactively collect and evaluate clinical data from the use in or on humans of a CE marked medical device, placed on the market or put into service within its intended purpose, as referred to in the relevant conformity assessment procedure.” Because the requirements for a PMCF Plan as described in Annex XIV Part B include many data collection activities that have not traditionally been considered PMCF, the current interpretation from Team NB and the Commission is that use of the word PMCF alone in Annex III refers to a PMCF study, whereas the PMCF Plan will include other forms of post-market data collection (such as literature review, user feedback 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

etc.), and may include a justification for “no PMCF study”. MDCG 2020-7 is presented as a template for the PMCF Plan with embedded guidance. A further consideration is that manufacturers must now register PMCF studies with Member States at least 30 days prior to their commencement, if the study would involve additional invasive or burdensome interventions than would be performed under normal conditions of use. It should also be noted that the definition of “normal conditions of use” may differ between Member States, increasing the likelihood that such registration may be necessary where a study is being carried out in more than one Member State. This registration would include all the relevant PMCF study documentation, including approval from the relevant national ethics committee(s). This could lead theoretically to studies being rejected by an ethics committee in cases where a notified body has made certification contingent upon the completion of the study in question. In such cases, the manufacturer should contact their notified body as soon as possible with respect to any changes to their PMCF plans. Additional Measures for Traceability, Transparency and Heightened Surveillance: Implant Cards, SSCPs, PSURs and EUDAMED The MDR includes several new measures to improve traceability, transparency and surveillance. These include the introduction of EUDAMED, implant cards, summary of safety and clinical performance (SSCP) and periodic safety update report (PSUR). EUDAMED is the IT system set up by the European Commission to manage information related to medical devices and in vitro diagnostics. Under the MDR and IVDR (In Vitro Diagnostics Regulation), it will be expanded to include registration of actors (manufacturers, authorised representatives, importers, etc.) and devices, information about notified bodies and certificates issued under the MDR and IVDR, clinical investigation and performance studies, vigilance and post-market surveillance and market surveillance. It will facilitate sharing of information between Member States and will have modules that are open to the public. The first module is due to go live in December 2020. The implant cards were a requirement under MDD for some Member States, but this has been formalised under the MDR. The implant card is a physical document

that will include information about the device, such as details needed for traceability, warnings, precautions and other safety measures, and requirements regarding device lifetime and followup. In addition to providing key safety information (in language understandable to a lay person), traceability information is intended to make it easier for a patient to identify if their device has been the subject of a recall or other corrective action. It can also be used to enable patients to identify themselves in case of special requirements (e.g. bypassing body scanners during security checks at airports). Implant cards are required for all implantable devices except those listed in Article 18(3): sutures, staples, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips and connectors. The summary of safety and clinical performance (SSCP)4 is a new requirement for Class III and implantable devices (excluding custom-made and investigational devices). The SSCP provide a description of the device (including any previous variants, accessories and other devices used in combination), its intended purpose including indications, contraindications and target populations, a description of possible diagnostic or therapeutic alternatives, and a summary of the clinical evidence demonstrating the clinical safety and performance of the device. It will also include a suggested profile and training for users and information on residual risks and undesirable side-effects. Two versions of the SSCP may be required. A clinician version is required for all Class III and implantable devices. The intent is to increase transparency to the clinician regarding the clinical evidence used to demonstrate the safety and performance of the device, and any planned or ongoing PMCF studies. For all implantable devices requiring implant cards, and for Class III devices used directly by the patient, a patient-specific SSCP will also be required. This is a simplified version of the SSCP, provided in language understandable to a lay person. The intent is to empower the patient to make more informed decisions regarding the treatment options available to them. MDCG 2019-95 Summary of safety and clinical performance: A Guide for Manufacturers and Notified Bodies, provides guidance on drafting SSCPs which expands significantly on the basic elements listed in Article 32. SSCPs will be publicly available via EUDAMED. The manufacturer label or Winter 2020 Volume 12 Issue 4

Regulatory & Marketplace instructions for use must also identify the location of the SSCP on EUDAMED. Periodic safety update reports (PSUR6) are another new requirement under MDR, applicable to Class IIa, IIb and III devices. The PSUR is a regular update of the results and conclusions of the analysis of the post-market surveillance data, including any PMCF studies. Although the original idea was based on the PSURs used for pharmacovigilance, the MDR PSUR goes beyond vigilance, into analysis of PMCF outputs, literature data, and other sources of clinical safety and performance data, to reconfirm the benefit-risk conclusion of the device. It also provides information regarding sales volumes, usage demographics and usage frequency, and reports on any preventive or corrective actions associated with the devices. PSURs are required at least annually for Class III and IIb devices, and at least every two years for Class IIa devices. An updated guidance document on PSURs is not yet available at the time of writing. Achieving Compliance in Time To start with, manufacturers must assess the clinical evidence available for the device, and determine if this is sufficient to demonstrate safety, performance and benefit-risk in light of the new MDR requirements and associated guidance. This assessment may lead to wider commercial decisions about device portfolios, as manufacturers may see opportunities for product rationalisation. Where certification under the MDR is desired, it is essential not only to have sufficient clinical evidence (for all device variants, combination, indications, patient populations, etc.), but also to present it in a clear and unambiguous manner. Lack of clarity regarding clinical evidence will lead to delays and requests for further evidence from the notified body, which can be significantly more costly in terms of potential delays to market access than the cost of preparing complete and compliant documentation. As noted earlier, manufacturers may be uncertain on what is meant by ‘sufficient’ evidence. For further clarity, it will be invaluable to seek support from experienced regulatory partners who have built up a strong understanding of the requirements. With limited time remaining until the EU MDR date of application in May 2021 and the last MDD / AIMDD certificates expiring in May 2024, industry experts can help to speed up the compliance www.ipimediaworld.com

process by formulating a strategy, identifying gaps in data or documentation, providing specialist medical writing skills, and maintaining the entire life-cycle of clinical data now required for regulatory compliance. This may be particularly beneficial for biopharmaceutical, biologic and pharmaceutical companies who may not have prior experience with medical device regulation. Reviewing clinical data for medical devices is a matter of commercial urgency so manufacturers must not be complacent about the consequences of non-compliance, and look to finalise their EU MDR submissions as soon as possible. REFERENCES 1. 2. 3.

4. 5.

MedDev 2.12/2 rev 2 Post Market Clinical Follow-Up Studies: A Guide for Manufacturers and Notified Bodies MedDev 2.7/1 rev 4 Clinical Evaluation: A Guide for Manufacturers and Notified Bodies under Directives 93/42/EEC and 90/385/EEC Medical Device Coordination Group Document, MDCG 2020-7 Post-market clinical follow-up (PMCF) Plan Template: A guide for manufacturers and notified bodies, April 2020 https://ec.europa.eu/health/sites/health/ files/md_sector/docs/md_mdcg_2020_7_ guidance_pmcf_plan_template_en.pdf See Article 32 of the EU Medical Device Regulation Medical Device Coordination Group Document, Summary of safety and clinical performance: A

guide for manufacturers and notified bodies, August 2019 https://ec.europa.eu/docsroom/ documents/37323 See Article 86 of the EU MDR

Dr. Amie Smirthwaite A clinical and regulatory affairs expert, Dr. Amie Smirthwaite has over 25 years’ postdoctoral experience in medical devices, spanning new product development, quality and regulatory systems, and clinical data evaluation. She is leading Maetrics’ global clinical practice and brings a wealth of knowledge and experience, having worked for medical device companies, academic institutions and notified bodies. Prior to joining Maetrics, Amie was the Global Head of Clinical Compliance at BSI, having been with the organisation for 12 years. Amie developed BSI’s clinical compliance team in response to requirements for Commission Implementing Regulation 2013/920 and EU Medical Device Regulation.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 21

Drug Discovery, Development & Delivery

Optimising Device Design for New-generation Biologics

New waves of biological drugs may vastly improve treatment for many diseases, but not without adapted delivery devices for effective subcutaneous administration. There is a need for innovative drug delivery devices that accommodate higher viscosity and higher-volume formulations, typical of new biologics and biosimilars. The increase in subcutaneous injection as a route of administration for drug delivery is the result of converging trends in the pharmaceutical and healthcare sectors. Since the 1990s, the pharmaceutical industry has made significant advances in biological drug development, with the latest wave of research focusing on oncology treatment. Meanwhile, healthcare systems have worked to enable home administration on a wider scale; this helps to alleviate pressure on hospitals and facilitates treatment for patients, especially those with chronic illnesses which may require frequent medication delivery. Since subcutaneous administration is more suitable for this purpose than intravenous delivery, the subcutaneous route for biotherapeutics is now well-established for many conditions, including diabetes and autoimmune diseases. Furthermore, access to these highly effective – but often costly – drugs is widening as biologics patents continue to expire and allow less expensive biosimilars to be introduced to the market. Critical to the continued success of subcutaneous administration is the design of drug delivery devices. This is starting to become more important with the increasing

22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

focus on reformulating even intravenous drugs for subcutaneous administration where possible. Biologics for subcutaneous delivery present a particular challenge for device development due to their molecular structure, and as new generations of biologics are created, there is a need for greater innovation to maintain safe and effective delivery as well as maintain ease of use for the patient. The Viscous Nature of Biologic Formulations Since biological drugs are made of large, complex protein molecules, the solutions tend to require injection and can have greater viscosity than chemically-based medicines, which can present challenges. When they are administered in increasingly higher volumes, this can create further challenges. For instance, as monoclonal antibodies (MAbs) often have high dose requirements, they are formulated at high concentrations and this causes viscosity to increase exponentially. This high-viscosity, high-volume combination poses a challenge for drug delivery design, particularly as new biologics are now surpassing previous design parameters. Standard prefilled syringes and safety devices have typically been designed for 1ml fill volumes, with a viscosity usually under 10cP. The emergence of higher viscosity drugs, typically biologics, has made drug delivery device modification imperative. From a patient perspective, there is also a clear benefit in enabling less frequent injections; however, this poses additional challenges in requiring larger volumes and potentially higher viscosity formulations.

drug. This increases the required volume of the dose, so companies must also factor in that the recommended maximum volume for a single subcutaneous injection is 2–3ml. Wearable injectors can enable selfadministration of volumes over 2ml, as they allow highly concentrated drugs to be diluted into larger volumes and administered subcutaneously over longer periods. However, uptake of these has been low to date, despite a plethora of products available and in development. Wearables need to be kept in place on the injection site for a period of time to allow time for drug delivery and where worn for extended periods, may be visible or impact areas of daily life such as showering or swimming. As a result, many patients may prefer single periodic injections, even if they are required more frequently. There is certainly scope for the development of safe, easy-to-use wearable injectors, particularly in diabetes management, but only 40% of respondents in the survey mentioned above reported their companies were ‘actively’ developing on-body injection devices for higher-volume subcutaneous administration. The Impact of Viscosity on Drug Delivery To ensure that viscosity does not negatively impact effective subcutaneous drug delivery, human factors specialists and design engineers must consider a number of factors. Firstly, biologics tend to be stored at low temperatures, which increases viscosity.

Strategies for Reducing Viscosity Methods of reducing viscosity, although potentially advantageous, can create new obstacles. For instance, excipients can lower viscosity but may alter the characteristics of the original formulation. There are varying attitudes to excipient use among pharmaceutical companies. In a recent survey, a third of respondents (35%) said their firms were highly likely to consider using excipients with biologics to improve subcutaneous absorption and dispersion, whereas 11% of respondents said their firms were highly unlikely to do so.1 Another solution is to lower the concentration of the Winter 2020 Volume 12 Issue 4

Drug Discovery, Development & Delivery This, along with increased patient comfort, is one reason why prefilled syringes containing biologics, which are typically refrigerated for storage, need to be removed in time to reach room temperature before use. Secondly, for manual injection, injection force should ideally not exceed 10 N, but this can be difficult to achieve if drug viscosity is too high. A further consideration is injection time, which increases with viscosity. Human factors observations suggest that typically patients have difficulty holding a device in place for over 10–15 seconds during dose delivery, so ideally the full dose must be delivered within this duration. Lastly, while larger gauge needles facilitate delivery of higher viscosity formulations, pain on injection can cause patients to remove the device before the full dose is delivered. 29G or 27G needles are commonly used for subcutaneous injections, or even 25G needles; any smaller gauge and larger needle diameter than this may cause pain during the injection procedure. For more viscous drugs, thin-wall needles have been developed and are commonly used to help improve the flow of the drug in needles of a small diameter. Since the level of pain and the difficulty of injection can have implications on patient compliance, the ergonomics and design of the delivery device are increasingly important for higher viscosity drugs. Adapting Injection Devices for Higher Viscosity and Volume Manufacturers are now developing syringes for fill volumes up to 2.25ml to accommodate high-viscosity drugs, and the delivery devices designed for these new syringes should provide a positive patient experience. Prefilled safety syringe devices allow patients to control injection speed and force, and possibly the level of pain, which is important for biologic drugs for all the reasons outlined above. Ease of use ranks highly in patients’ priorities so new-generation devices should avoid introducing new techniques

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or instructions for use as far as possible, to avoid confusing users. The design must take into consideration patients with impaired strength or dexterity limitations, who may find biologics particularly difficult to inject, and ensure that the device is comfortable to hold and that the plunger is easy to depress. A further critical factor to consider is that with biologics typically requiring dosage volumes of up to 2ml, patients must be able to clearly see the contents of the syringe before administration, to check for drug clarity and that the full dose has been delivered. Ensuring that the plunger cannot be removed from the device is another way of ensuring full-dose administration, as removable plungers can cause leakage. Failure to carry out robust human factors testing across the intended user population may result in a failed regulatory submission, and ultimately delay getting the combination product to market. The primary container for the drug, as well as the delivery device, must therefore be part of the product development process from the very beginning, to ensure that both the final combination product passes usability testing, and that all the components are compatible. Not only is the drug delivery device critical for patient adherence, ensuring that users obtain maximum benefit from a therapy, but its design features and associated benefits may also give manufacturers an additional advantage in a competitive market. The Merits of Intuitive Design in Biologics Delivery Enabling effective subcutaneous administration of new-generation biologics, which can be higher in volume and viscosity, requires careful consideration of patient and manufacturer requirements. Home administration has significant benefits for patient quality-of-life, while reducing increasing pressure on healthcare systems. However, patient adherence may be impacted if drug delivery devices

cannot maintain comfort and ease of use. Manufacturers must strive to maintain intuitive design and injection technique, appropriate for healthcare professionals and patients alike. Simple design is beneficial for all stakeholders; simplicity makes products less intimidating for users, but also facilitates production and assembly for manufacturers. Achieving this simplicity is by no means straightforward – especially considering the characteristics of biologic formulations – but the benefits on offer make this a worthwhile endeavour. REFERENCES 1.

Owen Mumford Pharmaceutical Services, in partnership with Pharma Intelligence, INJECTABLE COMBINATION PRODUCTS: Industry Insights On The Challenges Of Meeting A Growing Global Need, August 2020

George I’ons George is currently Head of Product Strategy and Insights at Owen Mumford, having worked for the former OEM and now Pharmaceutical Services division of the organisation since 2006. His current focus is on deciphering the rapidly changing pharmaceutical and biotech sectors in relation to their needs for combination products. In his previous roles in business development, he worked closely alongside R&D to develop devices for a variety of global pharmaceutical and diagnostic clients. Prior to Owen Mumford, George worked for Abbott in EMEA marketing roles in Germany, focusing on their diabetes business.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 23

Drug Discovery, Development & Delivery

The Heightened Case for IDMP in the Light of COVID-19

Lise Stevens of Iperion Life Sciences Consultancy explores what difference the ISO IDMP data standards, now slowly surfacing in Europe, would have made in the context of the continuing pandemic, in applications ranging from adverse event reporting and electronic prescribing to the control of falsified medicines. Once manufacturers, regulators and clinicians agree on consistent representation and description of the various attributes of a drug – the promise of ISO IDMP (Identification of Medicinal Products) data standards – it will be possible to assign globally-acceptable identifiers to drugs, their constituent parts and manufacturing processes. This, in turn, will make it easier to look up, compare and monitor relative differences in product formulations, biotechnology and other production-related information which could influence patient outcomes. Real-world Impact In the light of the continuing COVID-19 pandemic and the rush to bring beneficial new products to market, the potential for common identifiers is magnified. If IDMP had been widely in use by now, globally-agreed identifiers, such as substance/specified substance ID (SSID) and pharmaceutical product ID (PhPID), would be in use during drug development, and comparison of vaccine and therapeutic product characteristics across investigational new drug (INDs) applications / new drug applications (NDAs) would be much easier to achieve. Capturing and storing product information as globally-understood, multidimensional datasets, made up of consistent identifiers spanning all aspects of a drug’s provenance, make-up and distribution, has much broader scope too. The ability to share and integrate this data could help directly with the reconciliation of the global trade item number (GTIN), and IDMP identifiers such as the PhPID, medicinal product ID (MPID), package ID (PCID) and batch ID (BAID) assigned to new vaccines. This would 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

enhance planning of mass immunisation programmes around the world and help mitigate potential supply chain issues ahead of time. Myriad supply chain challenges could emerge, such as the lack of access to critical manufacturing raw materials due to regional lockdowns, distribution delays or geopolitical tension between countries. The ability to quickly assess the marketing status and availability of equivalent products or similar formulations would help stakeholders better negotiate agreements with alternative suppliers in advance and work out contingency plans. Once novel vaccines and other therapeutics are approved in a region, IDMP-based data exchange would support more effective and efficient reporting and analysis of adverse events (AEs) and/ or medication errors as part of ongoing pharmacovigilance efforts. For example, the ICH E2B (R3) individual case safety report (ICSR) specification was purposely harmonised to use IDMP identifiers and terminology for active ingredients, PhPID, dosage form, route of administration and units of measurement. This information is used to identify and reconcile domestic vs foreign products in ICSRs, and also supports traceability throughout the global supply chain. Such activity will be vital as drug companies and regulators strive to roll out COVID-critical products swiftly yet safely. Having this level of data granularity and traceability will also help to combat the threat of falsified medicines entering supply chains, especially in underserved populations. Improving International Collaboration Once information is being recorded consistently using IDMP data standards across country boundaries, the opportunity to build a rich international drug knowledge base is substantial, with implications for more enriched clinical decision support and improved e-prescribing/pharmacy information systems. The ISO 11615 specification provides a data exchange format and information models that can be leveraged to create more

robust drug knowledge-bases for regulated medicinal products. For example, one of the core classes of ISO 11615 is the clinical particulars class. This captures clinicallyrelevant information about a product, such as indication, target population, side-effects and contraindications. This information can be repurposed to populate drug formularies, medication management and usage guidelines in ePrescription/ eDispense applications. Healthcare providers and patients deserve access to accurate and reliable product information. This is crucial for reducing or eliminating patient harm, especially in cases where the use of equivalent or alternative products is warranted due to unwanted side-effects. Where speed is of the essence, as with critical new COVID-related products, global data insights offer to help fill gaps where clinical trials can’t attain the diversity of general populations. They offer to inform regulators and pharma companies what is working best for patients, especially in vulnerable populations. A trusted feedback loop between clinicians, industry and regulators will be crucial to building public confidence, especially as new therapies are developed, approved and used to combat the pandemic. Accelerating Global Learning The COVID pandemic has illuminated the importance to move beyond regulatory compliance as the driving force for IDMP implementation. The pandemic offers us an opportunity to apply the ‘bedside-tobench’ approach as healthcare workers strive to reduce COVID mortality and glean new insights about the longer-term effects of the disease. In the continuing pandemic, everyone is learning as they go and (ideally) feeding into a common knowledge pool: a learning health system which is expanding all the time, in turn informing healthcare processes and potentially transforming patient outcomes. In an IDMP-enabled world, this continuous learning will be facilitated by structured, high-quality data entered and updated in real time – not painstakingly transcribed and pieced together from a backlog of static documents. Where Winter 2020 Volume 12 Issue 4

Drug Discovery, Development & Delivery previously the link with translational science was seen as a softer benefit of IDMP, now the ability to analyse credible big-data sets to draw important conclusions has never mattered more. The Criticality of a Concerted Effort It is keeping real-world end goals in mind that will drive the next push to make IDMP a reality. But everyone needs to buy into this, and approach next developments with a shared sense of urgency. Until stakeholders globally concede some ground and work together to harmonise requirements, there will continue to be deviations in approach which threaten the speed of global conformance and the delivery of improved patient experiences. The IDMP standards are already undergoing systematic review in ISO, a process that occurs every five years. Similar to the learning health system, standardsdeveloping organisations (SDOs) need

feedback from implementers to understand adoption challenges and stay current with evolving technology. Yet, to date in the case of IDMP, the different global regions have deviated from the intent of the standards and are choosing their own formats and terminology – something which should ideally be discouraged. Failure to resolve the final details, such as establishing the needed governance structure to facilitate terminology harmonisation and data exchange profiles, is having an impact on optimised IT systems being developed and rolled out – delays which are enormously frustrating when there is such urgency around meaningful progress in life sciences linked to the current pandemic. For IDMP to fulfil its wider purpose, stakeholders around the world must view COVID-19 as a driver for more targeted and proactive harmonisation across the geographical regions. It must not take a new, future pandemic or bioterrorist

event to deliver what has been promised for years. We need those benefits now. Success today, while it counts, will depend on a federated approach similar to that which enabled the world wide web. We need a concerted effort led by global regulators, working together, to establish the governance structure and agreements needed to address the legislative barriers that prevent migration to global identifiers, terminology and greater alignment with healthcare. These are uncertain times, but sometimes it takes a crisis to focus attention and resources. A consortium approach to driving real change will be the most effective going forward. There needs to be a greater push and cooperation for an international framework with equal stakeholder representation. Regulators, biopharma, healthcare providers and academic researchers must each have a seat at the table with the common goal to advance real-world solutions, empowered by standardised product data exchange that results in better outcomes for patients. Closer cooperation and a shared sense of purpose will be important influencers during the next wave of IDMP progression, especially over the next two years as the specifications open for systematic review. With so much disruption and uncertainty still ahead, we need to incorporate IDMP data exchange into our global public health response planning as the surest way to harness the standards to meaningful and useful effect.

Lise Stevens Lise Stevens is Associate Director at Iperion Life Sciences Consultancy in Rockville, Maryland in the US. She is a specialist in project management, IDMP and ICSR training and implementation. Iperion, which operates globally, is paving the way to digital healthcare through its proactive support for standardisation and by ensuring the right technology, systems and processes are in place to facilitate process innovation. Email: lise.stevens@iperion.com

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 25

Drug Discovery, Development & Delivery

Critical Challenges and Potential Solutions to Optimise Downstream Bioprocessing Production The term “optimise” is often applied to complex manufacturing, automation and business processes. It suggests that the most efficient function of all the elements of a process — technologies, sequences and procedures — are not fully realised and are in need of updating with the application of new technologies or approaches. While no method can be perfect, every process can benefit from ongoing consideration about how new thinking, new techniques and advances in technology can yield significant improvements. In healthcare today, it is clear that the use of biologics across multiple therapeutic applications will only continue to increase. As the demand for these drugs accelerates, concerns are growing about their cost and availability. Biologics manufacturers are investigating ways to address these concerns — and downstream production in bioprocessing operations is one such area. Key Challenges in Downstream Production Downstream production currently encompasses about 60% of the total cost of producing a biologic drug. If new ways to remove bottlenecks and improve yields in downstream could be developed, there is the potential to achieve more cost-effective production. However, there are several challenges associated with this goal: Increased upstream yields: Significant investments have been made in the technologies and processes used in upstream production order to improve upstream yields. Efforts to improve raw material characterisation and add single-use systems, perfusion systems and more precisely controlled bioreactors are leading to measurable increases in upstream yields. At this point, downstream throughput has not kept pace with upstream improvements, leading to potential bottlenecks in the end-to-end process. One approach is to make a significant capital investment to create larger chroma26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

tography systems to handle the increased production. Downstream throughput could be increased, but this solution would do little to accomplish the goal of cost-effectively aligning the productivity of downstream production with upstream yields. Loss from upstream to downstream: One of the fundamental structural challenges in biologic production is the approximately 30% yields loss as harvest material goes through downstream purification. Any percentage of improvement in downstream recovery can contribute to improving the ultimate process yield for drug product of the target biologic. Complexity of downstream production: Upstream productivity may be improving because it involves a more straightforward process. Once the target molecule and raw materials are loaded into the bioreactor, the process runs to completion with the appropriate testing and quality control. On the other hand, downstream production is a more complex, multistage process. Biological material is moved from harvest, centrifugation and polishing to multiple chromatography steps before reaching final fill and finish. Each step requires a unique set of resins and buffers among other materials, storage and production systems at multiple steps, and analytical and quality control sampling activities in parallel. The more complex the process, the more difficult it can be to find efficiencies and economies of scale, since it can be harder to effectively analyse and pinpoint exactly where the inefficiencies exist. By investigating key aspects of current purification steps and technologies, new technologies and processes could yield cost-effective improvements, such as: •

•

Expanding the use of mixed-mode and multimode chromatography resins, including resins with targeted ligands with increased selectivity, to process targeted molecules more efficiently Exploring ways to make chromatographic buffers more effective

• •

through new kinds of additives Utilising more efficient prepackaged, single-use buffer materials to streamline buffer exchange steps Making wider use of data analysis tools to acquire the necessary insight into complex material interactions in downstream process steps, particularly as they relate to raw material characterisation.

Improving Process Chromatography Technology The ultimate goal of downstream optimisation is to improve recovery and therefore normalise, and potentially reduce, the cost per gram of protein produced. That means producing more drug product and using less time with the same amount of resin and buffer material. Making better, more effective use of the newest generation of mixed-mode and multimode resins can help achieve that increase in productivity without incurring significant additional cost. As biologic drugs become more diverse with more complex molecular structures, they can also yield by-products that are very closely related chemically or biologically to the target molecule with no therapeutic value. Separating undesired glycosylated molecules and aggregates presents major challenges, since they may have limited differential binding to traditional ion exchangers and can coelute. As a result, these more complex molecules, combined with increased upstream yields, call for new approaches to chromatography resins. To address this challenge, chemistry suppliers are focusing their efforts on process chromatography selectivity and efficiency. Traditionally, the way to solve this challenge is to use multiple downstream ion exchanges. While it yields the targeted drug, the cost per gram of this approach can become prohibitive. More advanced methods of achieving effective selectivity are based on new ligand chemistries engineered to achieve very precise, selective interaction with the targeted protein. Selectivity is increased Winter 2020 Volume 12 Issue 4

Drug Discovery, Development & Delivery while the required number of steps is reduced, helping control process complexity and costs. Targeted affinity chromatographic media are based on ligands tailored to interact with specific proteins, offering high selectivity for a target drug molecule. This can be a time-consuming approach if implemented for every new molecule; instead, mixedmode and multimode approaches offer advantages to be considered.

same media can be used for different purification steps, modulated by solution conditions, such as using multiple buffers or multiple elution steps. However, newer mixed-mode resins have ligand chemistry that enables use of multiple, sequential interactions during the normal chromatographic process. Multimode resins offer greater potential for efficiencies and improved yields. Rather than requiring multiple chromatographic

Mixed-mode ligand structure: Mixed-mode media offer more interaction possibilities with the targeted drug molecule.

dilution, which incur separate costs, process time and quality control steps. For example, typical chromatography processes may first use a separate cation exchange step, then an ion exchange step. The yield is about 80% pure after the first step, reaching upwards of 95% after the second step. With a multimode resin, it is possible to reach the 95% purity in one step. Even with using a multimode resin in the column, it is more efficient to process 70 grams in one batch versus running 100 grams through separate cation and ion exchange steps. This approach reduces the buffer consumption, types of filtration systems used, and ancillary costs associated with each chromatographic step. And since each step typically takes up to two hours, costly production time and labour can be cut in half. Another method for optimising process chromatography is using the continuous chromatography method. In continuous multi-column chromatography, the large column is effectively split into a number of much smaller columns that operate in series over a larger number of cycles. While product is loaded onto some columns, other columns in the set are going through the wash, elution and regeneration phases. Combined with resin optimisation and merging two chromatography steps into one, there is the potential for a three-fold improvement over traditional processes. New Approaches to Buffers Improving the ways buffers are formulated and delivered to the end user can also positively impact downstream productivity.

Multimode ligand structure: Multimode resins have the capacity to simultaneously interact with different sites or regions of the protein molecule.

Mixed-mode chromatography media are based on ligands that offer two or more interaction possibilities with the targeted drug molecule. It has proven to be effective and more productive in applications, such as intermediate and polishing steps, for purifying proteins based on differential salt-induced hydrophobicity. The advantage with the mixed-mode approach is that the www.ipimediaworld.com

purification steps, the simultaneous interaction makes it possible to separate very closely related proteins in a single step. This means it is possible to have the primary, secondary and tertiary interactions all happening at the same time. This simultaneous purification makes it possible to eliminate additional intermediate steps, such as buffer exchange, buffer titration or

Traditionally, buffers have been very targeted: One type of buffer targets one type of pH in a column, then a different buffer is used to target a different pH. There is a move to more universal buffers that can be used in multiple process steps; while it’s not possible to reuse the buffer, having to acquire, store and manage fewer buffers can help control costs. There is also a greater focus on the use of additives to improve buffer performance. For example, in hydrophobic interaction chromatography (HIC), bioprocessors are working to fine-tune the selectivity of HIC functional groups. One method being explored is to use a select range of additives in the chromatographic media INTERNATIONAL PHARMACEUTICAL INDUSTRY 27

Drug Discovery, Development & Delivery upstream and downstream production; however, much of the focus is on the process data itself, somewhat in isolation. In many cases, the biologics manufacturing sites are simply using standard certificate of analysis (CofA) data received with the delivery of chromatography resins, buffers and other production materials. There is an opportunity to expand the application of data analytics beyond the process to more precisely and completely characterise the raw materials used in both upstream and downstream production, then integrate the data into overall optimisation efforts. Avantor-biopharma

to improve the retention and selectivity of proteins as they move through the media, modulating their hydrophobic interaction and improving separation efficiency with decreased retention time, thereby improving throughput.

formulate very specific buffer materials with stringent and well-documented materials characterisation, so that the biologics manufacturer can be assured that the buffer’s performance in the chromatographic step is always on target.

The advent of mixed-mode and multimode media and the increased selectivity they offer presents significant potential operational cost savings by eliminating intermediate purification steps that require additional time, materials, equipment and personnel.

Enhancing Use of Data Analytics Tools One area where the biopharmaceutical industry lags other manufacturers is the aggressive use of data and predictive analytics to mine for and uncover ways to improve productivity, process yield and costs. The industry is making significant investments to improve its use of data.

Another innovation in buffer technology is the standardisation of buffer packages, predesigned for specific applications and delivered ready-to-use in single-use packaging. Leading buffer suppliers are now implementing “buffer-on-demand” programmes designed to eliminate bufferrelated costs in terms of labour, time and capital expenses from downstream production. In this new approach, buffers are supplied in single-use packages – either pre-weighed and ready-to-use in solution, or as concentrates that can then be diluted and used in the columns.

Currently, much of the focus is on using process data to optimise a process, then reliably repeat that batch by reaching the perfect balance of process parameters. These efforts are being conducted for both

Raw material variability presents serious issues impacting downstream efficiency, resulting in long investigations and potential delays in making drugs available for patients. Leading chemistry suppliers are implementing more advanced characterisation efforts that provide manufacturers with more comprehensive insights into the variability of materials within the integrated supply chain. These include supplying e-datasets, such as: • • • •

CofA data for all raw material lots manufactured Manufacturing in-process data In-test actuals for conforming specs Stability testing interval data.

This approach could enable a biologics manufacturer to more accurately assess and predict the process performance of any given raw material ahead of its use. This is a more holistic and data-driven way to

This can eliminate capital expenses associated with buffer preparation tanks and equipment, as well as storage space. It also can eliminate multiple-buffer preparation, testing and validation production steps, directly impacting labour costs, time management and documentation activities. Chemistry suppliers providing these buffers on demand can work with the manufacturer to recommend and 28 INTERNATIONAL PHARMACEUTICAL INDUSTRY

“Buffer-on-demand” programmes can eliminate buffer-related costs in terms of labour, time and capital expenses from downstream production. Buffers are supplied in single-use packages — either pre-weighed and ready-to-use in solution, or as concentrates that can be diluted and used in columns. Winter 2020 Volume 12 Issue 4

Drug Discovery, Development & Delivery assess the total impact of other downstream optimisation steps, such as adopting more targeted resins or implementing the use of novel additives in buffers. New Potential for Downstream Optimisation The ultimate goal for downstream optimi-

sation is clear: controlling or even reducing the cost per gram of value biologic drugs. Many of the more expensive elements of current downstream process steps, such as chromatography media, can be utilised more efficiently by investigating how newer, stateof-the-art materials offer ways to condense and streamline process steps.

Each downstream process has requirements unique to each target drug. Working with suppliers of downstream materials who have deep insights into how process chemistries and raw materials perform can be a highly productive way to advance downstream biologic optimisation.

Nandu Deorkar

Claudia Berron

Nandu Deorkar, PhD, MBA, is the Vice President of Research & Development for Avantor. His expertise in materials technology research & development includes chemical/polymer R&D, drug development, formulation, drug delivery technologies, process development and technology transfer. Dr Deorkar earned his PhD in chemistry from the Indian Institute of Technology, Bombay, and his MBA from Fairleigh Dickinson University, New Jersey (USA).

Claudia Berron is Senior Vice President, Clinical Services at Avantor. Berron’s expertise includes B2B strategic marketing ideation, value proposition strategies, market segmentation, and marketing and sales plan through product launch. Berron holds an MBA from the University of North Carolina, Kenan-Flagler Business School, Chapel Hill, and a BA from the Monterrey Institute of Technology.

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Drug Discovery, Development & Delivery

The Rabbit and the Horseshoe Crab

The LAL method, which is today’s industry standard for the detection of gram-negative bacterial endotoxin, was largely preceded by the rabbit pyrogen test by about 30 years. In order to better understand the benefits of current testing, as well as, the industry’s shift from the rabbit to Limulus polyphemus or the Atlantic horseshoe crab, it is important to follow the path through which testing has evolved. When speaking of rabbit pyrogen testing, we would first need to discuss pyrexia. Pyrexia, or fever, is the elevation of the body temperature from the normal. A pyrogen is a substance which induces pyrexia. Endotoxin, also known as lipopolysaccharide (LPS), is our main pyrogen of interest due to its deleterious effects on the human body. The term "endotoxin" was coined in 1892 by Richard Pfeiffer during his studies of Vibrio cholerae, the bacterium responsible for cholera. Pfeiffer observed that the bacteria produced a toxin that was attached to their cell wall. The toxicity of this substance was unchanged by killing the bacteria. Around the same time, Eugenio Centanni successfully isolated endotoxin from bacterial lysates using a complex workup. He observed that all gram-negative bacterial species could produce this toxin. Additionally, Centanni noted the high heat stability of the toxin and suggested that it was likely not proteinaceous, as had been previously assumed. Many researchers later improved upon Centanni's workflow to produce highly pure endotoxin isolates. These efforts culminated in the work of Otto Westphal and Otto Luderitz, who developed the hot phenolwater extraction method. This protocol, which is still used to this day, enabled researchers to isolate protein-free LPS isolates, proving to be a boost to the field of endotoxin research for decades to come. Today, purified LPS is a staple for any immunology laboratory. Scientists continue to unravel the mystery of how this simple 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

molecule can trigger an intense immune cascade and how we can develop better treatments against septicaemia. LPS is made from a lipid (fat), which anchors the structure to the cell wall, and an oligosaccharide (sugar), which extends from the bacterial surface. The lipid moiety, known as lipid A, is the main structure that's recognised by the immune system. Specifically, lipid A is recognised by a complex of two immune system proteins: Toll-like receptor 4 (TLR4) and MD-2. When activated, this complex triggers an innate immune cascade to fight the pathogen.

with a product sample to determine the presence or absence of pyrogens. If a pyrogen is present in the test substance, it will cause an elevation of the animal’s body temperature from normal. Rabbits have a similar temperature response to endotoxins as humans. For this reason, they are ideal for use in pyrogen detection.

The most common variety of lipid A contains six acyl chains. This form is found in many common gram-negative bacteria, including E. coli, and can elicit a strong immune response via the TLR4/MD-4 complex; however, other species of bacteria express forms of lipid A with more or fewer than six acyl groups. These unusual forms of lipid A do not stimulate the TLR4/MD-2 complex as strongly.

The U.S. Pharmacopeia gives a description on the administration of pyrogen testing. A test solution is administered intravenously into the animal’s ear. The rate of administration is not to exceed 10ml/ kg for 10 minutes. All materials, diluents and solutions used should be sterile and pyrogen-free. Healthy, mature rabbits are selected and housed in temperatures of 20 to 30 degrees Celsius. They are also kept free from any disturbance or excitement. This will later be discussed further as there are other situations which may cause increases in body temperature. A rabbit can only be subjected to a test solution once every 48 hours and well outside of two weeks of having a body temperature greater than 0.6 degrees Celsius from its normal. The baseline temperature of the rabbit is measured not more than 30 minutes prior to the testing. It should not exceed 39.8 degrees Celsius. Rabbits used in group testing should have a variance in temperature of only one degree from each other. The rabbits are tested in temperatures similar to their natural environment. Food is withheld during the test. Water may be withheld or be made available to the test animals. Temperature is measured through rectal probes while the rabbit is restrained in its natural resting position. Test solutions are injected into the ear vein after being warmed to between 35 and 39 degrees Celsius. Temperature readings are taken at 30-minute intervals for the next 1–3 hours. Three rabbits will be tested per solution.

The rabbit pyrogen test is basically a test which involves inoculating a rabbit

A negative test is an elevation in the rabbit’s temperature of less than 0.5

Both the lipid and oligosaccharide components of LPS vary considerably between different species of bacteria. These variations can have a dramatic effect on the host's ability to recognise and respond to the infection. The oligosaccharide tends to have the highest degree of variability in terms of both size and structure. In fact, the LPS oligosaccharide is frequently used to classify different strains of bacteria. In contrast, variations of lipid A between bacterial species are more subtle. The general structure of lipid A consists of two units of glucosamine (a form of sugar), each of which is attached to one phosphate group and several acyl (fatty acid) chains.

Winter 2020 Volume 12 Issue 4

Drug Discovery, Development & Delivery

degrees Celsius. The test solution may then be considered pyrogen-free. A temperature elevation of 0.5 degrees or more will warrant a repeat of the testing in five more animal subjects. A negative result is an elevation in temperature of 0.5 degrees or greater in only two out of the eight rabbits or if the total temperature rise in all eight rabbits does not exceed 3.3 degrees Celsius. The endotoxin limit is expressed as K/M, where K is the threshold pyrogen dose for both humans and the rabbit animal subjects. K has a value of 5 EU/kg. M is the maximum human dose to be administered per kilogram in one hour. Intrathecal injections have a K value of 0.2 EU/kg. www.ipimediaworld.com

There are numerous limitations in using rabbit pyrogen testing for determining endotoxin content. Endotoxins and pyrogens are two entirely different entities. Endotoxin is a molecule contained in the cell wall of gram-negative bacteria. It is a known pyrogen. Pyrogens are any substance which causes febrile responses in both humans and rabbits and they encompass several entities and situations beyond endotoxins. Mycobacteria, fungi and viruses which do not contain endotoxins may still cause febrile reactions. We have endogenous pyrogens, substances inherent to our metabolic system which can induce fever. We have interleukins which are known to raise body temperature during activation

of the inflammatory pathway. Our thyroid and oestrogen hormones are known to regulate body temperature and can elevate or decrease it depending on its level and activity. We have exogenous pyrogens that, when introduced inside of our bodies, can cause a febrile response. Blood and blood products when transfused may cause a rise in body temperature. Medications we take in may cause different bodily reactions which may include elevated temperatures. Other conditions may lead to elevations in body temperature as well. Exercise causes an increase in metabolic rates. The increase in blood flow and rapid cellular metabolism causes a transient fever. Emotional stress or INTERNATIONAL PHARMACEUTICAL INDUSTRY 31

Drug Discovery, Development & Delivery excitation may cause a similar response. A tumour or malignancy, with its increased metabolic requirements and release of endogenous pyrogenic substances can also produce fever episodes. Temperature control of the body is regulated by the hypothalamus; therefore, any defects or injuries to the hypothalamus and the central nervous system can alter the regulation of body temperature. As there are so many factors which may cause pyrexia, there are, in turn, also many contributors to variability in rabbit pyrogen testing. Being an in vivo test, various studies have shown that multiple exposures to endotoxins and pyrogens produced tolerance in the test animals. Over time and after numerous tests, the febrile response of the rabbit became diminished. The bacteria Legionella pneumophilia has also been found to induce little pyrexia in rabbits but is readily detectable through the LAL procedure. In fact, a 1000-fold difference was found between the results of the two procedures in detecting Legionella endotoxin. L. pneumophilia is the bacteria responsible for causing the notorious pneumonia outbreak among the attendees of the American Legion convention at the Bellevue-Stratford Hotel in Philadelphia in July 1976. That outbreak involved 182 cases and resulted in the death of 29. The rabbit test was determined to be inadequate for detecting pyrogenic substances in radiotherapy products, chemotherapy drugs, steroids, narcotics and other substances which had inherent probabilities to react with the human immune system and produce pyrogenic reactions even in the absence of bacterial pyrogens. This would lead to numerous false positive results. Rabbit pyrogen testing is also obviously more time-consuming, rigorous and expensive. The biggest drawback of this test procedure, however, is the inability to quantify the endotoxin levels. As the fable goes, the rabbit was fast and started early. In the comparison of rabbit pyrogen testing with the LAL method, the rabbit is compared this time to the horseshoe crab, which, like the turtle, is a slow-going resident of the sea. The horseshoe crab from the Atlantic, commonly known as Limulus polyphemus, has existed for more than 200 million years. It has been classified under the category arthropods since the 19th century, and not under crustaceans as it was first thought. This close relative of arachnids 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

has historically been harvested for its use as a fertiliser or bait, and more recently it is used for the extraction of blood for the Limulus amebocyte lysate (LAL) Test, used for the detection of bacterial endotoxins in pharmaceutical products and other medical applications. Limulus polyphemus plays a vital role in human medicine. It is a model for the study of the innate immune system. As an invertebrate that does not have immunoglobulins, the horseshoe crab has developed a unique mechanism for detecting and responding to the antigens from the microbial surface, such as lipopolysaccharides (LPS), lipoteichoic acids, lipoproteins, peptidoglycans (PGN) and 1,3-β-glucans. This mechanism is the coagulation of the hemolymph. The blood cells of Limulus, called amebocytes, clot in the presence of antigens from the microbial surfaces mentioned above. This reaction involving the clotting of the hemolymph is precisely the biochemical principle of the Limulus amebocyte lysate (LAL) Test. These days it is accepted that the coagulation phenomenon of the Limulus blood is not an isolated reaction, but a cascade of enzymatic activation steps which end with excision of the protein, leaving an insoluble product that combines via an ionic interaction. If enough quantities of this coagulate are found, turbidity appears, followed by the formation of a clot with the consistency of gel. From this the fundamentals appeared which gave rise to the method to detect the presence of these bacterial endotoxins, better known as the Limulus amebocyte lysate test (LAL) or bacterial endotoxin test (BET). The LAL method was officially accepted by the FDA (U.S. Food and Drug Administration) in the 1970s and has remained until now the official basis for endotoxin testing across the globe. In fact, the U.S. Pharmacopoeia (USP) establishes the quantification of pyrogens or lipopolysaccharides for more than 90% of parenteral-use drugs via this method. Though the main use of the LAL test is for the detection of LPS in pharmaceutical products, its use extends to the diagnosis of endotoxemia associated with cirrhosis, cancer, meningitis, ocular diseases, infections of the urinary tract, as well as the analysis of water quality. Today, we continue to find new applications for the LAL test, such as its use in the detection of bacterial contamination in food, including frozen products.

Rabbit pyrogen testing was adapted by the U.S. pharmacopeia in the early 1940s, predating the use of LAL endotoxin testing by 30-40 years. Due to the advantages of the LAL procedure in terms of cost, specificity, less variability, convenience and being quantifiable, the LAL test has now replaced pyrogen testing in detecting the presence of bacterial endotoxin. Horseshoe crabs are a vital species whose ancient longevity has not only intricately tied them to the wellbeing of our ecosystem, but also to the safety of modern health and medicine. Their annual spawning activities along the shoreline provide a necessary source of food for migratory birds. Horseshoe crabs are caught by fishermen who rely upon them as a source of bait. They are also a critical resource used by biomedical companies, who collect their blood to produce a reagent for the LAL assay, an FDA required quality test of intravenous pharmaceuticals for bacterial endotoxin contamination. Thus, in our story, the horseshoe crab has undeniably outraced the rabbit.

Lisa Komski Lisa Komski is the Sales General Manager for the LAL Division of FUJIFILM Wako Chemicals U.S.A. Corporation. With a nearly 30-year career of working in the chemicals and life science industries, she has established herself as a strong business development professional skilled in U.S. Food and Drug Administration (FDA) requirements and cGMP. Lisa holds degrees in biology and medical technology. Email: lisa.komski@fujifilm.com

Winter 2020 Volume 12 Issue 4

LAL REAGENT PRODUCTS For the Detection of Bacterial Endotoxins in the Battle Against COVID-19

FUJIFILM Wako Chemicals U.S.A. Corp. © FUJIFILM Wako Chemicals U.S.A. Corp. - 2020

As laboratories across the globe focus their research efforts on the development of a vaccine for COVID-19, it is crucial that quality control standards are maintained throughout the research and development process. The Limulus Amebocyte Lysate (LAL) assay for endotoxin detection helps www.ipimediaworld.com INTERNATIONAL PHARMACEUTICAL INDUSTRY 33 reduce the risk of contamination during vaccine research and manufacturing.

Clinical and Medical Research

Powerful, Large-scale Analytics Brings Single-cell Omics into Clinical Reality Abstract / Summary Recent advances in sample preparation, biochemistry, and informatics tools for single-cell analysis have enabled the rapid adoption of single-cell omics in both biomedical research and, more recently, in clinical practice. While empowering the development of better therapeutics and diagnostic tools, the ongoing evolution of such methods, including single-cell DNA and RNA sequencing and proteomics, has resulted in vast, ever-growing datasets that require powerful data management and computational capabilities to capture clinical value. Here, we highlight the challenges imposed by current single-cell computational methods in handling vast datasets from disparate sources, and what is needed from an analytics platform for robust and reliable scientific data modelling, storage, and large-scale computation. We present the results of a recent study demonstrating the utility of such a platform, which enables the rapid profiling of key genes involved in COVID-19 infection. Growth of Single-cell Analysis Developments in single-cell analysis have substantially improved our understanding of disease mechanisms in recent years. The single-cell analysis market is projected to reach USD 5.6 billion by 2025 from USD 2.1 billion in 2019, with its growth attributed to technological advancements in single-cell analysis products, increasing government funding for cell-based research, growing biotechnology and biopharmaceutical industries, wide applications of single-cell analysis in cancer research, growing focus on precision medicine, and the increasing incidence and prevalence of chronic and infectious diseases.1 Single-cell analysis has therefore become a major focus for translational and pharmaceutical research, enabling multi-omics analysis at the singlecell level and allowing the identification of minor subpopulations of cells that may play a crucial role in various biological processes. 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

As a highly-sensitive tool, single-cell analysis can clarify specific molecular mechanisms and pathways, and even reveal the nature of cell heterogeneity. With this advancing technology, researchers and clinicians can look for insights into the transition from ‘healthy’ to ‘disease’ states, study potential biomarkers, and assess response to drug targets or available therapeutic regimens. Market Shift The notion of precision medicine – designing healthcare strategies according to a person's genes, lifestyle, and environment – is not a new one. Over the last two decades, significant advances in genomic, proteomic, transcriptomic, and epigenomic sciences, in conjunction with the growing availability of vast patient data repositories, have gradually facilitated a landscape of data-driven clinical decision-making. As well as predicting personal risk factors for particular diseases and how individual responses to various treatments might differ, this precision medicine methodology is slowly extending into the drug discovery paradigm. In 2018, a record number of 25 new molecular entities (NMEs) approved by the U.S. Food and Drug Administration (FDA)’s Center for Drug Evaluation and Research (CDER) were categorised as personalised medicines (42% of all 2018 new drug approvals).2 In addition, governments around the world are recognising the considerable potential of precision medicine to transform patient care. Former US President Barack Obama launched the Precision Medicine Initiative in 2015, which has since evolved into the National Institute for Health (NIH) All of Us Research Program that aims to gather health data from more than a million US volunteer-citizens to enable individualised treatment and healthcare.3 The ‘Cells-patients-data’ Relationship Despite the potential of single-cell omics to bring precision medicine approaches into routine clinical practice, the lack of analytics solutions available to cope with large-scale single-cell datasets poses a significant barrier. Single-cell DNA and RNA sequencing produce vast amounts of

data. Information from tens of thousands of cells per patient is available and while this provides clear opportunities in terms of increasing the statistical power of growing datasets, the technical and interpretative challenges associated with such ‘Big Data’ are currently limiting accessibility to biological insights. To unlock the value of recent advances in single-cell technology, life scientists will need to tackle the variety of omics layers (genomes, epigenomes, transcriptomes, and proteomes), along with reference maps like the Human Cell Atlas (HCA), at unprecedented levels of resolution, specificity, and volume. As the scale of single-cell datasets continues to increase, there is an unmet technological need to develop database platforms that can evaluate key biological hypotheses by querying atlases of single-cell data. However, current single-cell data are generated from a small number of individuals, and statistical significance relies on the number of patients studied, rather than the number total of cells. This is because cells from the same patient are ‘siblings’ and not true biological replicates, so datasets with 100,000s of patients/ treatment conditions will necessitate technology to manage billions of cells. For example, the Immune Cell Survey in the HCA – an initiative aiming to map the numerous cell types and states comprising a human being – currently contains 780,000 cells from only 16 individuals. The HCA itself has fewer than 400 patients, with very few patients donating cells from more than one organ system. This ‘cells-patients-data’ relationship is further compounded by a lack of scalability of single-cell software, as well as temporal factors, as researchers study the evolution of cell (sub) populations and the effects of treatments over time. Overcoming the Data Dilemma As well as moving beyond the small number of patients currently used in the available datasets, the pharmaceutical industry must take several steps in order to overcome the data management and analysis roadblocks in single-cell workflows. Firstly, there is a need for a single unified repository to store an organisation’s entire single-cell data – both raw and normalised – that is Winter 2020 Volume 12 Issue 4

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 35

Clinical and Medical Research organised intuitively and enables secure data transactions from unlimited users, in contrast with the persistent use of files and silos of data. Current tools also limit cross-study analysis, which is crucial for confirming results. As a root cause, data sparsity limits the extraction of maximum value from single-cell omics data. For example, in single-cell RNA sequencing, when a given gene in a given cell has no unique molecular identifiers or reads mapping to it, large numbers of observed zeros occur in the measurement values.4 The proportion of observed zeros, or degree of sparsity, can hinder downstream analysis performance and requires significant bioinformatics expertise to handle storage and computation. Statistical models that inherently model the sparsity, sampling variation, and noise modes of single-cell RNA sequencing data with an appropriate data generative model are needed. Empowering Drug Discovery To accompany the growing focus on precision medicine, the pharmaceutical industry is embracing the challenge of Big Data. The ability of single-cell analysis to assist the creation comprehensive tissue and cell atlases is driving discoveries in pharmaceutical research. For example, singlecell RNA sequencing in respiratory research has led to the detection of a transcriptionally novel cell type – termed a ‘pulmonary ionocyte’ – that expresses large quantities of CFTR (cystic fibrosis transmembrane conductance regulator), the causal gene of cystic fibrosis.6,7 Findings such as this have had and will continue to have important implications for gene-therapy approaches to cystic fibrosis, and change the way drugs are developed to treat such diseases. Despite such discoveries, challenges still exist regarding the mapping of single cells to reference atlases, as they are under constant development. New solutions are emerging that aim to overcome this barrier, to enable biological meaning to be derived from subpopulation identification and facilitate operation at various levels of resolution of interest. An ideal platform would also cover continuous, transient cell states, quantify the uncertainty of a particular mapping of cells of unknown type/state, scale to increasing numbers of cells as well as broader coverage of types and states, and ultimately integrate information generated through multiple types of measurements.4 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Case Study: COVID-19 and the Need for Rapid Data Analysis The recent advances in high-throughput single-cell analysis technology have expedited the HCA Project – an international collaborative effort that aims to define all human cell types in terms of distinctive molecular profiles (e.g., gene expression) and connect this information with classical cellular descriptions (e.g., location and morphology).8 The translational promise of the cell atlas ranges from basic biology of the human organism, to disease mechanism, diagnosis, prognosis, and treatment monitoring, to immunotherapy, drug development, and cell and organ replacement.9 Sophisticated single-cell analysis platforms are allowing researchers to gather crucial insights from databases such as the HCA, which is now emerging as an important contributor to the effort to better understand mechanisms underlying coronavirus disease-19 (COVID-19).10 Evaluating the expression profile of key genes, such as those encoding key viral entry associated proteins, in large single-cell datasets can facilitate testing for diagnostics, therapeutics, and vaccine targets. For example, initial work aimed at understanding SARS-CoV-2 pathology at the single-cell level – some of which used previously generated HCA data – focused on understanding which cell types expressed the gene encoding the SARS-CoV-2 receptor, ACE2. While large single-cell datasets like the HCA and COVID-19 Cell Atlas (CCA) are excellent resources for profiling target genes involved in infectious diseases like COVID-19, collating data from multiple research groups internationally is a significant feat, and the full utility of these atlases is limited due to the lack of a database management strategy. Such a strategy would facilitate cross-comparison of the distribution and

levels of specific gene expression between samples and projects, without a significant bioinformatics and computational effort. Elucidating Relationships The development of scalable platforms is now enabling researchers to make simple queries in reasonable timeframes and, for example, to access and evaluate multiple single-cell sequencing datasets to develop improved therapeutic targets for clinical studies. This is particularly pertinent to the ongoing effort to develop successful COVID-19 treatments and vaccines. Recent research has indicated that in addition to the well characterised respiratory disease resulting from SARSCoV-2 infection, the virus can cause systemic pathology including in the gastrointestinal tract,11 cardiovascular system,12 endocrine system,13 and central nervous system.14 Elucidating the relationship between these observations and tissue/cell distribution of receptors and gene expression profiles is time-critical. One study assessed the capabilities of a new single-cell data analysis platform in querying all cells in the HCA and CCA databases that express either the ACE2 receptor, TMPRSS2 – the entry facilitating enzyme, transmembrane serine protease – or co-express both markers15 (Figure 1). The majority of cells expressing ACE2 had a cell type tag of PC_vent1 (heart tissue); the majority of cells expressing TMPRSS2 had a cell type tag of AT2 (alveolar epithelial type II cells found in the lung parenchyma); and most cells co-expressing both ACE2 and TMPRSS2 were tagged as gallbladder cells. Rapid Gene Profiling The results go some way to explaining the multi-organ involvement in infected patients observed globally during the

Figure 1: Percentage distribution of cells expressing ACE2 and/or TMPRSS2 in different organ systems. Winter 2020 Volume 12 Issue 4

Clinical and Medical Research and sharing datasets from laboratories across the world, and integrating existing repositories such as the HCA and the COVID Cell Atlas, would not be possible without powerful computational tools that are now providing insights into the impact of SARS-CoV-2 on different cell types in the body. This single-cell level analysis gives hope of addressing key questions in the virus’ transmission, epidemiology, and pathogenesis, ultimately informing pharmaceutical research. For more information about how to empower your single-cell-based research, please visit https://www.paradigm4.com/. ongoing COVID-19 pandemic, as multiple cell types in the human body express genes utilised by SARS-CoV-2 for infection. The analysis platform enables quick profiling of key genes involved in the infection and supports additional use cases that require evaluation across a large database of single-cell expression datasets such as vaccine candidates for infectious diseases, biomarkers for oncology patient stratification, and immunology-related disorders. Single-cell in the Future Single-cell omics technologies, such as single-cell RNA and DNA sequencing, have evolved significantly in recent years, resulting in enormous datasets that require powerful, optimised processing and data management and analysis methodologies to extract translational value. Classifying cells into cell types or states is essential for many secondary analyses, for example to study and classify how expression within a cell type varies across different biological conditions, to understand the cellular basis of off-target drug effects, and to find new indications for approved drugs. Cell atlases like the HCA and CCA, as reference systems that systematically capture cell types and states, must be able to embed new data points into a stable reference framework that allows for different levels of resolution. In turn, pharmaceutical R&D requires a nextgeneration analytics platform that enables scientific data modelling, storage, and large-scale computation to allow single-cell analyses to drive future clinical decisionmaking. Such advances are being demonstrated today in the ongoing COVID-19 research effort, which has posed a unique challenge to scientists collaborating at an unprecedented scale. Coordinating, pooling, www.ipimediaworld.com

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Single-cell Analysis Market by Cell Type (Human, Animal, Microbial), Product (Consumables, Instruments), Technique (Flow Cytometry, NGS, PCR, Mass Spectrometry, Microscopy), Application (Research, Medical Application), End User - Global Forecasts to 2025, MarketsandMarkets, 2020. Personalized Medicine at FDA: A Progress & Outlook Report, Personalized Medicine Coalition, 2018. http:// www.personalizedmedicinecoalition.org/ Userfiles/PMC-Corporate/file/PM_at_FDA_A_ Progress_and_Outlook_Report.pdf [Accessed 30/09/20] National Institutes of Health (NIH) All of Us Research Program. https://allofus.nih.gov/ [Accessed 30/09/20] https://www.marketsandmarkets.com/MarketReports/single-cell-analysis-market171955254.html Lähnemann D, Köster J, Szczurek E et al. Eleven grand challenges in single-cell data science. Genome Biol 21, 31 (2020). https://doi. org/10.1186/s13059-020-1926-6 A new approach to R&D at GSK, GlaxoSmithKline, 2018. https://www.gsk.com/media/5041/ rd-update-slides-hal-barron.pdf [Accessed 30/09/20] Alexander MJ, Budinger GRS and Reyfman PA. Breathing fresh air into respiratory research with single-cell RNA sequencing, European Respiratory Review, 2020; 29(156):200060. Plasschaert LW, Žilionis R, Choo-Wing R et al. A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte. Nature, 2018;560: 377–381. Regev A, Teichmann SA, Lander ES et al. The Human Cell Atlas, bioRxiv. doi: https://doi. org/10.1101/121202 The Human Cell Atlas White Paper, The HCA Consortium, 2017. https://www.humancellatlas. org/wp-content/uploads/2019/11/HCA_ WhitePaper_18Oct2017-copyright.pdf [Accessed 30/09/20] Teichmann S and Regev A. The network effect: studying COVID-19 pathology with the Human Cell Atlas. Nat Rev Mol Cell Biol, 2020;21: 415– 416. https://doi.org/10.1038/s41580-020-0267-3 Cheung KS, Hung IFN, Chan PPY et al. Gastrointestinal Manifestations of SARS-CoV-2

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Infection and Virus Load in Fecal Samples From a Hong Kong Cohort: Systematic Review and Meta-analysis, Gastroenterology, 2020;159(1): 81-95 Zhou L, Niu Z, Jiang X et al. Systemic analysis of tissue cells potentially vulnerable to SARSCoV-2 infection by the protein-proofed singlecell RNA profiling of ACE2, TMPRSS2 and Furin proteases, bioRxiv, 2020. doi: https://doi. org/10.1101/2020.04.06.028522 Somasundaram NP, Ranathunga I, Ratnasamy V et al. The Impact of SARS-CoV-2 Virus Infection on the Endocrine System, Journal of the Endocrine Society, 2020;4(8): bvaa082 Najjar S, Najjar A, Chong DJ et al. Central nervous system complications associated with SARS-CoV-2 infection: integrative concepts of pathophysiology and case reports. J Neuroinflammation, 2020;17: 231. Kumar N, Golhar R, Sharma K et al. Rapid Single Cell Evaluation of Human Disease and Disorder Targets Using REVEALTM: SingleCell, bioRxiv 2020.06.24.169730; doi: https://doi. org/10.1101/2020.06.24.169730

Marilyn Matz Marilyn Matz is CEO and co-founder of Paradigm4. She completed an MS degree at the MIT AI lab and was one of three co-founders of Cognex Corporation. Marilyn received the sixth annual Women Entrepreneurs in Science and Technology (WEST) Leadership Award and was a corecipient of the SEMI industry award for outstanding technical contributions to the semiconductor industry; and a 2020 NACD Directorship 100.

Zachary Pitluk Zachary Pitluk is the Vice President of Business Development, Life Sciences and Healthcare at Paradigm4. He has 23 years’ experience in sales and marketing ranging from being a pharmaceutical representative for BMS, to management roles in life science technology companies since 2003. His academic positions include Yale University Department of Molecular Biophysics and Biochemistry: Associate Research Scientist, Postdoctoral Fellow and Graduate Student.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 37

Clinical and Medical Research

The Importance of Anonymised Unstructured Data in Advancing Medical Research and Patient Outcomes Unstructured free text in electronic health records (EHR) can provide an invaluable source of information beyond structured (coded) information for medical research. Free text within EHRs may contain diagnoses, investigation results, medication side-effects, symptoms, social issues, reasons for switches in therapy and cause of death. It may also contain third-party letter entries, for example, secondary or private care and laboratory results. If health records are sufficiently anonymised and the NHS Health Research Authority (HRA) provides approval, the data can be used for research without requiring patient consent. The Health Improvement Network (THIN) is a research database containing GP records which has overarching HRA approval. However, free text in health records may contain information that could potentially identify a person. Therefore use of this information for research generally requires individual patient consent, which is a major barrier for large population-based studies. Data protection regulations such as GDPR and the Common Law Duty of Confidentiality prohibit the use of identifiable patient information for research without consent, unless specific legal exemption is granted. In England and Wales, such an exemption (known as Section 251) can be granted by the HRA Confidentiality Advisory Group, but these exemptions are usually granted for one-off use of identifiers to link patient datasets, rather than ongoing analysis of identifiable free text. Some large NHS trusts have developed inhouse capabilities to analyse the text within their patient records without the data leaving the trust. However, for GP data, records from a large number of practices need to be combined to create a large enough research database for statistical power. To be successful in harnessing this data, we need a system that is secure, and has enough trust built into it, to enable the data to be analysed at scale whilst maintaining patient confidentiality. 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Samir Dhalla, Head of THIN and Dr. Anoop Shah, Clinical Lecturer at UCL Institute of Health Informatics highlight how the ability to re-harness the use of free text is paramount in the medical research arena, providing access to millions of patient records with a higher quality of data and information. Therefore, it was vital to overcome the challenge of handling identifiable free text in a safe, legal and privacy-preserving way that has patient and public support. Benefiting Patient Outcomes with Free Text Data remains critical in informing healthcare pathways and provision, but the way it is recorded can significantly impact its usability. Clinical data stored in electronic health records can be either classified as structured or unstructured. Structured data is highly organised and follows a prescribed data model and value set which is easily searchable, including numerical and categorical values. However, using structured data alone can limit the data that is available to research topics, such as patient experiences or clinical reasoning, because this information is rarely recorded in a structured way. In contrast, unstructured data has no predefined format, offering more flexibility and freedom when recording an entry, which can make it more complex to collect, process and analyse. This type of data is typically found in GP notes, for example, and can often require manual interpretation. The free text may contain information that provides insight into the consultation and decision-making process. GPs may record the final diagnosis in a structured format, but during the consultation process will typically make notes, which are recorded as unstructured data. It’s this narrative that sits between the initial consultation and the ultimate diagnosis that is going to help inform future patient consultations, pathways – and outcomes. Previous research conducted around heart failure, for example, has found that symptoms such as shortness of breath, tiredness and leg swelling may arise months before a formal diagnosis is made.

Research using the free text can help to understand the reason for any delays and help to improve patient pathways to reduce these delays in the future. It may also enable GPs to make better, more informed decisions to investigate patients at risk earlier. Another potential benefit of using free text is to study the side-effects of medication. Medication tested in clinical trials only involves a few thousand patients, compared to tens of thousands of patients in practice. There may be rare side-effects that are only found out when a larger number of patients or a more diverse group of patients is exposed to specific medication. Some of these symptoms or adverse effects of medication might not be coded, but will be recorded in the free text. The Technology Behind the Solution With the future of healthcare acknowledged as being data-driven, technology continues to reshape the way data is collected, coded and used. Natural language processing tools can be used to automatically anonymise, classify or extract coded information from unstructured free text. Automated anonymisation software based on rules or a machine learning approach can redact identifying information in the text. Although such automated methods can never be 100% effective, they form a key part in the data minimisation process so that when personal data is analysed, the amount of sensitive and uniquely identifiable information being processed at each stage is minimised. Machine learning algorithms can ‘learn’ features from the text and apply them to classification tasks. A possible application might be to classify the purpose of the consultation, such as whether it was an emergency or a routine patient appointment. The algorithm learns from manually annotated samples (‘supervised learning’), and applies the learned model to classify new texts. Information extraction algorithms can be used to extract a range of different items of information from the text. This Winter 2020 Volume 12 Issue 4

Clinical and Medical Research To understand what information is in the text of clinical notes and letters, we can create a secure research database. Computers analyse the text (natural language processing, NLP). NLP can remove names and other identiﬁers, and extract clinical information. Samples of text are checked by researchers. "Mr Bloggs was admitted with heart failure on 19/06/12." NLP (de-identiﬁcation) "XXXXXXX was admitted with heart failure on 19/06/12." Researcher can be done using rules-based algorithms, which break down the text into individual words, detect parts of speech and context, and map words and phrases to standard terminology. Such algorithms can then be used to extract a list of diagnoses or symptoms from the text, along with their context, such as negation. Machine learning algorithms have also been developed for this type of task, and have the advantage that they can learn from additional data that is labelled by manual annotation. The benefits of using an automated approach include saving time and learning on the job from the outcomes – ultimately learning from any mistakes to achieve the correct results. As discussed, there are many technologies available to extract information from unstructured data. However, there is also the opportunity to use these same technologies to create structured information in real time. A new project in University College London hospitals will use natural language processing (NLP) within electronic health records to create structured data as soon as the free text note is created. The clinician will automatically receive suggestions for structured data, which can be inserted and validated at the point of care. The aim is to create structured data more efficiently from the outset, which will have widespread benefits. www.ipimediaworld.com

NLP (information extraction) 19/06/12 - Heart failure Key Challenges There remain some fundamental barriers to the wider accessibility of anonymised unstructured data that, if we are to truly advance patient outcomes on both a population health and personalised level, need to be overcome. These include preand misconceptions at both a patient and healthcare professional level. Arguably, singularly the largest challenge to overcome is an understanding of the importance of this data and how it will be used. A second major consideration is the security, privacy and ethical application of this data. For research to be patient-centred, healthcare practitioners and patients have to understand what their records are being used for, why this is happening and what the benefits of this are. Patients and the public are only likely to consent to their records being accessed, if healthcare practitioners advocate this. This primary challenge can be overcome by healthcare practitioners educating patients on the application of unstructured data in painting a much wider, long-term picture of healthcare and patient outcomes. With different levels of health literacy, understanding and involvement, there also has to be access to a range of educational activities

to meet the needs and levels of different individuals. With regard to concerns around security, privacy and ethics, it is also critical that we collectively address patients’ suspicions around how their health data is being used, especially with the influx of negative news about the UK government selling patient data to US corporations, and fake news being spread around COVID-19 with the track and trace app, amongst others. Corporate and organisational reputations are critical. The Health Improvement Network (THIN) is a large database of anonymised electronic medical records collected at primary care practices throughout the UK and mainland Europe. As part of its organisational structure, THIN has an advisory committee with patient representatives which takes into account patient views, ultimately supporting the THIN application for use of unstructured data, and initiating projects with patient input throughout. Fundamentally, there remains a lack of awareness around the process of clinical research, how patient data is used and the positive impact this has on patient outcomes. There must be an emphasis on educating patients about how their data can be used to benefit the healthcare system as a whole, as well as individual patients. INTERNATIONAL PHARMACEUTICAL INDUSTRY 39

Clinical and Medical Research

Using Anonymised Free Text in Healthcare The use of anonymised free text in the healthcare and life science industries has the potential to make a vast impact, improving pathways, outcomes and access to medicines, and reducing the cost of healthcare. For example, King’s College Hospital’s database of unstructured data enables searches to identify patients on a particular drug or with a particular diagnosis. This information can be used for managing cohorts of patients or monitoring the quality of care. Mental health is another area that may particularly benefit, because much of the information in mental health records is unstructured. The South London and Maudsley NHS Trust has a secure environment which enables researchers to use unstructured text in their health record database, which has been particularly beneficial for mental health research. Specifically in the pharmaceutical industry, free text may present an opportunity to bring faster and more effective treatment to market. With the use of unstructured data providing a greater evidence base, proposals for new treatments can be pushed forward. Additionally, suitable patients can be identified earlier for treatments based on this smarter use of data, as well as being much easier to carry out research and develop therapies. Similarly, the use of free text will impact how patients are recruited for clinical trials, with the ability to completely transform this pathway. By looking at patients’ records and clinical criteria, the process of identifying and matching eligible patients with trial requirements is much easier. This change in thinking becomes more inclusive, particularly to clinical trials from the point of view of the patient. There are the additional benefits of time-saving, allowing trials to 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

progress more quickly and efficiently the first time around by having the right person in the right place. The use of free text in electronic health records is largely discussed, but there are other potential uses of free text within social media and patient reports. There have been multiple research studies which have looked into identifying symptoms that people report on social media and detecting trends using social media and patient reports. This can help clinical teams become aware of anything new and innovative that might be developing, or perhaps, linking to our current challenging times, have the potential to spot signs and symptoms of a pandemic earlier. Conclusion Unstructured data is an invaluable source of information which has the potential to reveal a deeper understanding of the ‘why’ behind healthcare pathways and clinical decision-making. By combining the ‘what’ from structured data with the ‘why’ from unstructured data, healthcare professionals, researchers, and policy-makers will gain a much more cohesive and holistic picture of patients' diagnoses, pathways and, ultimately, help inform personalised healthcare. With the increasing range of artificial intelligence and machine learning solutions available, these healthcare stakeholders stand to benefit more than ever by reharnessing the use of free text. Improved access to data allows for better clinical decisions and informed patients, which as a result, has a positive impact on patient pathways now and into the future. By recognising the value of unstructured data, overcoming these existing challenges and joining databases such as THIN together, both patients and healthcare professionals can leverage the benefits of this enhanced visibility, and put patients first.

Samir Dhalla Samir has a wealth of experience across the healthcare industry having started his early career as a pharmacist. He has worked with some of the UK’s most influential Hospitals, creating efficiencies as well as new entities/ departments all with a view to improving patient care and ensuring the NHS organisations were able to be sustainable as part of a long term strategy. Today Samir sets the strategy and innovation for Cegedim Health Data in the UK as well as leading Cegedim’s world-renowned healthcare database THIN; The Health Improvement Network.

Dr. Anoop Shah Dr. Anoop Shah is a clinical academic at the Institute of Health Informatics, University College London, and a consultant in clinical pharmacology and general (internal) medicine at University College London Hospitals. He has 15 years' experience in using electronic health record databases for epidemiological research, including the use of natural language processing to extract information from the free text. He is currently undertaking a postdoctoral fellowship funded by THIS Institute, to improve the recording of problems and diagnoses in electronic health records. He is a Fellow of the Faculty of Clinical Informatics (FCI) and he leads the FCI Diagnosis Recording Special Interest Group.

Winter 2020 Volume 12 Issue 4

At Avantor®, we know that quality is non-negotiable when developing treatments that help save lives. That’s why we make sure you have innovationadvancing solutions, from single-use assemblies that streamline mAbs production to buffer components for vaccines — every solution engineered to the highest quality standards and regulatory requirements. Through research and manufacturing, we provide the workflow expertise and regulatory support to keep therapy approval and delivery on track. Get trusted biopharma solutions that accelerate your breakthroughs. avantorsciences.com/moves-science-forward/ biopharm/quality

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 41

Clinical and Medical Research

Designing for Success

A Multi-stakeholder Approach to Clinical Development to Optimise Patient Access Developing new drug therapy is complex, taking many years to move from proof-of-concept to final data read out from the Phase III pivotal trial. After years of substantial investment, the end goal is to bring the therapy to patients in need. A significant number of pharmaceutical or biotech drug development companies are based in the USA, which is often the first market priority for commercialisation. Where companies are not commercially present in Europe, they have much to gain from a successful market entry into Europe, considering it generates the second largest global pharmaceutical sales revenue (approx. 20%) after the USA and Canada, which account for approx. 50%1. The European Union offers a certain degree of harmonisation; however, only with regard to the coordination of drug approval. When a drug is approved, it is valid for all countries within the European Union. Europe is a diverse and complex marketplace made up of more than forty distinct country-centred markets. Beside the more obvious differences in languages, each have their own specific methods to evaluate new drugs entering the market, and have differences in supply chains, patient demand, healthcare system setup and medical standards. Given these differences, bringing a new therapy to market in Europe takes time. According to the latest European Federation of Pharmaceutical Industries and Associations (EFPIA) data (Figure 1), the average time between marketing authorisation and patient access for a new drug varies from 119 days up to 925

days across Europe. Where a company has developed an orphan drug for a rare disease, time to market increases, and the average time between marketing authorisation and patient access increases, varying from 113 days up to 1141 days across Europe. In order to ensure patients in need can access new therapies as quickly as possible, it is critical that a multi-stakeholder approach is taken early on in the drug development process to maximise long-term success. Designing for Success - A Multi-stakeholder Approach to Clinical Development Planning for successful patient access for new drug therapies must start early in the life-cycle of the drug, right at the time of clinical development. Traditionally, drug development has operated in a siloed approach, whereby functions that are critical to the drugs success post-Phase III are missed from early consultations with research and development teams. Over the years, many companies have adopted a multi-stakeholder approach to drug development, involving other critical functions, such as regulatory, medical, commercial and patient access, and importantly, patient groups, early in the development process. For a new drug therapy to be commercially successful, it must satisfy the three critical external stakeholder needs; physicians want to prescribe it, patients see the benefits and individual market budget-holders are willing to pay for it. Research and development teams will engage with relevant clinical experts in the field to provide input into the acceptable

Figure 1: The average time between drug marketing authorisation and patient access.2 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

minimum efficacy outcomes, trial design and likely best patients to include into the trial. However, all other functions should be consulted and involved thought the whole development programme. Commercial and Medical Input and Opportunities Commercial and medical aspects can easily be missed at an early stage of drug development and can have severe consequences in the future. For example, working closely with the regulatory team to have a clear idea on the future label is critical. Small wording differences in the label such as “and”, “or” or “with” can have a significant impact on future positioning and promotion for commercial field force teams. Understanding the patient pathway and how physcians would intend to use and prescribe a new product is often a key medical input. However, understanding how the new drug may impact patients, and how they will use the product, should not be overlooked and should also be considered in early planning. Receiving input from patients early on can help inform R&D teams on aspects that may not have been considered before. For example, considerations regarding packaging, such as size and shape, especially if the drug requires cold storage in the patient’s home refrigerator, considerations to the type and size of syringe used, items included in ancillary sets or size of tablets and frequency of dosing. Patient Access Input and Engagement Opportunities Patient access (market access) input from an early stage is often missed. In cases where new drugs are developed in companies solely focusing on R&D, input is often overlooked and may not be considered until after Phase III initiation. Often the focus is just on pricing and reimbursement and the likely “achievable” price. However, patient access considerations should not just be focused on price, but also consider appropriate and relevant trial endpoints and evidence requirements from a budgetholder's perseptive that will allow them to clearly understand the value demonstrated by the new therapy. Winter 2020 Volume 12 Issue 4

Clinical and Medical Research Healthcare budget-holders vary across markets; those at national level, often involved in health technology assessments (HTAs), regional level commissioners for primary or secondary care, and hospital pharmacists and hospital business managers at the local level. All the different budget-holders are key stakeholders for engagement. And each type of budgetholder requires different types of evidence and they assess value in different ways. For example, the UK and Sweden focus more on cost-effectiveness and health technology assessment (HTA), whereas Germany and France focus more on clinical evidence and the “added benefit” that the new therapy brings compared to existing therapies. Companies must understand the budgetholder mindsets and differences in applying “value” and should seek opportunities to engage early, either via formal engagement routes that allow companies to discuss trial designs and data in more detail early in the development process, or via informal engagement pathways. Experience with early engagement has shown that companies are able to build longer-term partnerships. Such partnerships give companies time to consider and plan for endpoints that can deliver evidence that is aligned with budgetholder valuation needs and time to develop a strong value story, which is especially important when developing a therapy that may come to market with a high upfront price and potential long-term cost (e.g. gene therapies). With well executed engagement, new therapies have the potential to gain access to patients quicker, resulting in a win-win for companies, budget-holders, physicians, and ultimately the patient. Considerations for Early Access Opportunities and Planning In addition to planning suitable clinical trials, there has been a recent trend across large pharma to formally include preapproval access planning (compassionate use, managed access, expanded access early access) into the clinical development process. Increasingly, pre-approval access is seen as a key aspect of the commercialisation pathway of a drug. Typically, large pharma are making an assessment at the end of Phase II as to when and if pre-approval access will be granted to that medicine. As part of the decision process to help a company decide where and what type www.ipimediaworld.com

of pre-approval access is applicable and available, some of the key questions (below) should be addressed in order to provide clarity as to whether pre-approval access is likely to achieve the intended objectives. Key questions to address: • • • • • • • •

Is there a high unmet need? Have access requests been received which have been denied or not actioned? What is the expected future demand? What does the safety and efficacy profile look like at end of Phase II? Is there enough stock available to allow pre-approval access supply? What, if any, data collection is required? Have preparations been made to interact early with HTA bodies? What are the commercialisation priorities and are there any territories which require extended pre-approval use support?

Data In recent years there has been a greater focus on outcomes data collection in the pre-approval access environment. Any realworld data (RWD) collection during preapproval access should not be viewed as a substitute for clinical trial data. The scope and depth of data which can be collected means that any RWD should be considered as supplemental only.

Once companies have navigated the clinical trial pathway, their attention soon turns to commercialisation, and how to ensure patients can access the new therapy across the world. In the next section we explore the different options available to companies for commercialising in Europe. Commercialising in Europe – Key Considerations Despite the great potential of Europe, some pharmaceutical and biotech companies that do not have a European operational footprint can be put off from launching in Europe and question the need. But the question should not be if you should enter Europe, but rather when and how. An initial question to address is: what is the long-term objective of the company? For a company that has started out as an R&D company and is considering moving to commercialising, is a commitment to commercialising your product on your own the best way to maximise value? Or is it better to divest the IP immediately? Still another option is to enter Europe through a commercial partnership and hold the option for IP divesture open and by that create a higher longer-term value for the asset and the company. The importance of reflecting on this question comes from the fact that entering Europe requires you to make certain strategic commitments that may both open and close future options.

That said, data collected during preapproval access programmes can provide insights into how the product works in a patient population more similar to the commercial patient population and can help feed in to planning for subsequent clinical trials.

Although there is a continuum of strategic options to enter the European marketplace, these can be summarised into the following three:

Usage of RWD in HTA decision-making processes varies across Europe, but is still generally agreed to lack the robustness of controlled clinical trials. However, some HTA bodies do accept that in rare diseases, where patient numbers in a clinical trial are low, data collected through other mechanisms may be used for decision-making.

To establish and build up the company’s own complete commercial infrastructure in all targeted countries. To establish a partnership in all countries in Europe. To engage in partnership in Tier II countries whilst establishing the company’s own commercial infrastructure in Tier I countries – hence a combination of the above options.

These options all have pros and cons, with differing risk, investments requirement and level of future strategic flexibility. 1. To establish your own complete commercial infrastructure in all targeted countries The advantage of this approach comes from retaining full control over your assets and receiving all revenues. INTERNATIONAL PHARMACEUTICAL INDUSTRY 43

Clinical and Medical Research

Establishing commercial infrastructure in Europe requires a large set of operations, including: European medical approval, patient access with reimbursement approvals, preparing and executing the market launch with key opinion leader targeting, launch-sequencing of European countries, supporting operations such as medical, pricing and reimbursement, marketing, communications, sales, legal, logistics, finance, and managerial capabilities. Establishing such operations requires significant upfront investment some two to four years ahead of first revenue streams, and can limit a company’s ability to invest in other opportunities, such as R&D efforts or a successful US launch. Establishing your own commercial platform in Europe may be attractive in the case your company’s strategic goal is to become a global pharmaceutical company. In the situation when you have a very strong product at hand or you have a portfolio of products to bring into Europe, then the large upfront investment and its risks can be justified for establishing yourself in Europe. 44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

2. To establish a partnership in all countries in the region A second option for an entry into Europe is to engage in a partnership. The more classical approach to partnership is to strike a deal with a large pharmaceutical firm that has a regional or global presence and already commercialises its own products. The other kind of partnering option represents the specialised commercialisation companies. a. Partnering with big pharma A large or big pharma company that has many assets and a commercial infrastructure with dedicated resources and financial muscles may be attractive from a partnering perspective. Such partnership deals normally offer a certain upfront fee and then an ongoing payment, such as smaller royalty and/or milestone fees. This is attractive in itself, as it may provide you with quick access to needed cash and simultaneously eliminates most of the challenges inherent in building your own commercial infrastructure. Experience shows that deals with a large pharma company may give poor terms and conditions in terms of royalty levels, and since the large pharma company typically

holds the rights to your asset for a long time, it effectively means that you are locked in and prevents you from exploring other strategic options that may emerge in the future, such as divesting the product or the company. A deal with a large pharma company may be good in a situation when you do not have other financing options for your company, can’t find an alternative partner, and are very dependent on quick upfront cash. b. Partnering with a specialised commercialisation company Due to the limitations inherent in both options above, a third strategic alternative has emerged that attempts to offer the advantages and eliminate the disadvantages of the two alternative partnering options. There are many partnering companies that offer niche services limited to certain countries or operations. There are also a handful of commercialisation companies that offer operations in all or most countries. Given the complexity of Europe, it is often recommended to choose one pan-European partner. From a business perspective, a commercialisation firm that operates Winter 2020 Volume 12 Issue 4

Clinical and Medical Research across the whole of Europe generates a unique understanding of the dependencies between the various local markets and countries in Europe which may mean a difference between success and failure when entering Europe. In addition, working with one partner avoids the complexities of managing multiple partners, each potentially with different compensation models and challenges posed by reference pricing and parallel trade. Partnering in this way offers flexibility for the markets you wish to target, of the operations you need support with, the length of the deal, and the payment model. 3. Engage in partnership in Tier II countries whilst establishing your own commercial infrastructure in Tier I countries This option is good in terms of gaining experience in Europe and establishing a European presence. However, it still requires a focused approach and a significant upfront investment even if the

company just plans to launch in the major Tier I European markets; France, Germany, Italy, Spain, and the UK. Choosing a partner that the company could launch together with usually reduces the launch cost dramatically while increasing the quality of the launch, as your team can focus on the customers and launch strategy instead of the details around supply chain, permits, office set-ups, etc. Conclusion Planning for patient access for new therapies must start early in the lifecycle of the product, right at the time of clinical development. By engaging relevant stakeholders early in the clinical development process, it is ensured that the therapy meets the expectation of the prescribers, patients and importantly, the budget-holders. Carefully consider the different options to enter the European market, either by going it alone or through partnering to enable new therapies to reach patients in need. To design for success is to take a multi-stakeholder approach, to engage and plan early, and optimise patient

access through a carefully considered commercialisation strategy. REFERENCES 1. 2.

EFPIA The Pharmaceutical Industry in Figures, Key Data 2020 EFPIA Patients W.A.I.T. Indicator 2018 Survey, IQVIA, February 2019

Any general recommendations, considerations and interpretations are Inceptua’s views, and should not be relied upon as specific recommendations or guidance for a reader and or recipient.

Clive Whitcher Clive Whitcher, Ph.D., is Executive Vice President, Head of Inceptua Pharma, and is an expert in commercialization and patient access and brings experience from both pharma and consulting across a wide range of therapeutic areas. Clive joined Inceptua from Swedish Orphan Biovitrum (Sobi), where he held the role of Vice President, Head of Global Patient Access & Community Engagement. He was responsible for developing and delivering patient access launch strategies, including launch sequencing and innovative pricing and contracting strategies to secure sustainable access for rare, specialty, and orphan therapies.

Stuart Bell Stuart Bell, Ph.D., is Vice President, Consulting, Inceptua Medicines Access, and has more than 20 years of healthcare consulting experience, with a particular focus in unlicensed medicines and pre-approval access. Stuart is responsible for Inceptua’s consulting covering strategy and policy, real-world evidence, communications and market access. Prior to Inceptua, Stuart pioneered the development of global corporate strategies on preapproval access and developed the first pre-approval-specific EDC for realworld data collection at Idis/Clinigen.

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 45

Technology

What is Preventing the Industry from Providing Electronic Product Information? Abstract In 2017, the European Commission published a report regarding the possible improvements for product information texts used for human medicinal products. The improvements aim to facilitate safe and effective use of medicinal products and, as a result of the report, the European Medicines Agency (EMA) and the national heads of medicines agencies (HMA) agreed on a project to implement structured electronic ePI. Several national electronic patient information (ePI) projects have already demonstrated the potential of a triple-win situation: •

•

Patients: Effective provisioning of information to patients, elevating their “user experience” and improving the overall compliance; Industry: Optimising internal processes and improved compliance for managing documents containing patient information; Agency: Facilitating improved work processes between industry and agencies, streamlining the review process and improving analytics capabilities.

It is the intent of the ePI project to harmonise the national initiatives to achieve a common solution related to the identification medicinal product (IDMP) master data, including the controlled vocabularies provided by SPOR. This paper looks at what is preventing us from providing electronic product information as well as how industry can support the wider ePI project. Background In 2004, the requirement “the package leaflet shall reflect the results of consultations with target patient groups to ensure that it is legible, clear and easy to use” was added to Article 59, Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004. And in 2017, the long-awaited 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

report providing an overview of patient target group experiences was finally published. Before the 2017 report was published, two studies were published, each initiated by the European Commission: The first one was on the package leaflet (PL) and the summary of product characteristics of medicinal products (SmPC) for human use (so called PIL-S study)1. The second report gave more insight into feasibility and value of a possible “key information section” in PLs and SmPCs for human use (PILs-BOX study)2. The general result concluded that readability (comprehension and layout) still needs to be improved for PLs rather than for SmPCs. It was recommended to consider revising the existing guidelines (e.g. readability, content and layout-related issues), to allow more flexibility among different medicines in the QRD template (in the framework of the existing legislation) and to introduce guidance on translations. In parallel, the input from patients should be improved and a more iterative assessment process may be introduced without delaying the authorisation process. The final report from the Commission on the SmPC and PL for medicinal products for human use was adopted by the European Parliament and the Council on March 22, 2017 3. It concluded that the use of electronic formats brings new opportunities for these documents and recommended exploring the use of electronic media to provide information included in these documents to the patient in the future. However, the report does not recommend the removal of the paper leaflet from the box, which some may consider unfortunate, as removing the need for the paper leaflet could bring benefits to the patient. Continuing to provide paper in the box and give the patient the option to view the ePI could cause confusion if the electronic version differs (because it reflects recent updates) from the paper. Removing the need for a paper leaflet in the box and having the electronic version as the legal requirement would take away this potential confusion and ensure patients always have access to the most recent version. Action Plan EMA took the leadership in generating an

action plan on how to achieve the abovementioned objectives4. The starting point was a publicly broadcasted workshop that took place on November 28, 2018, in London at EMA. Representatives of all national competent authorities (NCA), EMA including European Commission, several pharmaceutical industry associations, patients and consumers’ organisations, healthcare professionals’ organisations and academia, health technology assessment bodies (HTAs) and payers took part in the information exchange. EMA presented an outline of potential future use cases and international standards to be employed in the event of an electronic PL being generated5. Representatives from several Member States as well as from pharmaceutical industry projects on electronic developments presented and ran a live demonstration on what an ePI could look like and what the advantages would be. Up to now, a broad range of similar, deviating proposals and developments are underway in many NCAs6. However, for European purposes a harmonised and standardised approach is essential as marketing authorisation holders and regulatory agencies will not be able to assess each electronic publication on a national or company specific solution. In addition, the publication process needs to be automated based on the authorisation issued by the competent authority. In addition to several technical requirements, the features of an application presenting an electronic product information need to be evaluated against patients’ requirements, whether they can and will use them and whether this approach supports the required improvement of comprehension and better readability of PLs7,8 and thereby the better use of medicines by patients and consumers. Whatever improvement of the design and layout of paper PL has been achieved, the flexibility due to the legal framework remains restricted. The access to an electronic version could offer many more benefits to the patient, including: • Improved searching of product information with the potential for tailoring it for personal use of patient, or advanced analytics from regulators; Winter 2020 Volume 12 Issue 4

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RGCC is a specialist medical genetics company, established in 2004 with headquarters in Switzerland. We are experts in developing and providing personalised cancer genetics tests for doctors and patients, and testing tumours for sensitivity and resistance to chemotherapy treatment and a range of natural substances. We are actively involved in pharmaceutical research and development. Our facilities are equipped with the most technologically advanced equipment and specialised software for data analysis. RGCC is a global organisation, and we work in collaboration with branch offices and distributors to provide a worldwide service. RGCC HEADQUARTERS RGCC International GmbH Baarerstrasse 95, Zug, 63OO, Switzerland email: office@rgcc-international.com, tel: +41 (O) 41 725 O5 6O LABORATORY FACILITIES RGCC SA Florina, Greece, email: office@rgcc-genlab.com, tel: +3O 2385 O 4195O RGCC India Gajularamarm, Hyderabad, India RGCC Central Europe Biozentrum, Martin-Luther-Universität Halle-Wittenberg, Weinbergweg 22 O612O Halle (Saale), Germany

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Technology • • •

• •

Offers options to explain medical terms; Monitors updates of a patient’s regularly used medicines; Enlarges the font size on the screen or ‘reads out’ the product information text (for patients with impaired visibility, for example); Easy access to educational material, informing videos etc.9,10; Easy automated translation to other languages, in addition to the EU ones (e.g. Arabic, Turkish etc).

In the best case, these developments and their evaluation of usefulness are accompanied by scientific support, analysis and assessment. Key Principles for ePI The key principles of the expectations, requirements and conditions of an electronic version of the PL were published by EMA in January 202011. The EMA’s key principles focuses on six areas: • • • •

•

Defining what ePI is and the standards to be used to generate it; Benefits for public health, making information more accessible to all patients; Efficiency gains within regulatory systems; Existing legislative framework, confirming that ePI must comply with existing legislation and complement the paper PL; Processes for reviewing/assessing the ePI and how some NCAs may take a different approach.

The EU context confirms that ePI should support all official EU languages so that patients can read information in their preferred language, but patients would benefit from ePI being automatically translated into other languages outside the EU ones, so that they have access to the information they need in a language they understand. It is important to understand that ePI covers all authorised, statutory product information for medicines (i.e. SmPC, package leaflet and labelling), but not additional information under the responsibility of NCAs such as educational material. However, this additional information may be published electronically via the same application using the common EU electronic standard, which has not yet been agreed. ePI is adapted for electronic handling and allows dissemination via the worldwide 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

web, e-platforms and print. ePI will need to comply with the published key principles. Managing electronic product information could be split into two distinct areas – data management and patient usage: Data Management: Companies will need to have the ability to manage the data content of the PL; traditionally this is managed in Word and PDF in a generally unstructured format. Companies may need to consider how they manage this data within their organisation, potentially using structured authoring tools to ensure the data complies with the requirements, which may be more detailed than the current QRD templates. Data used within the PL will need to be validated and controlled to ensure that it remains compliant throughout the product life-cycle. Patient Usage: Users of the medicinal products will have access to trusted data in a well-regulated format as outlined in the Directive 2013/37/EU12 and the General Data Protection Regulation (Regulation (EU) 2016/679)13. The benefit for users (patients, care givers and healthcare professionals) is the provision of up-to-date information from a trusted source available in several formats to best support the needs of the patient. Overview of Current National ePI Initiatives In several EU Member States, different projects have been initiated by pharmaceutical companies, trade associations or agencies to demonstrate how ePI can be realised and disseminated. In most cases the current QRD Template was the starting point to create an XML structure and the appropriate style sheet transformed the text file into a format that can be presented by browser technology. Norway: The Norwegian Medicines Agency (NOMA) started a collaboration with the Norwegian pharma association (LMI) which publishes a compendium of product information representing about 80% of the market. As the paper version is also available online, this electronic version has been adapted for mobile devices and includes search for medicines, barcode reading, personalised medicines list, “My daily dose” function, photos of tablets/capsules, and instruction videos. PLs are imported from EMA & NOMA as well as real-time alerts from NOMA on important safety issues, shortage situations, etc. For HCP users, additional information is offered: Prescription texts (mainly based on the approved SmPCs, risk management plans (RMP) from NOMA and drug interactions from NOMA’s database. Winter 2020 Volume 12 Issue 4

Technology Sweden: Since 2018 the basic information for approved medicinal products is available on FASS via websites, apps and web integrations including SmPC and PL in XML format for most marketed medicines. 1. 2. 3. 4. 5.

Search functionality. Basic product information. Package leaflet. Summary of product characteristics. Fass-text (version of the SmPC adapted to HCP). 6. Images of tablets and capsules. 7. Information on medication management for capsules and tablets (i.e. whether they are to be swallowed without splitting, swallowed without crushing, may be split in two, etc.). 8. Information on which generic products are classified as interchangeable by the Swedish Medical Products Agency (MPA). 9. Information on whether the company participates in the Swedish Pharmaceutical Insurance (insurance system for injuries related to medicinal products). 10. DHPC (Direct Healthcare Professional Communications), from the MPA. 11. Contact information to the companies. 12. Pharmacies' inventory status (to check if a specific medication is in stock in a

certain pharmacy). 13. Packages and prices within the Swedish reimbursement system, and conditions in the reimbursement. 14. Swedish environmental classification of pharmaceuticals. 15. Text-to-speech, print, print in large text. Alerts on changes of product information. FASS for Mobile Devices 1. 2. 3. 4. 5.

Search product or substance. Basic information. Package leaflet. Expand selected text section. Pharmacies' inventory status (to check if a specific medication is in stock in a certain pharmacy). Check for pharmacies nearby.

Germany: The scope of the project is to provide up-to-date PLs real time on mobile devices and desktop computers, based on a validated process using authority approved information in a user-friendly electronic format. This includes a reader option to help people with disabilities, a font size enlargement or a print option as well. The screen shots display the functions in more detail: www.ipimediaworld.com

1. 2. 3. 4. 5. 6. 7. 8. 9.

General menu. Search for product name or PZN. Scanning PZN-& FMD-Code. List of individually selected products. Package leaflet of the selected product. Search for a term of interest. Navigation through sections. Back and forth button. Enlarge font size button.

Spain: The agency requires the use of a specific application to create a semiINTERNATIONAL PHARMACEUTICAL INDUSTRY 49

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structured SmPC and PL. The tool allows the import of an existing product information text, editing information snippets (using XML editor functionality) and interactions with the agency to assess and confirm the modifications. The authorised product information (1 SmPC; 2 PL) is published at https://cima. aemps.es/cima/publico/home.html The text information is fragmented by sections (not only Word and/or PDF any more) using an XML editor (as mentioned above). The patient and HCP benefits from easy search and navigation. The semistructured version allows personalisation (favourite medicines with alerts whenever a change occurs). Links with other information formats (images, video...) are possible, so is the offer of information for people with disabilities and/or relevant 50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Technology for subpopulations (children, elderly, by gender, etc…). In addition, it is possible to map data from section 4.1 of the SmPC with diagnostic codes or cross-reference the content section 4.8 of the SmPC with the ADR database. Netherlands: The KIJKsluiter Foundation uses animation videos and accessible software to make information available to patients. KIJKsluiter is available as a web and mobile app containing over 8000 animation videos, which takes the most important information from the PL and explains it in a very easy-to-understand way. The videos are personalised to the patient’s age and gender and to the medicine’s form of administration. They provide targeted information to the patient (omitting details that they do not need to read) and explain why the medication has been prescribed. The videos are available in multiple languages, namely Dutch, English, Turkish and Arabic.

Belgium: In 2018, a 24-month-project was set up to evaluate whether the paper PL and an e-PIL offer similarities regarding safe and effective usage of a medicine. The scope is restricted to a selection of 15 centrally approved medicinal products restricted to hospital use only and marketed in Belgium and/or Luxembourg.

The PL and SmPC is available in Dutch and French language. There is some navigational support, but not as sophisticated as in some of the other national projects. However, the focus of the project is quite specific. The results of the 24-month survey should be available in autumn 2020 and due to very positive feedback so far, the project will be extended for one year and the scope extended to include more products. International Project Overview In February 2018, the EMA survey14 resulted in several international projects to provide product information electronically with a certain degree of structured information15. The analysis of all responses was separated into several areas of interest and did predefine the subsections of the Key Principles Document11. USFDA and Health Canada (HC) implemented the HL7 Standard on Structured

Product Labeling (SPL)16 combining the content of labelling and the data structures from the Common Product Model (CPM), both based on HL7 Version 3. This standard has not been updated since 2016. Nowadays, a more implementer- / user-friendly follow-up was published to allow a more straightforward implementation of software solutions: Fast Healthcare Interoperability Resources (FHIR). According to HL7 “FHIR combines the best features of HL7's v2, HL7 v3 and CDA product lines while leveraging the latest web standards and applying a tight focus on implementability.”17. For the new EU ePI standard it is likely that FHIR will be considered as a re-use of data elements from other IDMP-related implementations. Expectations and Challenges As demonstrated in the overview of national solutions, ePI (mainly PDF format) is already offered by some regulatory agencies via their websites, or in cooperation with pharmaceutical trade associations. In those

cases, the authorised text is generally used, however, the ePI project intends to offer much more, but that doesn’t come without challenges. Paper PL versus ePI “…Implementation of ePI does not imply any change to the legislation currently applicable to the PI. The development of ePI does not change the content of the PI (the information contained within the PI, headings, text or formatting) or create a new legal obligation to use ePI. In addition, this initiative does not change the interpretation of European pharmaceutical legislation...”11 Having both paper PL and an ePI available may result in a patient having access to different versions of the patient information. It takes time for changes to the text to be available in a printed PL, whereas the ePI could be updated (and available to the patient) almost immediately. Since electronic is always more accurate and upto-date, the purpose of the paper version of the PL should be questioned. This does

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Technology not mean paper is no longer a prominent medium to convey information on a medicine to a patient, but it could be printed at the site of the dispenser (pharmacy, doctor, shop, etc.) if and when required, rather than always being provided within the box. Rather than being considered an obstacle, this should be seen as a real valueadd opportunity, since access to electronic information becomes ‘the norm’ for most people, and it holds the potential to elevate the patient experience and compliance – with tailored information shared with the patient in a format that suits them best. The Belgian project may demonstrate that effective and safe use of a medicinal product is not impaired by the availability of just electronic product information (without the paper leaflet). Furthermore, there may be benefits to a patient if they are able to receive alerts about a medicinal product that they use regularly and if they have immediate access to the most up-todate patient information. Often the paper leaflet is discarded and cannot be referred to. Concerns will regularly be raised as the percentage of internet use is still not 100%, especially in the age group above 65, which is why it still may be necessary for printed copies of the patient information to be printed at the point of dispensing:

National Initiatives Patients are already benefitting from the national initiatives and can obtain information about their medication in electronic format. However, if national solutions continue to develop independently, challenges will emerge with the willingness of companies to use multiple, different solutions so there is a need for the ePI requirements and solutions to be harmonised, at least across the EU. Structured Data vs PDF “The structured nature of ePI will offer new opportunities to better personalize PI to the needs of individual patients / consumers by enabling more efficient retrieval of information (e.g. in online multi-level searches) and facilitating the use of their 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

preferred e-platforms. Although many future developments using ePI are outside the scope of this ePI initiative, structured ePI data will enable subsequent development of functionalities such as easier selection of information on medicines of interest, automatic update notifications, and access to authorized or supportive video or audio content or other interactive materials (in line with the appropriate guidance) and online adverse-reaction reporting tools.”11 The overview of current national ePI initiatives (summarised in this document) demonstrates that technically all of this is possible. In most cases, the number of medicinal products in scope is limited, but the processes to present up-to-date information, indicate relevant changes, and link important safety information, usage instruction videos or other important information is working well. Interoperability with other Initiatives Interoperability and the general requirements on how to exchange data from SPOR services and export towards a product information database is fundamental. The existing SPOR API may already provide a sufficient service to consume data. However, the substance database and the product database are still under development. So, the service is not yet complete.

The usage of FHIR offers pre-defined resources, which define the exchangeable content based on data types and common sets of metadata with an integrated human-readable component. Although a built-in extension mechanism to cover remaining content is available, it might be that for the purpose of ePI, additional resources are required or existing resources require modification. One of the benefits of ePI would be the improvement of data exchange; it is valuable to understand the large amount of dependencies, e.g. in case of dosing management, the intent to avoid medication errors and to support decision management systems in hospitals18 and the basic impact of authorised, statutory product information for medicines19.

Conclusion In summary, the electronic product information (ePI) will provide up-to-date information at any time or location to any user with an ‘easy-to-read’ font size (or read out for people with disabilities); it may include explanation of medical terms; it will allow for access to educational material and instructions for administration, and could indicate major changes for a certain period of time. As such, this initiative could also be considered as a way to facilitate marketing of (newly authorised) medicines in all Member States and redistribution of medicines available in other Member States to countries experiencing shortages or where medicines are not marketed. On its way to success, some hurdles need to be overcome, which could prevent the success of ePI within the EU – harmonisation and the potential conflict of paper versus electronic. A change of the current legislation by the European Commission is not foreseen in the short term, although ePI can provide significant benefits for patients, agencies, HCPs and the pharmaceutical industry as demonstrated by the national projects (reviewed in this document). It has also been shown that in collaboration between authorities and the pharmaceutical trade associations or dedicated information companies, the patient is already able to access electronic product information (in some countries). However, the missing part here is the agreement on a common technical structure and a proper tool to edit the information. Finally, the (currently) mandatory printed leaflet needs to be removed from the package and the respective legislation being replaced by more flexible regulation that improves usability and offers an improved experience for most patients with a tailored delivery of the PL information. According to B. Sträter, Article 58 Directive 2001/83/ EU could be interpreted such that the required content of the PL is provided on the outer package via a 2D-matrix code which navigates the user to the ePI21. If this is an accepted interpretation, then a legal change would not be necessary. REFERENCES 1. 2. 3. 4.

https://ec.europa.eu/health/sites/health/ files/files/committee/75meeting/pil_s.pdf https://ec.europa.eu/health/sites/health/ files/files/committee/75meeting/pilbx.pdf https://ec.europa.eu/health/sites/health/fles/ fles/documents/2017_03_report_smpc-pl_en.pdf https://www.ema.europa.eu/documents/other/ Winter 2020 Volume 12 Issue 4

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7. 8. 9. 10. 11.

12. 13. 14. 15.

16. 17. 18.

19.

european-medicines-agency-action-plan-relatedeuropean-commissions-recommendationsproduct_en.pdf https://www.ema.europa.eu/documents/ presentation/presentation-common-electronicstandard-potential-features-use-cases-escanlan_en.pdf https://www.ema.europa.eu/en/events/ european-commission-heads-medicinesagencies-hma-european-medicines-agencyema-workshop-electronic https://ec.europa.eu/health//sites/health/ files/files/eudralex/vol2/c/2009_01_12_ readability_guideline_fnal_en.pdf http://ipimediaworld.com/wp-content/ uploads/2012/05/Pages-from-IPI- Volume-2Issue-2-18.pdf https://www.ema.europa.eu/en/humanregulatory/marketing-authorisation/productinformation-requirements https://www.ema.europa.eu/documents/ presentation/presentation-what- packageleafet-how-review-it-claire-espinasse_en-0.pdf https://www.ema.europa.eu/documents/ regulatory-procedural-guideline/electronicproduct-information-human-medicineseuropean-union-key-principles_en.pdf https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2013:175:0001:0008:EN:PDF https://eur-lex.europa.eu/eli/reg/2016/679/oj https://ec.europa.eu/eusurvey/runner/EPI https://www.ema.europa.eu/documents/ presentation/presentation-overviewinitiatives-ema-hma-mapping-r-gonzalezquevedo_en.pdf https://www.hl7.org/implement/standards/ product_brief.cfm?product_id=440 https://www.hl7.org/fhir/index.html Maxwell S, Eichler HG, Bucsics A, Haefeli WE, Gustafsson LL; e-SPC Consortium. e-SPC - delivering drug information in the 21st century: developing new approaches to deliver drug information to prescribers. Br J Clin Pharmacol. 2012;73(1):12-15. doi:10.1111/j.13652125.2011.03981.x Ammenwerth E, Aly AF, Bürkle T, Christ P, Dormann H, Friesdorf W; ...Memorandum on the use of information technology to improve medication safety. Methods of Information in Medicine 53 (05), 336-343; 2014 doi: 10.3414/ ME14-01-0040

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20.

https://www.ema.europa.eu/en/documents/ other/european-medicines-agencies-networkstrategy-2025-protecting-public-health-time-

Dr. Klaus Menges

21.

rapid-change_en.pdf Sträter B; Pharmakovigilanz-Label-Change II; Pharm.Ind.82(09), 1089-1092, 2020

Stan van Belkum

Klaus Menges, Regulatory Affairs Senior Expert. Klaus joined the Federal Health Office in 1985. Until September 2018, Klaus represented BfArM in several European working groups and was nominated as Regulatory Chair in the ICH WG M8 on electronic submission Considering the broad regulatory experience he was also highly engaged in solutions for better readable product information texts.

Stan van Belkum, Deputy Director at Medicines Evaluation Board, The Netherlands. Stan has been Deputy Director of the Medicines Evaluation Board in the Netherlands since 2013. He has a long career in national and international initiatives around electronic regulatory information and information technology. He has also been part of the development of the eCTD with ICH and CESP with the HPRA in Ireland.

Jennie May

Peter Leister

Jennie May, Director Regulatory Informatics and Operations, PharmaLex. Jennie has over 20 years experience in the industry, with a focus on systems and processes to support the regulatory affairs business. She has held roles at Hospira and Allergan but has also worked for software vendors ISI (now DXC Technology) and IQVIA. Jennie has a wealth of experience including RIM System implementation, business process review and improvement, regulatory intelligence and publishing.

Peter Leister, Executive Consultant, Technology Enabled Smart Services (TESS), PharmaLex. Peter is a pharmacist by education and has over 20 years of experience in the Life Sciences sector, with a track record of successes as an entrepreneur and C-level executive for large global services firms. He has worked with most of the global pharmaceutical companies focussing on strategy, portfolio- and process-optimisation, eClinical-, Safety- and Regulatorytransformations, organi-sational redesign, outsourcing, large-scale change and implementations.

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Completing the Puzzle: Technology in Decentralised Clinical Trials The COVID-19 pandemic has pushed decentralised clinical trials (DCTs) to the forefront of clinical research as companies have adopted innovative ways to ensure trial continuity amid site closures and social distancing measures. From telemedicine and wearable sensors to home health visits and direct-to-patient drug shipments, the increased flexibility and new capabilities afforded by home-based DCTs have largely been embraced by patients, sites and sponsors alike. While opportunities abound, practical implementation of DCTs requires a skilled hand to create and deploy an effective strategy that integrates patient feedback, site preferences, regulatory expertise and the relevant tools and services into a coordinated DCT programme. Clear and thoughtful planning combined with stakeholder input are critical to informing DCTs, as the smallest of details can influence patient perceptions and behaviours. For example, in some cultures there is a degree of secrecy surrounding illness and home nursing is not welcomed, so finding neutral venues – such as nearby hotels or pharmacies – is proving to be a viable alternative. Equally important is the DCT technology itself, which must be clear, simple and intuitive for patients, sites, depots and CRAs to use for telehealth visits, eConsents, and data transfer and access. When these processes are seamlessly enabled, study compliance is high and data quality is optimised – both essential elements of successful DCT implementation. In this article, we will discuss new DCT technology platforms and best practices for employing them across the clinical trial continuum, as well as the growing regulatory acceptance of remote and real-world data that are fuelling widespread use of DCTs across the industry. Technology Connects the Pieces Running a DCT can be like assembling a jigsaw puzzle, connecting the various 54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

elements such as direct-to-patient drug shipments, sensors, telemedicine, patient apps and home health visits to piece together a complete view of trial components. Companies are increasingly turning to smartphone apps to integrate protocol elements on a single technology platform to simplify the process for patients and sites, which can sometimes prove challenging in remote or rural areas with slow or absent internet access. To overcome this challenge, new technology platforms enable data to be stored locally on a user device, then subsequently uploaded to the cloud when internet connection becomes available. Such devices and their preprogrammed apps also allow for video calls if the user has intermittent windows of internet access, thereby keeping patients connected to sites from afar. In this respect, DCTs have actually removed barriers to clinical trial participation for many patients who would otherwise be too far from physical sites to participate. While each DCT technology platform has its own customisable features and functionality, the most effective ones provide the full range of capabilities required to satisfy the varied requirements of all decentralised trials – among them, electronic clinical outcome assessment (eCOA), eConsent, telemedicine, notifications/ alerts and patient engagement and education. Having a flexible approach using a prevalidated and vetted toolbox from which to pull components of different shapes and sizes, and plug them into the DCT equation, ensures there are no gaps when running trials across varied protocols, patient populations, disease states, geographies and study designs. Selecting the Right Technology Vendor: Best in Class versus Home-grown Choosing the right vendor partners requires a deep dive into their respective capabilities and proven successes across a range of studies. A vendor that has run hundreds or even thousands of trials has thoroughly tested their software under a

broad range of conditions and has worked through the inevitable kinks along the way, vastly reducing the potential for technology glitches or failures throughout the trial. Moreover, the very process of ongoing vendor vetting is a valuable exercise. Staying abreast of the latest technology options allows for rapid selection of fit-for-purpose partners to accommodate the varying needs of specific protocols, sponsor preferences, and unique patient populations. Lastly, continuous vetting allows the freedom to test multiple technology solutions simultaneously without investing in a costly product that may prove to be a mismatch for you or your customers’ needs. This approach has proven particularly valuable in the face of the pandemic, in which an instantaneous shift to remote monitoring and electronic documents has necessitated quick decisions about moving to cloudbased platforms to securely upload confidential documents and conduct source data reviews. Behind-the-scenes Clinical Supply Logistics and Automation One of the most essential and perhaps least recognised components occurs behind the scenes in the majority of clinical trials, whether traditional, hybrid or fully remote. Informally known as RTSM or IRT – randomisation trial supplies management (RTSM) system or interactive response technology (IRT) – this automated system randomises subjects in a trial, documents patient visits, allocates medication to patients, and automates supplies and resupply to depots and sites. In short, RTSM systems are customised for each respective trial to ensure the right medication gets to the right patient at the right time. Because it uses a forecasting algorithm to manage provision of clinical supplies, including medications, RTSM systems can instantly respond to new input and adjust trial logistics accordingly. It is the infrastructure behind the technology, though, that enables seamless and accurate operations. When enrolment rates are different than expected (faster or slower), or in times of crisis – such as the recent pandemic and natural disasters – a flexible Winter 2020 Volume 12 Issue 4

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RTSM system allows study teams to adjust clinical trial supply strategies and therefore maintain patient access to study medication. For example, an RTSM system might be reprogrammed to frontload warehouses and reassign medications shipments directly to patients to mitigate supply chain risks in anticipation of site closures. Successful deployment of this approach has been a critical part of DCT implementation during the pandemic. DCTs and the Regulatory Process COVID-19 has magnified the urgent need for new drugs and more accessible and patient-friendly ways of evaluating them. The quest for effective COVID vaccines and treatments has condensed two-year development plans into months with the introduction of innovative technologies, more flexible regulatory guidelines and new emergency programmes to expedite testing and approvals. These rapidly evolving regulatory guidelines require an experienced, global regulatory team to navigate the wide variation of in-country requirements and the expansive geographic reach of DCTs. Simultaneously, greater reliance on remote subject enrolment, remote data collection and the use of real-world data (RWD) is paving the way for novel trial designs, such as synthetic control arms. This approach utilises previous trial outcomes and real-world data such as electronic medical records, disease registries, claims data and wearable devices to statistically create the control arm, instead of recruiting and assigning actual patients to a control arm. Regulatory authorities are increasingly accepting these types of innovative trial 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

models, which is speeding trial timelines and, in turn, drug approvals. This shift was already underway but is now accelerating across the globe as health authorities align their regulatory guidelines to make submissions faster, more efficient and less costly. Among the many examples, sponsors can now apply in parallel to the FDA and EMA for orphan drug designation using the same data and a single common form, and the Eurasian Economic Union (EAEU)’s new guidelines allow the five member states to operate a national medicines market in a single space. This means they can apply for registration of medicines and their release in all five markets simultaneously under common procedures and reduced administrative costs. Health authority inspections and regulatory meetings are now being conducted virtually or with careful social distancing techniques. Many health authorities are also accepting soft-copy versions or nonlegalised documents in place of physical copies, with the provision that the physical or legalised copy is provided when feasible. Timelines have become more flexible, particularly in countries where an in-person submission appointment is required, to allow for adequate protection of agency staff and visitors. Additionally, the pandemic has highlighted the need for more robust investment in electronic systems and software programs. Using cloud-based systems allows for multiple users to access and edit documents simultaneously, thereby simplifying document management and control while also allowing for real-time discussion and collaboration between team members.

Technology and the Central Site Model Technology has the power to unify people, processes and data in a single location. Even before the pandemic struck, the industry began exploring the potential of the central site model, in which a remote team of investigators, study coordinators and nurses enrol patients and oversee their participation. Technology such as telemedicine and patient apps allows the central site to remotely collect, monitor and evaluate study data. The benefits of a central site model include cost-efficiency, real-time data access, reduced variability of data, a larger geographic reach and greater diversity of trial participants. However, a host of complex and nuanced patient and data privacy issues complicate the tactical execution of central site models. First, widely varying laws and regulations in each region or country dictate access to and transfer of patient information. Select countries, for example, require data to reside in the country where it was obtained, thereby complicating the process for data transfers to a central site located outside the country. Second, sponsors, sites and study teams must carefully delineate in advance how patient and data privacy will be protected within technology systems to ensure the right people have the right access at the right time. Third, the sponsor must clearly define – in accordance with in-country regulations – what comprises personal data (e.g., anonymised data may or may not be considered personal data). Sponsors, CROs, vendors and sites often enlist a privacy officer to navigate these and a multitude of related challenges and ensure best practices that protect patient privacy. Winter 2020 Volume 12 Issue 4

Technology Keeping Patients First Among technology’s greatest assets is its ability to expand access to far greater numbers of eligible patients around the world. No longer is geographic distance a barrier to clinical trial participation. Telehealth visits and home health nurse visits are replacing many in-person site visits, while wearable monitors transmit data directly to the cloud. Patients can even obtain their own blood samples

Kieran Connolly Technology executive with 19 years of experience in clinical trial technology, product management, client services and sales for CROs and eClinical providers, including 4 years leading an APAC technology division in Shanghai.

using a novel home device that allows simple collection and shipment to a site or lab. Patients are embracing these decentralised approaches because they reduce their burden of travel, financial impact, childcare challenges, and time away from work or school, especially for patients and caregivers who live far from a study site. Early in the pandemic, these

benefits played an essential role in clinical trial continuity for patients whose medical conditions could not wait for the pandemic to end. Today, DCTs are critical to safely evaluating preventive and therapeutic options for COVID-19. Looking toward the future, the adoption of DCTs closely aligns with the industry's collective commitment to designing clinical trials with the patient and for the patient to accelerate the development of new therapies.

Nick Darwall-Smith

Rosamund Round Rosamund is Vice President 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.

Technology executive with 28 years in clinical research and development, including R&D Operations, IT and consulting, focused on enhancing the patient experience and optimizing sites and clinical trial teams through the right technology enablers.

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 57

Manufacturing

Secondary Drying: The Finishing Touch in Spray-dried Dispersion Manufacturing Introduction Pharmaceutical companies face increasing drug-development challenges given the challenging characteristics of compounds in their pipelines. Approximately 70% of new drug candidates fall into Class II of the Biopharmaceutical Classification System (BCS), indicating poor bioavailability due to low solubility. To increase the bioavailability of this problematic class of compounds, formulators are increasingly turning to amorphous spray-dried dispersions (SDDs) due to their applicability over a wide range of molecules and target product profiles. SDD technology can stabilise a drug in its amorphous state, increase bioavailability, and provide good physical and chemical stability during storage. It is critical for pharmaceutical manufacturers to maximise the efficiency of the final unit operation in pharmaceutical spray-drying, secondary drying to remove residual solvent. Optimisation of this step, which is needed to meet product specifications and ensure the physical stability of the drug product, is crucial since it can significantly affect manufacturing time at large scale. Three different methods of secondary drying are available using an agitated vacuum dryer: using vacuum only, humidity (water) assisted, and solvent (methanol) assisted. Methanol-assisted secondary drying. It is amenable to largescale manufacturing runs and can improve process efficiency, product quality, and manufacturing time. Drug developers may benefit from exploring methanol-assisted drying when formulating SDDs to enhance small molecule bioavailability. Improving Bioavailability with Amorphous SDDs Due to the increasing prevalence of drug candidates with low aqueous solubility, amorphous solid dispersions (ASDs) are becoming an increasingly popular technology choice. The amorphous (disordered) drug form is desired because it has higher aqueous solubility than its 58 INTERNATIONAL PHARMACEUTICAL INDUSTRY

crystalline polymorph forms, due to its high-energy state. However, formulating a drug in its amorphous state can be challenging, because the amorphous form is not thermodynamically stable and can revert to a lower-solubility crystalline form over time. ASDs prepared by spray-drying — SDDs — address this problem by using a dispersion polymer with a high glasstransition temperature (Tg). In the spraydrying process, the drug and the polymeric excipient are co-dissolved in a solvent and then pumped to a spray-drying chamber. The spray solution is atomised into droplets, which meet heated drying gas inside the drying chamber. The drying gas rapidly removes solvent from the droplets, forming solid particles. Due to the rapid solvent removal and evaporative cooling, the drug molecules are unable to crystallise before solidification and are trapped kinetically in the amorphous state. SDD powder is collected via a cyclone before it goes to the next unit operation: secondary drying.

tetrahydrofuran (THF) are 0.5% and 0.076% by weight, respectively. Secondary drying is important not only for product quality and patient safety, but also for the physical stability of the SDD product. The presence of residual solvent can lower the Tg of the SDD, increasing the risk of failure due to instability: the drug may recrystallise or particles may fuse together. Secondary drying is therefore a crucial unit operation for product success. At early clinical scales, secondary drying is often performed using tray dryers. Powder is spread into a thin layer on a tray and placed into a temperature-controlled oven. A sweep gas may be run through the chamber to increase convection, and/or the oven may be held under vacuum. The powder may also be exposed to humidity to speed drying. However, tray-drying becomes less practical as a programme progresses to larger scale. With kilograms of SDD per tray, the risk of operator exposure during loading and unloading becomes unacceptable. Also, large batches require time-consuming setup of many trays, each spread with a 1- to 2cmdeep layer of SDD.

Requirements and Equipment for Secondary Drying When it is collected, the SDD powder typically contains residual solvent, which For later-stage, larger-scale SDD manumust be removed via secondary drying to facturing, an agitated-vessel dryer is below a specified limit to meet International typically used instead. In this process, Conference on Harmonisation (ICH) Q3C(R6) powder is placed inside a temperaturequality guidelines. Both permissible daily controlled vessel, where it is agitated by a exposure limits and concentration limits spinning impeller. The vessel may be held are specified for solvents. For nearly all under vacuum or a sweep gas may be used cases (for all medications with a daily in the headspace between the powder and dosage-form mass of less than 10 g), the vessel. The sweep gas may be dry nitrogen concentration limit is more stringent and or contain water vapour or a solvent vapour Table 1. Examples of secondary-drying process parameters that will be the limiting factor. As an example, to expedite drying kinetics. This article for an and agitated-vessel residual solventconvection level limits for acetone discusses threedryer configurations of agitated-

Diffusion

Convection

Temperature

Sweep gas flow rate

Particle size

Impeller speed

Assisting solvent

Vessel fill volume

Drug/polymer properties

Residual solvent volatility

affect d

Powder surface area Table 1. Examples of secondary-drying process parameters that affect diffusion and convection for an agitated-vessel dryer

Secondary-drying processes may be limited by the rate of convection, the Winter Volume 12 Issuelimitations 4 or a combination of both. As a product is scaled up,2020 convection increasingly important. For an agitated-vessel dryer with a capacity exceed

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 59

Manufacturing vessel drying: (1) vacuum-assisted; (2) waterassisted (i.e., humidified); and (3) solventassisted, using methanol as the solvent. Secondary-drying Fundamentals Two phenomena are important for successful secondary drying in SDDs: (1) diffusion of the solvent to the surface of the particle and (2) convection of the solvent away from the particle. Table 1 summarises the main process parameters that affect diffusion and convection for an agitatedvessel dryer. Secondary-drying processes may be limited by the rate of convection, the rate of diffusion, or a combination of both. As a product is scaled up, convection limitations become increasingly important. For an agitated-vessel dryer with a capacity exceeding 1000 L, the powder bed may be over 1 metre deep. In this case, adequate turnover of the powder by the impeller is critical, because the sweep gas contacts only the particles near the top of the powder bed. Once the process is designed to maximise convection, diffusion may instead become the limitation to secondary drying. When diffusion is the limiting factor, it is tempting to simply increase the drying temperature to as high as possible. However, as the secondary-drying temperature gets closer to the Tg of the SDD, molecular mobility increases, meaning molecules gain the ability to rearrange and potentially crystallise. To ensure good physical stability, the drying temperature is adjustable only to a point, which will depend on the specific product’s properties. Much of what affects diffusion is determined by the composition of the powder particles. The diffusion coefficient of a solvent in an amorphous polymer is dictated primarily by the size of the solvent and the amount of “free volume” in the system. Free volume can be visualised as the molecular-scale holes found in between the diffusing species and the netlike drug/ polymer matrix surrounding it. As solvent diffuses out of a particle, the amount of free volume decreases, reducing the diffusion coefficient. This is why the rate of secondary drying slows over time if the system is diffusion-limited. Innovation in Secondary Drying Initial innovation in secondary drying SDDs at scale was described in a patent by Ray et al.1. This work identified an ideal process 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

space for solvent removal from SDDs using a combination of vacuum, agitation, and a nitrogen stripping gas in an agitated dryer with specified geometry. The process achieved a drying endpoint below 0.5 wt% within 20 hours drying time without negatively impacting physical or chemical stability of the product. For many SDDs, secondary drying is easily accomplished within 24 hours, even at commercial scale, using a vacuum drying process in an agitated vessel. For other more challenging systems, secondary drying can be slow and significantly increase manufacturing time. It is important to consider secondary drying early in the development process to identify potential issues early. Each active pharmaceutical ingredient (API) affects secondary-drying kinetics (via changes in diffusion coefficient) in ways that are difficult to predict a priori. To understand secondary-drying issues early in development, it can be useful to measure residual solvent after tray-drying a preclinical lead formulation. Dobry et al.2 introduced “solventassisted” secondary drying, using a similar agitated vessel at lower vacuum with a higher sweep gas flow rate. The key difference is that the inert sweep gas contains solvent vapour, such as water or methanol. In this process, the assisting solvent is absorbed by the SDD, increasing the available free volume in the matrix. In essence, the assisting solvent “loosens up” the molecular structure of the SDD, giving the residual solvent more room to move, increasing the diffusion coefficient, and reducing drying time. Especially when the residual solvent is nearly gone, the presence of the assisting solvent keeps the diffusion coefficient high. After the residual solvent

is removed, the assisting solvent is then removed as needed. Methanol-assisted secondary drying can help remove residual solvent the fastest for all three of these challenging systems. A detailed analysis of the mechanism behind this was presented in Shepard et al.3. In summary, methanol introduces more free volume to the SDD than similar quantities of water, leading to improved kinetics. Methanol is also straightforward to remove from the SDD after residual solvent removal is complete, typically requiring only one to three hours of additional drying time for common spray-drying polymers. Methanolassisted secondary drying can reduce water exposure and the risk of hydrolysis degradation in the API, eliminating the chemical stability risks seen with watersensitive APIs when water-assisted secondary drying is used. Solvent-assisted Secondary Drying: Case Studies A comparison study3 was conducted for three challenging secondary-drying cases: poly(methyl methacrylate-co-methacrylic acid) (PMMAMA, trade name Eudragit® L100 from Evonik4) spray-dried from acetone, PMMAMA spray-dried from THF, and cellulose acetate phthalate (CAP) spray-dried from THF. In all three of these cases, tray-drying at typical conditions took more than 48 hours. Additionally, diffusion was found to be the limiting factor, making these SDDs excellent candidates for assisted drying. For each of the case studies, three secondary-drying techniques were compared: vacuum, waterassisted, and methanol-assisted secondary drying, all conducted in a 3 L agitated vessel. A schematic of the experimental setup is shown in Figure 1. Using this setup, the relative saturation of the assisting solvent

Figure 1. Experimental setup for solvent-assisted secondary drying using an agitated vessel (T = temperature). Figure from Shepard et al.3. Winter 2020 Volume 12 Issue 4

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 61

Manufacturing

Assisting Solvent (wt%)

Residual Acetone (wt%)

ICH limit Methanol-Assisted 0

Drying Time (hr) Figure 2. Comparison of three techniques for secondary drying of PMMAMA spray-dried from acetone. Figure from Shepard et al.3.

Vacuum 1

Assisting Solvent (wt%)

Finally, Figure 4 shows the most challenging case study: PMMAMA spraydried from THF. The initial residual solvent content was very high at 12%. Though none of the techniques were able to reach ICH limit during the eight-hour experiment, methanol-assisted drying reduced the solvent content by two orders of magnitude. Extrapolating the log-linear data, methanolassisted drying would reach the ICH limit in approximately 20 hours, compared to more than 50 hours for the other techniques. Taken together, the three case studies show the promise of methanol-assisted

Water-Assisted

Water-Assisted Methanol-Assisted ICH limit

0.1

0.01

Drying Time (hr) Figure 3. Comparison of three techniques for secondary drying of CAP spray-dried from THF. Figure from Shepard et al.3.

Assisting Solvent (wt%)

In Figure 3, the same three techniques were used to remove THF from spray-dried CAP. Again, the methanol-assisted drying was fastest, reducing THF below the ICH limit (0.076%) in less than eight hours. Waterassisted drying was second fastest, and vacuum drying was slowest. PMMAMA and CAP are chemically dissimilar polymers, the former having a methacrylate chemistry and the latter a cellulose backbone. This case study demonstrates the versatility of the methanol-assisted drying technique.

Vacuum

0.1

Residual THF (wt%)

When PMMAMA was collected after spraydrying using acetone, it contained 10% residual solvent. Secondary-drying results for this system using vacuum, water-assisted, and solvent-assisted drying techniques are shown in Figure 2. Methanol-assisted drying reduced the residual acetone level below the ICH limit (0.5%) in approximately three hours. At the conclusion of the six-hour experiment, acetone was still above 3% for water-assisted drying and even higher for vacuum drying. This first case study clearly demonstrates that a methanol assist can accelerate secondary-drying kinetics.

Residual THF (wt%)

in the sweep gas stream can be adjusted independently of the flow rate and drying temperature.

Vacuum

Water-Assisted

Methanol-Assisted 1

Drying Time (hr)

Figure 4. Comparison of three techniques for secondary drying PMMAMA spray-dried from THF. Figure from Shepard et al.3. 62 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Winter 2020 Volume 12 Issue 4

Manufacturing

2. 3.

secondary drying in tackling the most difficult secondary drying problems. Conclusions To reduce SDD manufacturing time while ensuring a product with good physical and chemical stability, it is critical to understand the underlying mechanisms that affect secondary drying. The SDD formulation, spray solvent, and drying equipment parameters all impact the diffusion and convection of solvent during secondary drying. As demonstrated in these case studies, solvent-assisted secondary drying

can help solve secondary drying issues for the most challenging problem statements. Combining innovative secondary drying approaches with mechanistic understanding, the right secondary-drying process can be identified for each SDD product. Secondary drying can play its part in improving manufacturing times for bioavailabilityenhanced formulations, increasing speed to clinic and patient. REFERENCES 1.

Ray, R.J., D.D. Newbold, R.A. Beyerinck, D.E. Dobry

and K.D. Grove, “Drying of Drug-Containing Particles,” U.S. Patent No. 9,265,731 B2, 2016. Dobry, D.E., R.J. Ketner, D.K. Lyon and J.M. Mullin, “Drying of Drug-Containing Particles,” U.S. Patent No. 8,834,929 B2, 2014. Shepard, K.B., A.M. Dower, A.E. Ekdahl, M.M. Morgen, J.M. Baumann and D.T. Vodak, “Solvent-Assisted Secondary Drying of SprayDried Polymers,” Pharm. Res., 37:8(2020)156. Eudragit is a registered trademark of Evonik Industries AG and its subsidiaries.

Kim Shepard Kim Shepard is an Associate Principal Engineer in the small molecules R&D group at Lonza’s Bend, OR site. Her research there has focused on innovation in spray-drying processes and formulation of amorphous solid dispersions. Kim earned her PhD from Princeton University, studying polymer physics and amorphous materials under the direction of Professor Rodney Priestley.

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 63

Manufacturing

Preserving the Parenterals of Tomorrow

How the right components, and their manufacturing setup, can meet the needs of an evolving market Amid the evolution of the pharmaceutical industry, and more recently catalysed by the coronavirus (COVID-19) and its implications on drug demand, delivery and the supply chain, parenteral drugs are experiencing increased demand. Whether administered intravenously, intramuscularly, or subcutaneously, the format creates new and critical avenues for drug delivery thanks to some favourable attributes around safety and efficacy. For one, parenterals allow for a controlled release — either gradual or instantaneous — that an oral medication cannot always provide. This format is critical to providing immediate pain relief, such as with epidurals during childbirth, or for continuously managing fluid levels, such as with saline solutions delivered via IV. Parenterals also encourage patient adherence — often by requiring a clinician for administration — minimising the opportunity for error and the subsequent costly, dangerous consequences. Still, parenterals cannot perform correctly if the formulas are compromised while in production or en route to patients. Each medication must be safeguarded from the initial phase of manufacturing all the way to the point-of-use. This makes packaging a critical piece of the puzzle in sealing off the drug formula from any outside elements — and ensuring that no leachables from the packaging itself could compromise the integrity of the formulation. In addition, the market will continue to evolve and bring new drugs into the equation to meet patient needs. Emerging formulas will come with their own sensitivities and requirements for remaining sterile and effective, making that journey to the patient all the more complicated and demanding new measures to prevent contamination. As a result, packaging will play a vital role in the debut of potentially life-saving drugs and will need to be a core consideration in the design and manufacturing process of these new products. 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Anticipating the Next Generation of Parenterals Aiming for zero defects becomes even more critical as highly sensitive parenterals become increasingly common, with injectable biologics in particular emerging as chief drivers of sales growth in the pharmaceutical industry. According to a new study from Market Industry Reports, the sterile injectable drugs market was estimated to be over $500 billion USD in 2019 and is anticipated to grow at a doubledigit CAGR from 2019 to 2030. Considering the potential hazards facing parenterals throughout production and distribution, it may be surprising to learn that the market today still widely uses ampoules — small glass vials — to store and transfer medications. These containers, while offering an appealingly low cost, are susceptible to breakage. If glass particles fall into the drug as a result, the formula may be subject to cause contamination or harm. On the other side of the spectrum sit prefilled syringes and cartridges, which offer arguably safer transport but have not yet gained traction due to cost and a more complicated design. This type of packaging component, while providing a high-value option with little risk, represents the smallest footprint in the current market. Yet, the pendulum may swing as the pharmaceutical industry continues to evolve. As a whole, the prioritisation of risk reduction at point-of-use is driving the need for packaging components that enable more fool-proof drug delivery — especially when it comes to self-administered medications. The fewer the steps required, the lower the chance of error. As a result, personalised medicine is expected to become much more popular and present in the market, as drugs can be designed for more simplified administration and still maintain the necessary level of safety and control. This growth will likely boost the need for prefilled syringes and cartridges — devices that offer one-step use that are easier for both health professionals

and patients to navigate. Accompanying these devices will likely be a rise in digital health apps and other technologies that can simplify drug use and self-administration. The result? An increasing need for highervalue components. Addressing the Changing Demands of Parenteral Packaging While the adoption of personalised medicines may simplify product use for the patient, these higher-value components also make the manufacturing process more complex. Designing drug delivery to be virtually fail-safe for patients requires an intricacy of safety measures throughout the product packaging. When working with parenteral drugs in particular, it is important to be aware of potential hurdles posed by problematic packaging and to design production in a way that mitigates these risks. To start with, large-molecule drugs are often more sensitive to particle contamination than small-molecule drugs. This sensitivity can heighten the risk of contamination in the manufacturing process and ultimately render entire batches unusable, leading to major product loss and costs. It also makes the manufacture and packaging of larger batch sizes of drugs like biosimilars and biologics challenging. This is where the role of packaging components, including sealing solutions, becomes particularly critical. The duty of packaging technologies should be to meet stringent requirements for safety and security throughout the manufacturing process and applying the appropriate sealing solutions to keep parenteral drugs sterile can make the difference in a viable batch. These solutions may take the form of elastomeric plungers—essential features for prefilled syringes, which aim to enhance safety and product integrity by reducing opportunities for error in administration. When designed effectively, plungers provide a smooth glide throughout the syringe barrel. This attribute enables chemical purity by reducing friction and enabling safe administration in manually- or pumpactivated syringes — even after long-term storage. Winter 2020 Volume 12 Issue 4

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 65

Manufacturing

It will be important for these components to modernise in response to the changing needs of drugs. The new characteristics and behaviours of future drugs will dictate new considerations and requirements in drug packaging. As demand increases for large-molecule parenteral drugs, which exhibit significant sensitivity to leachables and other particle contamination, manufacturers can benefit from new innovations in spray coating technologies that enhance the protective barriers of plungers and stoppers. By completely covering such components with a proprietary fluoropolymer spray coating, manufacturers can reduce drug contact with the naked rubber and leachables as well 66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

as other external contaminates to better protect formula integrity. Yet, the trick is not to simply utilise the right components but to also engage the right partner in the implementation of those components. COVID-19 has demonstrated the merits of decentralised supply chains and suppliers that bolster continuous manufacturing capabilities for drug manufacturers, shining a light on service and process — not just materials and component design. New supplier manufacturing capabilities will shape the industry’s ability to respond to public health crises and pandemics, and packaging partners that take an

integrated approach to design can provide reassurance that foresight and precautionary measures were applied to each level of production. Achieving a Secure Parenteral Package To prevent opportunities for contamination throughout production, pharmaceutical companies should work closely with component manufacturers that can accommodate a range of batch sizes and will approach packaging for every product with the same care and scrutiny. As many companies move toward a modular facility design, flexibility and meticulous attention on the component Winter 2020 Volume 12 Issue 4

Manufacturing

Minimising Time to Market While Putting Quality First Helping drug developers to protect the integrity of injectables throughout development to distribution Drug manufacturers have always aimed to minimise time to market while also protecting injectables against contamination. However, the challenges COVID-19 has posed to global supply chains have placed even greater emphasis on this goal. According to an FDA study, developing a new medicine takes on average 10 years and costs $2.6 billion from discovery through approval. These are high stakes, so it is essential to utilise every available tool in creating an uninterrupted transition from the development stage to production. To minimise challenges along this process, drug manufacturers should work with suppliers that offer a “starter pack”, with a complete, readyto-use packaging system to support the development of parenteral drugs. High-performing components should foster sealing compatibility, prevent leaks and alleviate other seal integrity concerns throughout manufacturing and handling. This way, the components offer a comprehensive packaging solution that ensure drug efficacy, stability, and, ultimately, patient safety.

side will be increasingly instrumental in enabling efficiency. Focusing on component sterilisation further upstream in the production process can reduce the manufacturing footprint in a parenteral packaging facility, which can be designed to eliminate the presence of identified contaminants and to meet the highest manufacturing standards. For one, working with component manufacturers that use camera inspection in their manufacturing process helps add a layer of security the naked eye cannot achieve alone. Cameras do not get tired and do not miss even the smallest anomaly. Among regulators, the trend is continuing toward more stringent standards, pushing drug manufacturers and the designers of packaging and secondary devices to higher levels of scrutiny in manufacturing and design. Ultimately, an adjustable setup also supports the use of automation along the production line to minimise the risk of human contamination. www.ipimediaworld.com

In addition, pharmaceutical companies will find value in manufacturing processes that can customise packaging to address individual product needs. This is an important capability for complex parenteral drug devices like pump injectors — devices for which off-the-shelf components are often incompatible. In this sense, employing a tailored approach to device design serves as a major avenue for meeting safety and performance standards. Ensuring Scalability Agility along the production line may be helpful for preventing contamination and facilitating unique product needs, but it is also helpful for meeting changing market demands. Amid supply shortages for COVID-19 test kits, and speculation on potential shortages of important packaging components for vaccines or treatments, drug manufacturers should scrutinise the processes behind scaling up from development to production. They should take a moment to ask whether a sudden surge in demand would create shortages and capacity limitations in their output. If the answer is “yes”, the company should be aware that speeding product to market could result in damaging missteps. Drug and device manufacturers can mitigate these issues with a few considerations when selecting packaging suppliers. First, select a partner that offers a sample kit or “starter pack” to drug manufacturers that supports easy scaling between development, validation and production. Ensure the partner has expanded, decentralised manufacturing facilities around the globe to meet distribution needs as demand swells. Next, to harken back to the tailored approach, leverage a combination of batch and continuous manufacturing to provide crucial components in necessary volumes, and closely collaborate to design and quickly

produce custom components for effective sealing. Finally, create a manufacturing methodology based around quality control to mitigate defective components that can threaten drug integrity — a fundamental requirement to govern growing operations. As the market continues to evolve, it will be prudent for pharmaceutical companies to consider the types of parenteral products that will gain traction, their individual needs and where component manufacturing will require adjustment to keep up. Flexibility and customisation will serve as important points of differentiation in this process, enabling emerging medicines to reach the patient and perform as intended. The priority for all pharmaceutical companies moving forward should be to engage a partner that can provide a unique manufacturing approach prepared to meet these industry demands — and that can be ready for anything.

Glenn Thorpe Glenn Thorpe joined Datwyler in November 2017 as Senior Vice President – Pharma in the Healthcare Solutions business. Mr. Thorpe has 21 years of experience in the injectable drug delivery and primary packaging industry. Before Datwyler, he worked in various sales, marketing, business development and general management positions with BD Medical – Pharmaceutical Systems, West Pharmaceutical Services, Unilife Corporation, and SiO2 Medical Products. He is experienced in primary packaging, injectable drug delivery systems, clinical practice, and pharmaceutical industrialisation processes and equipment.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 67

Manufacturing

Managing the Mass-production of Tablets with Efficient Processes The growing demand for increased tablet quantities and the goal of reducing time to market is putting pressure on tablet manufacturers. In order to keep up with this requirement, innovative processes and systems need to be adopted to improve production efficiency. Here we look at the importance of tool management systems and online training in the quest to produce high quantities of quality tablets. Tablet Tool Management The availability and condition of tools is of primary importance for uninterrupted production. This is especially important in the pharmaceutical solid dose manufacturing environment where productivity is key. Shorter lead times and cost implications are putting pressure on manufacturers to invest in new technologies and processes. One area where investment is being made to meet demand is through new software solutions. The implementation of a comprehensive tool management system (TMS) is critical for a successful operation which improves the efficiency of manufacturing quality tablets. A primary objective of a TMS is to ensure that tooling is never a cause for delay in the production schedule. Ask yourself these questions: Do you know where your tools are? Do you know what condition they are in? Is all the tooling available when required to ensure production runs smoothly? If the answer to any of these is ‘no’, it is time to invest in a proficient TMS. Operating a manufacturing process without the appropriate management in place will affect productivity and profitability. Effective tooling management will not only increase efficiency, but also keep up with growing industry demands.

of maximised press uptime. Gone is the time when tool monitoring was achieved through modest manual methods. Recording data on paper is not sufficient or productive for today’s demanding high-volume manufacturing processes, which must be tightly controlled. Any problems within tool inventory management can have serious implications on the bottom line. In addition, manufacturers should have a complete audit trail covering tooling usage and maintenance. This is not only good practice but an important regulatory requirement in many tablet manufacturing environments. Without a robust management system that controls and documents the procedure efficiently, the consequences will be costly. Tablet tooling was once considered an expendable part of the manufacturing process and deemed part and parcel of production. But there are less obvious costs to consider, for example, those generated by the unavailability of tools due to avoidable damage or unexpected replacement – both leading to tablet press downtime. Through the development of computerbased monitoring systems, viewing tablet compression tooling as consumable items is changing and manufacturers are now maximising productivity per punch.

The growing requirement for quality mass-produced tablets has highlighted clear trends within modern tablet production. They include the increase of capacity, flexibility, the speed of response and robust traceability with the core objective

A core feature of a TMS is its capacity to keep track of the tooling maintenance. This is critical in obtaining the maximum life from punches and dies. It is important to maintain a logical, planned and professional approach to tooling maintenance to ensure

68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

tablet tooling failures are avoided; a TMS helps to achieve this. By implementing an advanced management system, problems like wear to punch heads and tips can be detected before they impact on production. It can also highlight when specific punch and die cleaning actions are required. These can be essential to avoid issues such as sticking and picking, cross contamination and corrosion. Implementation of a tooling management system can also drastically improve tooling inventory availability. Without this information, either unnecessary tooling replacements are made, reducing productivity, or punches are deployed when they should be in maintenance or replaced. The latter circumstance produces problems with the end tablet when it is found that the tooling being used does not meet the highly demanding process of tablet manufacture. Rejected tablets, wasted formulation, very expensive press damage and press downtime is a common result. In addition to this, not having a clear picture of tooling availability may lead to the loss of opportunities in a fast-moving and competitive environment. Key Points to Finding the Right System With a number of different tool management systems on the market, it is important to choose one which can effectively record everything required for greater productivity. Make sure the TMS covers the following essential features: Winter 2020 Volume 12 Issue 4

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talkfuture@pciservices.com INTERNATIONAL PHARMACEUTICAL INDUSTRY 69

Manufacturing

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Check it can proactively monitor tooling rotations, inventory which covers the tooling life-cycle and maintenance. It should be compliant with protocols like the FDA’s Code of Federal Regulations – 21-CFR part 11, so important electronic records can be traced. User-definable reporting will help to keep track of key performance indicators such as tablet quantities produced, per batch or yield. Tool measurement capability which is compatible with industry standard measuring equipment. It can access standard format documents so all previous drawings and images can be included. It incorporates an in-depth guide to tooling specification and troubleshooting so any problems flagged up can be traced and rectified. It features a warning to alert users of any problems including over-compression, when maintenance is required and even

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when tooling replacements should be planned. It includes an industry guide to compression tooling; for example, the Eurostandard educational suite. This advises tablet manufacturers on tablet tooling terminology, configuration and procurement and includes the latest technical specification compatible with ISO 18084:2005(E) – ‘Press Tools for Tablets’. It is a multilingual and adaptable system which is available in different configurations to work flexibly and seamlessly within an established manufacturing facility in any country. This ensures all sites in a global company can work from the same system.

Through the use of a tool management system, tablet manufacturers can fulfil a core requirement of managing tooling in an ordered and traceable way. It knows where every tool is, what condition it is in

and how long it has been in service, and can identify maintenance issues or poor handling problems by auditing all tooling and its respective processes. Educate to Accumulate To optimise tablet production, you must combine many factors, all of which will lead to better processes and a quality end product. Although the use of a tool management system will have a significantly positive effect on production, another method helping to improve production efficiency is education. Ensuring staff are skilled and knowledgeable in their roles is essential. In terms of tablet manufacture, knowledgeable staff can detect problems before they occur and identify solutions to overcome any issues that arise. Both lead to minimised tablet press downtime and will ultimately increase efficiency. Although training may take place ‘on the job’, finding the time and correct information is not always easy. The introduction of electronic enabled learning is helping companies improve the skills of their staff and is seeing huge growth in recent years. This increase is being seen through all industries including those in tablet manufacturing. E-learning programmes can combine comprehensive and flexible courses in a wide variety of disciplines with the convenience of learning taking place in the workplace or off-site. The material should be delivered in a multimedia format incorporating engaging animations, webinars and interactive content. Furthermore, the information can be validated by interactive quizzes to ensure key points are understood. This is accessed via desktop computers or mobile devices making it easily available, permitting Winter 2020 Volume 12 Issue 4

Manufacturing

make processes more effective and efficient, therefore helping to increase the output and quality of the tablet.

employees to be educated and updated on the best industry practices and tablet tooling developments whenever is best convenient. ‘E-Learning is a way to provide quick delivery of lessons. As compared to traditional teaching methods, this mode has relatively quick delivery cycles. This indicates that the time required to learn is reduced to 25%–60% of what is required in traditional learning.’1 Importantly e-learning can accommodate everyone from director level to engineers and operators looking to improve their

knowledge in areas of tablet compression tooling. Newly developed courses are also designed with a hierarchical system giving training managers and supervisors a full audit, tracking and reporting of employee development and certification. Following the completion of each course, certification can be issued in line with a company’s operating procedures and guidelines including scheduling re-qualification after a period of elapsed time. With a compartmentalised structure, courses can be used across different departments, job roles, sites and even countries for comparison purposes. By ensuring key training is achieved and being used, manufacturers are helping to

Take Control It is important to take control of tooling and production processes in order to achieve maximum productivity. Production management solutions have never been more important when it comes to the manufacture of tablets. The global growth of high-quality solid dose medication to be produced quickly and cost-effectively is putting an extra strain on manufacturers. To lessen the burden, new procedures need to be used, including incorporating advanced tooling management systems and investing in staff. Online training should be recognised as an important tool with which to share knowledge and improve technical skills and understanding. They say ‘knowledge is power’, and this is true when it comes to optimising tablet manufacture. By ensuring the correct skills, procedures and tooling are in place, manufacturing processes can only advance. REFERENCES 1.

https://elearningindustry.com/9-benefits-ofelearning-for-students

Marianna D’Onghia Marianna joined I Holland in 2016 after completing her master’s degree in marketing management. She recently hosted I Holland’s latest webinar and is heavily involved in the creation of the online training system platform. Marianna also hosts I Holland’s biannual Ultimate Guide Seminar.

www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 71

Manufacturing

HPMC and the Value of Vegetarian Hard Capsules

Oral solid dose (OSD) products continue to be the preferred drug delivery form for active pharmaceutical ingredients (APIs) for drug developers, due to their cost-effectiveness, comparative ease of manufacturing, and availability of patient-friendly dosing options. Of the 38 small molecule new molecular entities (NMEs) approved by the US Food and Drug Administration in 2019, 26 were OSDs1. In addition, the secondary manufacturing of OSD branded products carried out by contract manufacturing organisations (CMOs) accounted for $7.2 billion (USD) of market revenue in North America in 20182. Likewise, the small molecule outsourcing market is predicted to reach more than $69 billion by 20243. All of this demonstrates the continuing prevalence of OSD delivery. Compressed tablets currently dominate the OSD market, but hard capsules are becoming an increasingly attractive alternative. This is, in part, due to the reliability of encapsulation as a delivery method for medicines, including highly potent oncology APIs, which often have more complicated delivery requirements to ensure safety and efficacy. For patients, capsules are familiar, offer taste masking and good swallowability, making them preferable to more invasive dosage formulations. In this article with International Pharmaceutical Industry, Julien Lamps, Product Manager at Lonza Capsules and Health Ingredients discusses the various advantages of selecting a hard capsule over a tablet formulation. Julien also shares insight into how the introduction of hydroxypropyl methylcellulose (HPMC) alternatives could see the scales start to tip as developers look for ways to not only optimise their products but also meet consumer demand for vegetarian-friendly medicines. Hard Capsules: Improving Patient Compliance and Optimising Performance Patients may be reluctant or unwilling to 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

take medications that taste or smell bad, are difficult to swallow, or have the potential for adverse side-effects. With this in mind, compliance with a treatment regimen is fostered by the development of userfriendly dosage forms. Hard capsules are an attractive option for patients because, in addition to masking taste and smell, they can also decrease pill burden due to less frequent dosing and better release timing. This is achieved through the use of rapid, controlled, and extended-release formulations. Gaining more control over the release profile of a drug, for example by using pelletised API, can prevent dose dumping and may also reduce side-effects. Drug developers have found that encapsulated multi-pellet technology allows for increased flexibility and more effective handling of controlled-release APIs. It can even allow combinations of pellets containing different APIs within the same capsule, meaning multiple drugs can be delivered simultaneously in different doses, hence further reductions in dose frequency can be achieved. These formulations, including multipleunit pellet systems4, extrusion-spheronised APIs3, and fixed-dose combination systems5, also exhibit more reproducible pharmacokinetic and pharmacodynamic behaviours when compared to traditional formulations. Due to this combination of potential improvements in patient compliance and therapeutic efficacy, demand for hard capsules to encapsulate pelletised APIs is continuing to rise. Polymer Preference: The Need for a Vegetarian Alternative to Hard Gelatin Capsules While hard capsules have traditionally been made from gelatin, this polymer can be challenging to use with hydroscopic or moisture-sensitive molecules. Derived from animal by-products, gelatin capsules are susceptible to cross-linking reactions that may interfere with dissolution and have a relatively high water content to maintain pliability. This can lead to water exchange between the shell and the encapsulated API and excipients.

In addition to the impact polymer selection can have on product performance, an increasing number of patients are unwilling to ingest animal products for social or cultural reasons and are seeking medications that can be classed as vegetarian or vegan. In order to meet this demand, pharmaceutical companies are investing in drug delivery innovation to develop compatible vegetarian alternatives that are just as safe and effective. Recent advances in material science have allowed companies to develop alternative capsule polymers that have the benefits of gelatin capsules – swallowability, ease of manufacture, and cost-effectiveness – while offering patients a capsule derived from a non-animal source. Achieving Improved Dissolution and Compatibility: The Application of HPMC Currently, one of the best alternatives to gelatin is hydroxypropyl methylcellulose (HPMC), a polymer derived from the cellulose found in trees. HPMC is also less chemically reactive and absorbs water to a lesser degree than gelatin6. The low moisture content of HPMC capsules reduces water exchange between the capsule and the encapsulated formulation which in some cases can improve chemical and physical stability, increase shelf-life, and alleviate challenges with including hygroscopic APIs and excipients in the formulation. HPMC shells are also stable at a wide range of temperatures, which makes them easy to store and transport. With the increasing number of highly potent APIs in development with more complex requirements in terms of formulation, manufacturers are exploring the use of HPMC-based capsules as a potential alternative to traditional gelatin capsules and have so far experienced very positive results. In fact, HPMC capsules are now often preferred in clinical trials for investigational NMEs due to their ability to encapsulate a wide range of drug products and excipients7. The ongoing improvements in HPMC capsule technology have meant drug developers are able to take advantage of their dissolution parameters and their Winter 2020 Volume 12 Issue 4

Manufacturing

6. Figure 1

compatibility with many NMEs, including highly potent compounds. HPMC capsules that are produced without the need for a gelling agent provide ion- and pHindependent dissolution performance in a range of media, meaning patients will experience the same therapeutic efficacy in fasted or fed conditions. This is shown in Figure 1.8 As a result, these improvements in dissolution can lead to enhanced patient compliance simply because the patient has less to worry about in terms of timing their dose routine. Additionally, ongoing innovations in HPMC capsule film solutions can also allow for enteric protection and rapid release in a specific section of the GI tract, effecting targeted delivery for some therapeutics9 and further bolstering the potential application of HPMC capsules. Another potential application for HPMC capsules is for use in inhalation devices for pulmonary delivery. The prevalence of this dosage form continues to grow because of the potential improvements in bioavailability by avoiding the first pass liver and providing a more direct delivery route when targetting diseases such as asthma and chronic obstructive pulmonary disease (COPD). As pharmaceutical manufacturers look to develop cost-effective, patient-friendly, and effective treatments for respiratory conditions, as well as explore inhalation delivery for a number of central nervous system (CNS) diseases, the demand for capsule-based dry powder inhalants is www.ipimediaworld.com

increasing. The low moisture content of HPMC capsules makes them ideal for the type of hygroscopic or water-sensitive APIs used in dry powder inhalers, though electrostatic properties between the formulation and the capsule shell also have to be taken into account throughout the development process8. Final Thought Ongoing developments in polymer science and engineering have paved the way for HPMC to become a viable alternative to gelatin-based capsules for certain formulations, providing more options when it comes to optimising product performance. In addition, the increased prominence being placed on consumer preference and the high demand for affordable inhalation medications are bolstering demand for capsules that are compatible with moisture-sensitive molecules. However, polymer selection is a critical part of ensuring product success and the decision between gelatin and HPMC should only be made with access to the right expertise. Chosen correctly, a polymer can enhance efficacy and reduce adverse side-effects as well as overcome certain formulation challenges. REFERENCES 1.

FDA. 2019. Novel Drug Approvals for 2019. Accessed at https://www.fda.gov/drugs/newdrugs-fda-cders-new-molecular-entitiesand-new-therapeutic-biological-products/ novel-drug-approvals-2019 Persistence Market Research. 2018. Global Market Study on Oral Solid Dosage Contract Manufacturing: Tablets Dosage Form to Register Significant Revenue Growth

7. 8.

Through 2028. Accessed at https://www. persistencemarketresearch.com/marketresearch/oral-solid-dosage-contractmanufacturing-market.asp Ravetti S, Hergert LY, Sparo MD et al. 2016. Challenges in Protein Formulation Focused on Extrusion-Spheronization Process. Int J Pharma Research Rev 2016; Visiongain. 2020. Pharmaceutical Contract Manufacturing Market 2019-2020. Accessed at https://www. visiongain.com/report/pharmaceuticalcontract-manufacturing-market-2019-2029/ Panda SK, Parida KR, Roy H et al. A Current Technology for Modified Release Drug Delivery System: Multiple-Unit Pellet System (MUPS). Int J Pharm Sci Health Care 2013;3(6):51–63. Moon C and Oh E. Rationale and strategies for formulation development of oral fixed dose combination drug products. J Pharma Investigation 2016;46:615–631. Pinto JT, Wutscher T, Stankovic-Brandl M et al. Evaluation of the Physico-mechanical Properties and Electrostatic Charging Behavior of Different Capsule Types for Inhalation Under Distinct Environmental Co n d i t i o n s . A A PS Ph a r m S c i Te c h 2020;21(4):128. Al-Tabakha MM. HPMC capsules: current status and future prospects. J Pharm Pharm Sci 2010;13(3):428–42. Bordes-Picard F and Lamps J. “Advanced Capsule Technologies: Dry Powder Inhalers to Target Disease.” ONdrugDelivery, August 2020;110:54–57. Lynch M. Technology boosts access to biologics and insulin via oral delivery. BioPharma Reporter. 2019. Accessed 8 October 2020. https://www.biopharmareporter.com/Article/2019/03/18/Oraldelivery-of-biologics

Julien Lamps Julien Lamps graduated from Ecole Nationale Supérieure de Chimie de Lille with an engineering degree in chemistry in 2004. Julien joined Lonza CHI as a Quality Assurance Engineer in the Colmar plant in 2011. In this role he worked at the interphase of operations and customers within the well-known Lonza Quality Mindset. He specialised in coordinating new product introductions to develop innovative offers around modified release profiles and also inhalation products. He is now Product Manager for Lonza CHI’s Capsule Delivery Solutions business unit focusing on inhalation and HPMC portfolios.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 73

Manufacturing

Causes of Punch Tip Wear and How to Avoid Them

Punch tip wear is a commonly overlooked aspect of many tooling inspection procedures. Tip wear is typical and can be influenced by many different sources, including poor tablet and tool design, granulation characteristics, improper steel selection for the application, and improper press setup. It is quite typical for inspection technicians to pay attention to the punch cup face. Wear to the cup face is generally not responsible for typical tablet defects such as capping, lamination, and flashing. These tablet defects are more related to punch tip land and outer edge wear. Punch tip edge wear can result from a number of conditions and may cause myriad problems including raised edges on the final compressed tablet, commonly referred to as “flashing” (Figure 1). Tablet flashing, in turn, can cause many other issues after the compression event. When tablets are subjected to de-dusting, the flashed edges may break off and cause rough, poorly defined edges. Tablets with flashing and rough edges can be difficult to film coat and can lead to losing particles adhering to the coated tablet surface. To minimise defects and downtime it is important to understand the most frequent causes of punch tip edge wear.

Figure 1. Excessive flashing on tablet 74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The Main Causes for Punch Tip Wear The Design of Tablets Tablet design plays an integral role in the functionality and longevity of the tooling. Once the innovator travels down the path of tablet design, approval, R&D and scale-up, it must then move to production. When tooling is made for production, it is subjected to increased cyclic stresses than in the R&D phase. If the cup is excessively deep or if the concavity of the cup is steep near the edge (as with some compound cups) and creates near vertical surfaces they will be more susceptible to abrasion. This type of cup design is not as robust as a standard cup and will require more land than its counterpart. Steps to strengthen the edge of the punch cup include reducing the slope of the cup and more importantly, introducing appropriate amount of land into the tablet design. Land unfortunately gets a bad reputation, as many believe additional land will cause soft edges and more difficulty with film coating. Most tool vendors know the value of land and may incorporate it into the design. However, many are forced to use “minimal” land width which is usually only approximately 5% of cup depth. Knowledgeable tablet designers consider that land width should be closer to 10% of cup depth, and occasionally up to 2025% of cup depth, especially for difficultto-compress tablets that require high forces. Any punch tip with no land (razor sharp edge) is considered unwise. Having sufficient land in your tablet design adds strength and wear-resistance, both on the inside of the cup and on the outside of the tip, while creating a more robust tablet and enhancing tablet stability. Formulation/Granulation Characteristics Abrasion due to granulation is a common cause of tip wear and is generally a larger issue in the nutraceutical industry. Nutraceutical products are usually composed of different vitamins and minerals, most of which are quite abrasive, including magnesium, calcium, iron, and zinc. Pharma products with a higher percentage of API typically require higher compression forces which may accelerate tip wear.

Besides degrading the finish of the punch cup and wearing of any embossing or score lines, abrasive ingredients also wear away the land and the outer edge of the punch tip. Once any wear occurs to the edge of the punch tip, particles will become trapped in the increased gap between the tip edge and die wall. Then as the punch moves vertically, the abrasive particles are ground in-between the tip and die wall, accelerating the wear to both tool components. Once this occurs there is no turning back … the “snowball effect” takes over and the wear process is accelerated. Particle size can also affect tip wear. When small particles known as fines are present, they can sift into the gap between the punch tip and die bore. These small particles combined with the cyclic motion of the punches can cause wear on the outer edges of punch tips. While often there is little or no choice as to the components of a formulation, controlling particle size and tip-to-die bore clearance can work together to reduce unnecessary tip wear and extend tool life. Condition of Turret Even though your tooling may be in optimum condition and configuration, problems may quickly arise if they are used in a tablet press with a worn turret. The most common and unrecognised wear point of a turret are the die pockets. Dies are made from harder wear-resistant steel compared to the typical die table and are often installed without the proper installation tools and technique. If the dies are not installed with accurate vertical guidance, keeping them perfectly straight and aligned with the pocket, they will damage the top section of die pocket. Hence this will eventually result in oversized die pockets and loose-fitting dies. On a turret with worn die pockets, it is quite common for dies to fall in halfway, and then have to be driven in to be fully seated. This is an obvious indicator that the top half of the pocket is worn oversize. Dies that just “drop in” are easier to install but consider what happens when the die lock is tightened. The die, and more importantly the die bore, will be pushed out of centre to the punch tips. It is vital that the Winter 2020 Volume 12 Issue 4

Manufacturing die bore be accurately centred to the punch tips. If not centred, the upper punch tip edge may strike the lead-in chamfer at the top of the die upon entry (Figure 2). Repetitive striking will quickly cause wear to the edge of the upper tip (Figure 3). With continued use, this edge wear can cause flashing on the tablets as previously described. The striking can be so severe that it may curl metal of the tip inwards into the cup. This condition is called J-hook and may cause capping and lamination of the tablets. Also, if the die bore is not well centred, the lower punch tip will have contact with the bore on one side with all the clearance on the opposite side. This increased clearance will allow product to sift into the gap, also potentially cause excessive wear previously described. It may also create a defect to the tablet on the lower edge where the tablet band and the cup face meet (Figure 4).

How Can You Prevent Tip Wear? To prevent potential tip wear, good communication with your tooling supplier is vital. By having some forethought and seeking consultation regarding tooling material selection, periodic inspections of critical turret parts and adhering to proper press setup procedures can all work together to mitigate tip wear and extend tool life.

punch tip and die bore, resulting in accelerated wear to the outer edge of the upper punch tip due to contact with the die bore as it enters. Following simple setup procedures such as pre-loading, combined with periodic turret inspections, can greatly reduce unnecessary tip wear.

Analyse Your Press Setup Press setup can be critical in reducing and preventing accelerated tip wear. Pre-loading is the process of twisting the keyed upper punch in the direction of turret rotation while using the upper punch to set the angular alignment of the die bore shape. Pre-loading simulates the rotational forces that the upper punch experiences when the press is in operation. When using shaped/ Figure 5. Tip damage from lack of pre-load

Figure 2. “Drop in” die pushed out of centre by die lock screw causing tip edge contact with the lead-in chamfer of the die

Figure 3. Resulting damage to punch tips

Also, wear in the key slot of the upper punch guides on the turret can allow angular misalignment between the upper tip and the shape of the die bore. This may allow for opposite corner edge wear to the upper tip. This key slot wear can be addressed through the proper setup procedure called pre-loading, discussed later in the article. www.ipimediaworld.com

What Steel Type and Hardness is Right for Your Tooling? Selecting the proper steel type can help to reduce tip wear for abrasive granulates. Reputable tool vendors offer a variety of different steel types for challenging formulations. Abrasive wear-resistant tool steel grades include AISI (DIN) D2 (1.2379), M2 (1.3343), DC-53 and K-340. For very abrasive products, punches can be produced from premium wear-resistant PM grade steels (PM = particle metallurgy), such as, PM-3V, PM-9V and PM-10V. As the hardness increases on premium tool steels so does the abrasive

Figure 4. Off-centre lower face and resulting tablet defect

keyed tooling, pre-loading is often not practised. All presses have clearance in the key slot of the turret, which may increase further as the turret wears. If the punches are not pre-loaded when setting the die alignment, the upper punch will shift angularly as the turret rotates (Figure 8). This creates angular misalignment between

wear-resistance, but it must be noted that the impact toughness decreases somewhat. Some steels are required to be cryogenic tempered (-184°C, -300°F) to increase wear-resistance and receive full return on investment. If your vendor does not offer this tempering process, the steel type or your tooling vendor should be reconsidered. INTERNATIONAL PHARMACEUTICAL INDUSTRY 75

Manufacturing It is the combination of each steel’s unique chemistry and the related heat treatment process that allows the different steel types to attain their advantageous unique mechanical properties. This makes them ideal for the wear-resistance needed for abrasive formulations, yet still allows them to support the compression forces needed for the high-stress, high-cycle loading conditions of tablet compression. Design of Tooling and Their Configuration The rotary “B” tool was designed more than 120 years ago, during the early stages of the industrial revolution, with the “D” tool design quickly following. Refinements, often called tool options, are commonly made to the basic tool design for better performance and to extend tool life. One of the most commonly used options is tapered dies. This option is typically used to resolve capping and laminating issues, and to make it easier to eject the tablet from the die. Aside from resolving these tabletting issues, tapered dies can help offset mild turret misalignment by guiding the upper tip into the bore, bypassing the potential contact with the lead-in chamfer. The amount and depth of taper can be customised and machined to meet individual tabletting needs and press setup requirements. Alignment of Turret Most turrets are manufactured in three sections. When a press experiences a sudden stoppage event or accident, this can shift a section out of alignment. If any section of the turret is out of alignment, this can lead to unnecessary contact between the punches and dies resulting in wear to the punch tips. Periodic turret inspections can mitigate this by identifying that a turret is no longer properly aligned. Tolerance Stacking Tolerance stacking refers to the condition

where the dimensional and geometric tolerances on assembled parts (punches, tips, die O.D., die I.D., die pocket, punch guide, key, and key slot) combine to create the worst possible fit condition. In addition to alignment of critical components on the turret, tolerance stacking on the turret and tools combined, can also affect tip-to-die alignment. When all these tolerances are at their extremes, it creates a situation where punch-to-die contact is possible, even when all components are comfortably within tolerance. Inspecting the Tip for Punch Wear While proper inspection can help prevent many commonly encountered tabletting defects, the practice of punch tip inspection often only includes checking the size of the tip by measuring with a micrometer or calipers. Since the measuring anvils (contact surfaces) of these instruments are 3-6mm (0.120-0.250”) wide, they only check for the largest dimension. Often wear to the very edge of the punch tip is relatively small, undetectable using traditional measuring equipment and techniques and may not be easily observed by unassisted visual inspection. Some form of magnification is necessary to properly and thoroughly inspect punch tips for edge wear. The good news is that tip wear can be easily inspected using a horizontal optical comparator. Visual inspection for tip edge wear is quite challenging, especially without magnification. A horizontal optical comparator (often called a comparator) is an apparatus that applies the principles of optics to the inspection of manufactured parts. In a comparator, the magnified silhouette of a punch tip is projected upon a screen, usually at 10x, but can also be at 20x or even greater magnification. The wear of the part can be easily inspected, and

even measured against prescribed limits. Unfortunately, a comparator is not used often in the industry but is a valuable piece of equipment. Conclusion Punch tip edge wear can come from a variety of circumstances and may cause significant production quality-related issues. It is important to understand and know how to identify the most common causes of this type of wear. Punch tip edge wear can be difficult to detect because traditional methods of inspection are ineffective. Fortunately, the use of a horizontal optical comparator makes the inspection job easy – and fast. The most versatile piece of inspection equipment, a comparator provides a bright, crisp image for error-free inspection of the punch tips. Avoiding punch tip edge wear when possible, and quickly identifying when it does occur, will provide great benefits to the quality of your tablets and to your production operation.

Bill Turner Bill Turner is the Technical Service Manager of Tooling and Tablets at Natoli Engineering Company, Inc. His previous positions at Natoli were Engineering Manager and Tablet and Tool Designer for 20 years, and Technical Customer Service Representative for more than 15 years. He educates and trains Natoli sales and service staff and conducts industry training seminars regarding tablet design, tool design, and troubleshooting.

Kevin Queensen Kevin Queensen is a Mechanical Engineering and Technical Service Support at Natoli Engineering Company. His focus is primarily on specialty tablet/tooling designs along with determining new max compression force calculation methods and performing Finite Element Analysis (FEA).

76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Winter 2020 Volume 12 Issue 4

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Packaging

Exploring Pharmaceutical Packaging’s Top 2020 Trends Over the last decade, the pharmaceutical packaging landscape has begun to change at an accelerated pace in order to keep up with the unprecedented growth in the global demand for safe, more affordable medicines. Market analysts predict that the pharmaceutical industry is set to increase its value to $1.5 trillion by 20231. Keeping pace, the proportionate growth of the pharmaceutical packaging sector is being driven by several new trends across the pharmaceutical and healthcare market, as well as the forces driving pharma’s commercial interests and the increasing importance being placed on patient-centric products. The introduction of new technologies has paved the way for companies to explore more innovative solutions to this market demand, as well as discover new ways to improve their operations and drive efficiencies across the supply chain. In this article with International Pharmaceutical Industry, Marcelo Cruz, Director Business Development and Marketing at Tjoapack discusses the current market landscape and the key benefits of building strategic partnerships with specialised contract packaging organisations (CPOs). Injectable and Self-drug Delivery One key area of growth for the pharma and biopharma market has been parenteral drug delivery and new ways for patients to self-administer these dosage forms. Market analysts project the injectable drug delivery market to grow in value from $362.4 billion in 2016 to $624.5 billion by 20212. This growth has further propelled market demand for suitable packaging solutions to protect the products from point of manufacture to patient. The major factors responsible for driving growth in this market are the increasing use of biologics, the prevalence of chronic diseases and effective treatment options available via parenteral delivery, and the need to increase both the effectiveness and safety of parenteral therapeutics to enable 78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

safe delivery in a non-clinical environment. These factors have increased the demand for devices such as safety syringes, pre-filled syringes, and autoinjectors and, as a result, contract packaging organisations who can manage the complexity required by these products. Pre-filled Parenteral Administration on the Rise Recent reports projected the global prefilled syringes market to reach $10.57 billion by 2027, climbing at a compound annual growth rate of 10.5% during the forecast period3. The rising shift towards using prefilled syringes to deliver biologics and biosimilars will continue to drive market demand, particularly as these therapeutics are explored in response to the current pandemic. In addition, the already proven application of biologics in targeting diseases with limited treatment options such as some types of cancer, autoimmune diseases, and other non-communicable diseases, will increase demand further. Packaging Capabilities and Expert Support Traditionally, packaging has been seen as an extension of manufacturing operations and as such, many contract development and manufacturing organisations (CDMOs) have integrated packaging operations that allow them to provide end-to-end manufacturing and commercialisation solutions for their customers. However, with high demand and more complex products entering the drug pipeline, companies are not only struggling with capacity, but are also increasingly seeking the specialised packaging capabilities and dedicated capacity that can only be provided by experienced contract packaging organisations (CPOs). CPOs are taking a more prominent role in the pharmaceutical supply chain as the demand for economic, efficient packaging services which can be tailored based on product requirements continues to grow. Grand View Research projects the global pharmaceutical packaging market to reach $188.79 billion by 2027 at a compound annual growth rate (CAGR) of 8.5% over the forecast period4.

In addition, the increasing demand for patient-centric medicines and personalised therapeutic modalities will further augment the demand for advanced, flexible pharmaceutical packaging solutions and services for decades to come. Specialised Packaging Partners: Prepared for Performance CPOs, by their nature, have operations entirely focused on delivering this critical step in the drug supply chain. Their indepth knowledge of market requirements and the ability to tailor solutions to meet market and customer-specific needs mean that CPOs can add increasing value over a product’s entire life cycle. Whether drug products are distributed in vials, combination devices or in complex personal medicine kits, the demand for experienced CPOs ability to tackle these requirements and adopt a solution-focused approach to overcome potential product packaging challenges is high. As with the contract services industry in general, CPOs are evolving from transactional service providers to more strategic and integrated commercial partners. Value Chain Expander, Supply Chain Connector Within the context of global regulatory compliance, packaging plays a critical role in connecting the final links in the pharmaceutical supply chain. With an exclusive focus on packaging’s value chain, CPOs can now provide more strategic support well beyond the traditional primary and secondary packaging operations. Dedicated CPOs offer a broader range of services, ranging from primary packaging, quality assurance and complex assembly, to global cold-chain custody logistics and international regulatory support. As such, the role of packaging in pharma is expanding to cover the entire packaging value chain, and its role in serving pharma’s strategic and patient interests will therefore continue to evolve. Postponement Packaging Driving Complexity Along with adapting to increasingly complex packaging requirements, as the Winter 2020 Volume 12 Issue 4

Packaging to fully realise the broader impact on supply chain management. Final Thought Engaging with competent CPOs as strategic outsourcing partners can allow companies to reap the benefits associated with years of packaging expertise when it comes to catering for more complex products. As the demand for parenteral delivery and self-administered medication continues to rise, particularly given the restrictions imposed by COVID-19, these relationships will become even more important when developing fit-for-purpose solutions. Access to this level of expertise, along with new approaches to supply chain management such as postponement packaging, will inevitably allow pharma and biopharma companies alike to ensure safe and steady supply, improve efficiencies by reducing costs and waste and ultimately reduce the rising cost of healthcare for the end user. last production step before a product starts it final journey to market, CPOs are also well placed to help develop solutions to supply chain inefficiencies. For example, the concept of postponement packaging is being explored to reduce forecasting inaccuracies and the resulting repackaging work required. In traditional packaging, a CPO provides bulk packaging services, ensuring large volumes of pharmaceutical product is primary and secondary packed ready for a specific market. The product is then shipped to the country it is intended for, and likely stored in a warehouse until it is needed. Whilst widely adopted, this approach can be wasteful. Volatile demand can either stall distribution and as a result, generate high inventory costs often across multiple locations, or mean extensive repackaging work is required to make supply intended for one market suitable for another. In recent years, companies have started exploring the idea of late-stage customisation or postponement packaging. Essentially blank product components such as the blister packs, boxes and leaflets are produced and stored in a central warehouse. When demand arises, products can be customised, for example with local language requirements, and then shipped to a specific market. Within well-ordered postponement operations, a product can usually be shipped within hours of receiving the order. www.ipimediaworld.com

Postponement packaging has huge potential to improve supply chain efficiency and reduce waste and ultimately costs. Given the variety of regulations, the advent of serialisation and languages across international boundaries, postponement is becoming an attractive option for companies. However, with so many different shapes, sizes and formats for medicines, it can be a complex process to implement postponement strategies across global supply chains, making strategic partnerships with CPOs capable of delivering this service a logical alternative. The Benefits of Staying Ahead of the Curve Postponement packaging has huge potential to help pharma transform the way that healthcare is delivered to patients. Personalised, patient-specific packaging is coming, and postponement could allow companies to quickly and efficiently respond to very specific needs. Furthermore, drug products could potentially eventually even be delivered direct to the patient, ultimately streamlining the supply chain. Companies who take a proactive approach to developing their packaging solutions with third-party providers and incorporate new approaches into their operations will inevitably find themselves in a better position when these new digital processes become more widely adopted. It is important that the industry continues to drive these developments forward in order

REFERENCES 1. 2. 3. 4.

https://pharmaceuticalcommerce.com/businessand-finance/global-pharma-spending-will-hit1-5-trillion-in-2023-says-iqvia/ https://www.marketsandmarkets.com/MarketReports/injectable-drug-delivery-market-150. html https://www.fortunebusinessinsights.com/ industry-reports/prefilled-syringes-market101946 https://www.grandviewresearch.com/pressrelease/global-pharmaceutical-packagingmarket

Marcelo Cruz Marcelo Cruz is Director Business Development and Marketing at Tjoapack. With over a decade of experience in the pharmaceutical industry, and over 15 years of driving global strategic sales, marketing, business and product development, Marcelo is responsible for strategy and organic growth activities at Tjoapack. In his role, he also leads the development and implementation of inbound and outbound marketing strategies to accelerate lead generation and drive the wider commercial strategy for the business.

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Packaging

In Highly-regulated Industries your Labelling Must Speak for your Product – Compliance is Non-negotiable! Computerised systems validation is essential for medical device and pharmaceutical manufacturers. Here, Beth Peckover, VP Global Delivery at Kallik, pinpoints the three areas businesses need to get right to ensure computerised systems used for labelling meet all GxP requirements set out by industry regulators. Validation of computerised systems is a non-negotiable requirement enforced by regulators such as the FDA in the US, EMA in Europe, TGA in Australia, and HSSC in Canada. The ability to demonstrate adherence to appropriate practice and processes that underpin a quality-driven, risk-based approach to computerised systems validation is a pre-requisite to being able to operate in any highlyregulated market, including medical device and pharmaceutical manufacturing. As part of GxP regulations, manufacturers involved in these highlyregulated industries must adhere to Good Manufacturing Practices (GMP) defined as “a system of processes, procedures, and documentation that help ensure that products are consistently produced and controlled according to quality standards”. It’s necessary to zero in on GAMP 5 guidance for GxP computerised system compliance and validation – this is the standard regulators work to.

are not willing to bear the validation burden of implementing a new system. Validation of newly-built computerised systems is an involved task. It can take several months to complete successfully. Usually, it entails performance, operational and infrastructure qualification of regulated systems used to manufacture medical devices and pharmaceuticals. Product Recalls Carry a Heavy Cost Correct labelling is a key requirement for manufacturers of medical devices and pharmaceuticals. Analysis of FDA drug recalls shows that, between 2017 and 2019,

14.9% of recalls occurred due to labelling issues. Recent statistics also highlight that 9% of global medical device recalls were due to label errors, equating to over one million items. The FDA explains that medical device manufacturers must incorporate several elements in their quality assurance (QA) programme that relate to labelling in order to meet the GMP requirements of quality system regulation. The potential damage to consumers and company reputation due to a recall from not meeting these standards is extreme – patient safety can be put at

Outdated Labelling Systems are in Need of Overhaul Enterprise labelling is a classic area where computerised systems play a vital role in providing the highest quality and most accurate description and branding of products, such as medical devices and pharmaceuticals. Meeting these regulations requires applying the best quality management systems and standard operating procedures (SOPs) to the design, development and delivery of labelling software. Medical device and pharmaceutical labelling is ripe for modernisation, but many manufacturers are still using outdated systems for product labelling because they 80 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Winter 2020 Volume 12 Issue 4

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Packaging risk and businesses shut down because of incorrect labelling. Putting in Place a Bespoke Computerised System for Labelling Requires Significant Effort But validating a new computerised system is an involved task. Many medical device or pharmaceutical manufacturers find themselves in a catch-22 situation when assessing their labelling system options. On the one hand they may have a legacy labelling system, which is in need of updating but is validated – on the other, developing a new system requires full validation from scratch. Developing a system in-house puts the entire validation burden on the medical device or pharmaceutical manufacturer themselves. If a manufacturer cannot trace the driving factors behind why a computerised system was built or selected, or how to satisfy and test them, then it becomes challenging to establish whether the system is fit for purpose. The lack of a proper definition of why a particular system is in place can lead to inconsistent and incomplete computerised systems, as well as feature creep gaps when deploying the system. If a manufacturer does not document their requirements and testing process clearly, it becomes impossible to claim to have a compliant system in place.

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Ongoing Compliance Adds Further Cost and Process Headaches Manufacturers are likely to incur high costs and spend more effort in the validation of their own bespoke on-premise applications when labelling processes update or develop – because the responsibility of performing the qualifications after each release is on the organisation themselves. And constant rule assessment doesn’t stop there. Requirements must be kept up to date throughout a software system's lifecycle. To ensure all regulations are followed through on a regular basis, manufacturers are required to establish standard operating

procedures and a lean governance structure to interpret all regulations and requirements on the organisational level, and ensure action is taken where appropriate. Validation-ready Alternatives Thankfully, there are pre-validated thirdparty solutions which can ease the compliance pressure of having a modernised, best-practice labelling system. Such a solution should build and demonstrate GxPcompliant processes across the creation, review, print and publication of all product and package labelling, in particular, software and processes that align to GAMP 5 quality guidelines and 21CFR Part 11 regulations.

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Packaging

With this in mind, there are three critical areas to consider when setting criteria for a validated enterprise labelling system.

It’s possible to ‘outsource’ the majority of these activities to the supplier, leaving only the execution of the UAT to the manufacturer.

1. Validation straight out of the box An alternative option to developing a bespoke solution in-house is to leverage existing software on the market. This can be locally installed ‘on premise’, but having the software delivered in a software as a service (SaaS) model can offer significant benefits when it comes to efficient validation, both during the initial implementation and as part of the ongoing maintenance of the system.

3. Regulated industry alignment brings compliance expertise and collaboration Working with a trusted software partner brings industry-wide compliance expertise and knowledge. While every medical device or pharmaceutical manufacturer will have their own unique processes and business requirements, there are common industry challenges and scenarios which medical device and pharmaceutical labelling software providers will have encountered before. An industry-specific partner should speak the language of GxP and GAMP 5, with in-house experts dedicated to continuous education and training to stay up to date with latest guidelines and best practices.

By using software which is hosted in the cloud, the software provider takes responsibility for the IQ/OQ validation activities with each software release, meaning the manufacturer minimises their own validation efforts and cost with a ‘validation-ready’ software system. 2. Transfer the validation burden to your supplier Beyond delivering a validation-ready system, a software supplier who is experienced in delivering validated software to regulated customers will have the capabilities to be able to further relieve the burden by taking responsibility for other aspects of the validation if requested, such as creating a traceability matrix or writing the test scripts to be using during user acceptance testing (UAT). www.ipimediaworld.com

This enables that partner to collaborate directly with a manufacturer, consulting with them on how changes to labelling may impact compliance going forward and discussing steps required to make sure new processes adhere to current best practices. Guarantee a Validated Platform The speed of change in information technology, combined with constantly evolving manufacturing processes, makes adhering to GxP and GAMP 5 regulations in highlyregulated industries a continuous task. This quickly becomes unsustainable when a manufacturer weighs up the compliance

pros and cons of deploying a bespoke onpremise system for enterprise labelling. Partnering with a reliable software provider becomes a critical factor in guaranteeing computerised systems validation, creating a platform for compliance with industry mandates now and into the future. The result is a collaborative and efficient process that satisfies compliance and eliminates risks and delivers huge value to your manufacturing processes.

Beth Peckover As VP of Global Delivery at Kallik, Beth Peckover is responsible for ensuring that Kallik technology delivers transformational results through appropriate project planning and change management. She has previously worked as a business consultant at DXC, CSC and Atos Consulting, and has a wealth of experience of working closely with global organizations in the chemicals industry, life sciences, and other heavilyregulated markets. Beth is highly skilled in business trans-formation, management consulting, and business process improvement. INTERNATIONAL PHARMACEUTICAL INDUSTRY 83

Logistics & Supply Chain Management

Working Together to Beat the Drug Counterfeiters

Alf Goebel, CEO of advanco, which was acquired earlier this year by Parabellum Investments, led by founder and CEO Rami Cassis, analyses how pharmaceutical serialisation providers can step up the fight against drug counterfeiting by adopting a more open and agile supply chain. The problem of counterfeit medicines remains as the new vaccine is rolledout across the globe. With a new, mutant strain of COVID causing global concern and ongoing issues across the world, the virus remains on the global consciousness, the most high-profile and damaging epidemic in living memory. We are all living with its consequences, every day. The pandemic is constantly evolving; therefore, the exact long-term consequences are still not clear. However, what we do know is that it needs to be stopped in its tracks as soon as possible. Not only is the pandemic responsible for a high number of deaths across the globe, but its repercussions are also expected to be felt by generations to come from economic and business fallouts. While we cannot prevent dangerous viruses such as COVID-19 emerging, we need to do all we can to stamp out their damaging effects on society. That is why the world should be grateful to those who have developed a vaccine. A vaccination programme is now underway across the globe, thanks to a mammoth effort from the pharmaceutical sector which has defied all odds to produce a vaccine in record time. Several efforts have helped this mammoth journey, including the US government’s Operation Warp Speed initiative, which has pledged $10 billion and aims to develop and deliver 300 million doses of a safe, effective Coronavirus vaccine by January 2021. The World Health Organization is also coordinating global efforts to develop a vaccine, aiming to deliver two billion doses by the end of 2021. As it points out, vaccines 84 INTERNATIONAL PHARMACEUTICAL INDUSTRY

save millions of lives each year by training and preparing the body’s natural defences – the immune system – to recognise and fight off the viruses and bacteria they target. If the body is exposed to those diseasecausing germs later, the body is immediately ready to destroy them, preventing illness. The World Health Organization estimates that immunisation currently prevents up to three million deaths every year from diseases like diphtheria, tetanus, pertussis, influenza and measles. There are now vaccines to prevent more than 20 lifethreatening diseases, with COVID-19 being the latest to join the list as a vaccinepreventable disease. It can typically take 10 to 15 years to bring a vaccine to market, with the fastest-ever – the vaccine for mumps – still requiring four long years in the 1960s. Vaccines go through a three-stage clinical trial process before they are sent to regulatory agencies for approval – which can be a lengthy process itself. In short, we should be thankful to the agile teams that have produced a vaccine in record time. We just need to ensure now that attention is given to quick production, attention will then need to focus on quick production, and the agile and smooth distribution of the doses across the entire world. Just as COVID-19 is a worldwide pandemic, the global pharmaceutical sector will need to coordinate well to ensure the vaccine is rolled out in the most efficient manner possible. Problems Caused by Drug Counterfeiters While potential vaccines are being developed, there is a very real issue that we all need to be aware of. It is predicted that 10% of pharma products worldwide are counterfeit, with British researchers estimating that the death toll caused as a result could increase to 10 million people by 2050. Already, the global counterfeit drug market exceeds an eyewatering $75bn – and as the COVID vaccine is rolled-out, these figures are set to explode over the coming years. Further estimates by the World Health Organization show that between 72,000 and

169,000 children may die from pneumonia every year after receiving counterfeit drugs, and that fake anti-malarial medication might be responsible for an additional 116,000 deaths. According to the World Health Organization, counterfeit medicines are medicines that are mislabelled deliberately and fraudulently regarding their identity or source. Fake birth control pills, cough syrup for children that contained a powerful opioid, and anti-malarial pills that were actually just made of potato and corn-starch are just a few examples of poor-quality or counterfeit medicines they have identified in recent years. All kinds of medicines have been counterfeited across the world, both branded household names, and generic, own-label ones. In addition to the shocking amount of deaths, illnesses and disabilities caused by fake drugs across the world, the impact of counterfeits on legitimate pharmaceutical producers is endless. They include lost sales, costs of protecting brands, loss of reputation, the potential cost of managing the disposal of counterfeits and litigation costs involving counterfeiters and possibly people who were unknowingly victimised by counterfeits. Counterfeit pharmaceuticals can result in squandered health resources, not only for individual patients, but also for international humanitarian organisations, NGOs and national government programmes. Counterfeiters divert resources away from genuine treatment, robbing limited health budgets of already scarce resources. At the same time, counterfeits can mean losses in corporate taxes and VAT, increased regulatory and enforcement costs for securing the supply chain, and higher healthcare costs to treat the adverse effects of fake drugs. Environmental problems – a major topic for most industries across the world nowadays – can also be exacerbated by drug counterfeiters. As you would quite rightly expect, the pharmaceutical sector Winter 2020 Volume 12 Issue 4

Logistics & Supply Chain Management must abide by strict guidelines to meet environmental protection standards and reduce the amount of chemical waste and by-products that they produce. In direct contrast, the producers of forged drugs often completely disregard the effect that the illegal disposal of toxic chemicals and waste materials can have on the environment around them. The overall problem of counterfeit pharmaceuticals is so severe that the sector is, quite rightly, stepping up the battle against the fraudsters by ramping up essential serialisation services to caveat the efforts being made to develop a COVID vaccine. The solution needs to be based around achieving a much tighter and a much more agile track-and-trace solution. To do this, the hardware and the software among different vendors needs to be much more aligned and should work much more closely together. Although, on the surface, this might seem a bold step within the pharmaceutical sector, we are already seeing some inroads being made, which will help to provide a solution to

the dependency on the production of medication in China – and any potential shortage because of the ongoing effects of COVID-19. Strategic Partnerships We are seeing partnerships formed, alliances which are overturning pharmaceutical track-and-trace from a rigid to an agile model, encouraging industry openness while significantly lowering the cost for serialisation services. One such partnership was announced earlier this year between ourselves and Syntegon. Developments such as these are bringing tremendous value to pharmaceutical companies by significantly lowering the total overall cost and preventing a lock-in effect, allowing vendors to choose different machines from different suppliers, if they choose to do so. Developments such as these will open out the whole serialisation sector – an essential move to allow us to channel our collective efforts into both stepping up the fight against the drug counterfeiters and optimising the supply chain.

Introducing Industry Standards Following on from the introduction of powerful strategic partnerships, the implementation and encouragement of open standards is crucial. Therefore, the establishment of OPEN-SCS, the industry body responsible for promoting common standards across the pharma sector, is another solid step forward in the fight against fake medicines. OPEN-SCS, which was formed in September 2014, is a working group in the OPC Foundation, whose success speaks for itself. Today, there are more than 4200 suppliers who have created more than 35,000 different OPC products used in more than 17 million applications. The estimate of the savings in engineering resources alone is in the billions of dollars. OPEN-SCS, of which advanco was a founder member and remains a steeringboard member, has already contributed enormously to the fight against fake medicines. It has officially released three key documents – a use case document which explains typical uses of serialisation and how it fits into the production

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Logistics & Supply Chain Management

environment, a specification document that defines the specific services needed for a sterilisation solution and how the EPCIS and GS1 specifications should be used in interoperable solutions, and finally the OPC UA Serialization Companion Specification which defines in extensive detail how to use OPC UA to provide an interoperable solution that will seamlessly fit into a complete serialisation system. Documents such as these provide an invaluable reference point for the serialisation sector. Not only do they provide a blueprint to how we can arrive at an open, agile supply chain, they also allow us all to work towards lowering the overall total cost of ownership (TCO). Expanding the Importance of Serialisation (Track-and-trace) In the early years of serialisation in the pharmaceutical sector, vendors were busy learning about the sector and focusing on how their own solutions would fit. Indeed, the return on investment for serialisation was still being calculated – it was seen as a basic cost factor and little more else. Fast-forward to today and serialisation is now viewed as an essential tool to protect not just patients, but everyone in the valuechain, against falsified and dangerous drugs and medicine – especially while we continue to search for a COVID vaccine. And it is important to point out that the pharmaceutical sector could be blazing a trail for other industries. For example, food serialisation would technically allow any outbreaks of food poisoning to be nipped in the bud immediately, as 86 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the source of all manufacturing could be spotted in an instant. It could also be used in the fight against counterfeiting in most manufacturing sectors, not just the pharmaceutical industry. The COVID Effect Although we have now seen a breakthrough in the fight against COVID-19, the counterfeiters are sure to continue their illicit trade. Therefore, in today’s climate, the need for a watertight, reliable supply chain has never been greater. Moving forwards, trends to look out for include digital transformation in the serialisation sector, with an increased usage of barcoding helping to reduce errors in dispensing in stressful periods. Vaccines and test-kits developed to detect the virus will need to be supplied across the world quickly and efficiently – which require more standardisation. Even when more countries will change production strategies and localise, most of the drugs will continue to be manufactured in China and India, again emphasising the need for an efficient distribution system. Capital Injection We are seeing increased capital being injected into firms to provide the extra backing and support needed to elevate them onto the global stage. Such market movements are a clear indicator of the importance of getting pharmaceutical track-and-trace in the very best shape possible, providing the pharmaceutical sector with essential services, ready not just for the introduction of an essential COVID vaccine, but also

to provide the overall drugs sector with a watertight method of weeding out the counterfeiters. Conclusion The pharmaceutical serialisation sector is currently in the middle of a transformation as it plays an important part in battling the very real, increasing problem of counterfeit drugs. An increased cash injection, the formation of strategic alliances and the formation of important industry standards are just some of the ways that the sands are shifting. These are all combining into the overall effect of opening up the serialisation industry, moving it from the previously rigid model to a much more open and agile model. Never before has such a change been needed, a change that will be of vital importance as we all work together to find a solution to COVID-19.

Alf Goebel Alf is a senior enterprise software sales and marketing executive, with over 25 years’ enterprise software industry experience. He has strong operational experience, specialising in high-growth businesses in Europe and the US. He has extensive experience with Global Partnerships SAP and Lupo Ventures, and has held senior executive positions at a number of leading technology companies, including Snow Software, MSC Software and Software AG. Winter 2020 Volume 12 Issue 4

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COVID-19 Vaccine: Unique Distribution Challenges Call for a Unique Monitoring Approach The COVID-19 vaccine will leverage new distribution approaches, so monitoring its physical integrity through the supply chain from manufacturing to point of use will also require fresh thinking. With a lot at stake for all parties involved such as states, regulators, pharmaceutical companies and the general population, the margins for error in delivering a vaccine promptly and with uncompromised efficacy have never been tighter. COVID-19 Vaccine’s Unique Integrity Challenges Distributing the COVID-19 vaccine will be unlike previous vaccine distribution efforts due to its scale and urgency. These key factors will provide new challenges for pharmaceutical companies and the logistics companies that will support them. 1. Unprecedented Speed to Market Multiple COVID-19 vaccine development efforts are happening today at a swift pace; that is expected to accelerate throughout manufacturing and distribution. Unlike other vaccines such as the hepatitis, polio, or even the seasonal flu vaccines, test data on temperature excursions affecting the efficacy will be limited and the COVID-19 vaccines will have to be shipped under ideal conditions. Therefore, speed to market and maintaining cold chain integrity will be bigger considerations for all actors in

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the supply chain than distribution cost or logistics efficiency. 2. Unfamiliar Shipping Networks The demand for the COVID-19 vaccine is not specific to a certain demographic or region, unlike traditional vaccines. Vaccine supply chain actors will be shipping to new customers through unfamiliar trade lanes, using new transporters, and using new shipment modes. Vaccines will be distributed to new or unfamiliar storage facilities, in geographies that may not be familiar with modern cold-chain management. The vaccine supply chain will be stretched to meet demand at a national, continental and global scale requiring multi-, inter-, and intra-modal means of shipping all without typical supply chain planning and evaluation periods. 3. Unmoderated Scale-up COVID-19 vaccines will require shipping at scale from day 1. Unlike traditional vaccine supply chains which begin with lower doses shipped to established regions, the COVID-19 vaccine will require full-scale manufacturing and distribution from the start. When combined with the use of unfamiliar networks, the amount of risk entailed in the process is multiplied. These unique challenges will force the industry to rethink traditional approaches to vaccine cold chain and shipment monitoring. COVID-19 vaccine manufacturers and shippers cannot settle for accepting

or rejecting goods upon arrival and they cannot rely on touchpoints in the chain of custody to provide information. They will need to act in real time, take pre-emptive measures and guide people downstream proactively. The Monitoring Approach Needs Fresh Thinking The COVID-19 vaccine supply chain requires a top-down monitoring approach that doesn’t rely on the touchpoints in the chain of custody for information. It requires real-time signals generated by the vaccine shipments which can be shared with all actors within the chain of custody, much like a reverse blockchain system for physical integrity. However, current vaccine cold-chain monitoring methods largely work in a bottom-up manner with many dependencies, making visibility time delayed, incomplete, or unverifiable. 1. Time-delayed Visibility Data loggers can track the temperature of a vaccine shipment accurately, but the data is typically collected only upon arrival. The captured data is manually uploaded in most cases, creating room for error that could impact the efficacy of the vaccine if some vials slip past the distribution chain. Even if the data is collected without lapses, its value is restricted to determining whether to accept or reject a shipment upon arrival; it cannot prevent a stockout as it cannot provide early warning signals.

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Logistics & Supply Chain Management 2. Incomplete or Unverifiable Visibility While GPS tracking solutions can provide vehicle-level visibility, it cannot provide condition and does not work for multimodal shipments. Visibility aggregators have done some work in aggregating ELD, flight, and vessel data to offer a level of unified shipment visibility but this data still does not provide location and condition that is truly live or verifiable. There could be lanes or touchpoints which are not integrated. There could be errors and delays caused due to manual updates especially in multimodal shipping scenarios like air shipping.

and shippers in control from manufacturing to point of use.

technology stack enabling a single-pane experience.

It will achieve this by integrating firsthand location and condition data collected in real time using NIST-certified sensors that work multimodally, globally, and at a package level – indoors, outdoors, and intransit. It will also leverage sensors that are purpose-built for air cargo monitoring and are compliant with all regulations including those that pertain to the quantity of sensors usable per airway bill, whilst providing unrestricted shipment granularity.

With this robust end-to-end monitoring approach, regulators, manufacturers, distributors and third part logistics companies in the COVID-19 vaccine supply chain, can address the unique challenges.

The monitoring approach fit for COVID-19 must address this through real-time ondemand goods and asset monitoring, creating a push mechanism that gives vaccine supply chain actors uninterrupted end-to-end visibility.

This approach will also be CAPEX-free and incorporate management of reverse logistics where required, thus enabling vaccine manufacturers and shippers to scale without upfront investments or sensormanagement hassles, in a truly on-demand manner that is deployable in days.

A Vaccine Monitoring Approach Fit for COVID-19 The ideal approach must enable actors in the COVID-19 vaccine distribution chain to own their visibility initiative across all touchpoints. It should provide real-time, on-demand signals that put vaccine makers

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Finally, and crucially, the ideal approach will leverage first-hand sensor data to help all actors in the vaccine logistics chain of custody own their visibility across all touchpoints, whilst staying 21 CFR Part 11-compliant and interoperable with existing

Vidya Subramanian Vice President of Products at Roambee. An energetic leader and results-driven executive with over 15 years of solution delivery experience, Vidya is responsible for product strategy, product delivery, and product mana-gement with a singular focus on product-market fit. Before Roambee, Vidya held senior leadership roles at KeyTone Technologies Inc, Global Asset Tracking UK Ltd, Plexus Technologies Inc., KPMG Consulting, Unisys, and PriceWaterhouseCoopers (PwC).

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How the War on COVID-19 is Driving Innovation in Temperature-controlled Packaging – and Beyond It has been a tough year. At times, throughout 2020, it has felt like we have been facing a battle with little end in sight. Although this may seem like an overly dramatic statement, the challenges brought by COVID-19 have invoked all kinds of wartime comparisons – we talk about health professionals on the ‘front line’, in the UK lockdown has rekindled memories of the ‘blitz spirit’, news conferences speak about ‘defeating’ the infection as if it is a physical opponent, with some going as far as to label the virus as an ‘invisible enemy’. And, of course, the grim reality of the tragic deaths caused by the pandemic regularly reminds us that lives are at stake. Yet in a switch in perspective, we can also seek a more positive parallel between the last few months and times of war: the inevitable and necessary acceleration in innovation – and innovative thinking – that is driven by the need to overcome a crisis. In this article, I want to outline how I believe the vital work being done to defeat COVID-19 is sparking innovative thinking and driving change, by looking at the pharma packaging sector both in terms of method of delivery and sustainability. It is also proving what can be done, with collaboration, focus and the will of humanity if we really want to make a change. Of course, I am not seeking to deny or downplay the clear challenges and tragic impact on so many that COVID-19 has ultimately brought with it. However, I want to focus on what could be the post-virus positives, those takeaways that I personally feel are so important to keep focus in times like this. We all need a potential silver lining when things feel so dark. Just as the technological innovations of the Second World War led to the moon landings and the social impact of World War One brought a revolution in housing, the response to COVID-19 will drive 90 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Right now, as the world holds its breath for news of the successful development of a viable vaccine, the pharma industry is very much in the public’s thoughts.

scientific advances and societal change, ultimately bringing about improvements to benefit future generations.

the vaccines, syringes to deliver them, and on efforts to ramp up manufacturing and capacity.

Let’s return to the wartime analogy. There is no doubt that the horrors of 20th century conflicts drove medical and scientific advances. The challenges of treating troops in the field resulted in surgical advances. World War I brought about the regular use of blood transfusions. World War II expanded the use of antibiotics, which were mass produced for the first time. Vietnam saw the introduction of frozen blood products, and the use of antiseptic and antibiotic impregnated dressings.

The effects of this vital research – and the challenging times we live in – are also tangible in attitudes to packaging, delivery chains and business practices. For a start, the advent of lockdowns has accelerated the growing trend for home delivery and home working. The 21st century was already fast becoming an era of doorstep delivery, thanks to the growth of online shopping and global brands such as eBay and Amazon.

These were all life-saving advances triggered by crisis and, as we face the COVID-19 pandemic, innovation has once again been accelerated. In pharma, of course, that vital work can be most readily be seen in the more than 150 vaccines currently being developed across the globe at an accelerated pace, backed by eye-watering levels of funding. In the US, it has been reported that the federal government has allocated more than $9 billion to develop and manufacture candidate vaccines. More than $2.5 billion more has been earmarked for vials to store

When we first began our business producing temperature-controlled packaging, online shopping and commerce was seen as a novelty that was mistrusted by many – but we have seen it grow and grow. Enforced lockdowns have driven this trend further and faster, with home working and courier delivery growing exponentially. It could be argued that, in the lockdowns of 2020, online commerce finally came of age. In pharma, that has meant a need for passive temperature-controlled packaging solutions that can deliver medicines reliably to the doorstep – thanks to a sudden boom in online pharmacy, driven by the pandemic. Winter 2020 Volume 12 Issue 4

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It has been reported that there are the more than 150 COVID-19 vaccines currently being developed across the globe at an accelerated pace.

Elsewhere within the sector, we have seen clinical trials switched to the home setting, providing efficiencies for firms developing treatments while ensuring patients do not have to travel. The response to the pandemic is driving innovation, and challenging the ‘way things always have been done’, to perhaps looks at ways to improve. This has been reflected in more online pharmacies and life sciences firms enquiring about the benefits of sustainable packaging solutions. Again, this reflects the recent acceleration of an already growing trend. Improvements in passive temperature-controlled packaging have been attracting interest from the pharmaceutical sector for some time, not least because of the reliability it provides in challenging delivery chains – for example delivering into rural or remote areas, where refrigerated transit is difficult. For passive solutions, hard scientific data has proven to pharma buyers that sustainable options now outperform manmade options such as polystyrene, and they have been beginning to take notice. This acceleration of a trend indicates that the pandemic is not only driving direct innovation but innovative thinking too, with firms choosing to bring forward a change to a sustainable packaging option. The pandemic is forcing more people to use online pharmacy services, but it is the pharmacies themselves who are choosing to drive societal change by embracing www.ipimediaworld.com

sustainable packaging now, rather than later. Accelerated societal change such as this, driven by a major crisis, is not unusual. To return again to the wartime analogy, World War One brought about significant changes to the role of women in the workplace. In the UK, after playing their part in the war effort, women moved from traditional work as household servants to better-paid jobs in industry and clerical roles. Nearly half of the first recruits to the London General Omnibus Company in 1916 were former domestic servants. The number of women in the civil service increased from 33,000 in 1911 to 102,000 by 1921. Similarly, the Second World War provided the social and political momentum that led to the creation of the National Health Service and the UK’s modern welfare state. It is arguable that the worldwide crisis we now find ourselves in is building the momentum that was already behind societal changes in sustainability and social responsibility. Again, the packaging sector provides a window on these changes. Prior to the pandemic, the corporate world was clearly and very publicly reacting to climate change and fears about environmental impact. Corporations were committing to sustainable business approaches, with promising results. Unilever, for example, has seen its much-heralded 26 ‘sustainable living brands’ outperform the average rate of growth for the rest of its stable over the last four years.

Even a cursory look at media reports around the packaging industry over the last couple of years would show how the ‘green’ agenda was driving decision-making more and more for all kinds of products and manufacturers. Pharma products, of course, are different. They demand exacting standards when it comes to packaging. The delivery of medicines, vaccines, treatments and medical equipment can literally be a matter of life and death. So, lofty ambitions to avoid plastic or glass in packaging may be possible for some sectors, but in pharma the viability of contents and the health of the consumer must always come before sustainable ideals. It always has to be about creating the right packaging solution for the job at hand first and foremost – although in the last few years, we have seen the growth of sustainable ambitions within the pharmaceutical sector, with individuals or departments responsible for improving the sustainability of companies and their commitment to ‘greener’ policies both internally and externally. The pandemic, and the necessity to deliver straight to the consumer more often, is encouraging pharma to look again at the wealth of scientific evidence that they too can choose sustainable options tailored to their needs, without undermining the high standards they have always set. The pandemic is also changing the way companies act. For evidence of the growing INTERNATIONAL PHARMACEUTICAL INDUSTRY 91

Logistics & Supply Chain Management deterioration of the vaccine and lead to hairline cracks in the ampoule, vial or prefilled syringe which could potentially allow the contents to become contaminated. Effectiveness cannot be guaranteed for vaccines unless they have been stored at the correct temperature, so the right choice of delivery solution is crucial. While the original packaging is vital for the above reasons, extra passive temperaturecontrolled packaging is often required for deliveries.

The US federal government is said to have allocated more than $9 billion to develop and manufacture candidate vaccines.

move towards social responsibility in the business world, look no further than the growth of the B Corporation movement.

vaccine development. Public understanding of just how challenging it is to produce a vaccine has probably never been higher.

Certified B Corporations are businesses that meet the highest standards of verified social and environmental performance, public transparency, and legal accountability to balance profit and purpose. There are currently over 3500 Certified B Corporations in more than 70 countries, with 188 in the UK.

Once a vaccine is developed, governments worldwide face another huge challenge – delivering it across the globe. Work on this huge task has been running parallel to the search for a vaccine, overseen by the COVID-19 Tools Accelerator which was convened by the World Health Organisation and global vaccine agencies such as CEPI and GAVI.

Put simply, B Corps are developing a global culture shift which aims to redefine business success and build a more inclusive and sustainable economy. Idealistic? Certainly. Achievable? Evidently. The B Corp world is not a fluffy commune of well-meaning hippy start-ups, it is a global network of forward-thinking businesses with a growing pharma membership, from Italy’s Chiesi Group to California’s Neotech Products. Tellingly, this summer Fortune magazine reported that interest in The B Corp movement is accelerating during the pandemic, with a spike in interest at B Lab, the non-profit that certifies new B Corps. Again, the pandemic appears to be driving innovative thinking. Right now, as the world holds its breath for news of the successful development of a viable vaccine, the pharma industry is very much in the public’s thoughts. Much has been written about the possible timeline of 92 INTERNATIONAL PHARMACEUTICAL INDUSTRY

It is supporting the building of manufacturing capabilities, and buying supply, ahead of time so that 2 billion doses can be fairly distributed by the end of 2021. Here, packaging will be crucial. Even in the demanding world of pharma, the transportation of vaccines enforces remarkably exacting standards if the contents are to arrive fit for purpose.

Innovation, however, has a habit of moving the goalposts. Pfizer and BioNTech’s vaccine – reported as 90% effective – is an RNA vaccine, and was created after researchers genetically engineered SARSCoV-2 genes and captured their blueprint. During shipment and storage, the vaccines must be kept at a staggering -70°C in order to maintain optimal efficacy. As a consequence, Pfizer is building a massive cold-storage supply chain to handle transporting limited doses of its coronavirus vaccine from manufacturer to any point in the US within two days. Logistics of this scale alone will drive new innovations in the field. In the UK, doctors’ surgeries are being given instructions on how to set up clinics to deliver the jabs. Whether it is delivering the Pfizer vaccine or one of the 10 others around the globe now reportedly in the final stages of testing, pharma packaging is about to be put to the test like never before. Perhaps it will also provide the ultimate test of how far the pandemic has accelerated innovative thinking within the sector, when it comes to sustainability.

Keeping the original packaging is critical too, as it is printed with the relevant expiry dates and batch numbers.

With so many millions of vaccines to be sent out, will pharma and governments opt for the man-made options of polyboxes, which will go on to clutter up landfill sites and pollute the environment? Will the carbon impact of the enormous cold chain infrastructure required be taken into account, or is this simply a time when speed of delivery – and lives – should take precedence over ‘green’ ideals?

Some vaccines have fairly short expiry dates, while all of them are sensitive to heat and cold. Heat speeds up the decline in potency of most vaccines, thus reducing their shelf-life. Freezing may cause

You can only really assess how a worldwide crisis sparked innovation with the benefit of hindsight. Things we take for granted today – from vacuum flasks to computer chips to nuclear power – can trace

Usually, vaccines must be stored in their original packaging at +2°C to +8°C and protected from light, as exposure to ultraviolet light will cause loss of potency.

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Whether it is delivering the Pfizer vaccine or one of the 10 others around the globe now reportedly in the final stages of testing, pharma packaging is about to be put to the test like never before.

their lineage back to breakthroughs made in the heat of war. We will only truly know how COVID-19 has driven innovation in years to come.

The indications are that, just as the world has come together to fight the infection, the hardships many have suffered through lockdown are driving innovation in how

life-saving pharma products are delivered. Besides, this pandemic is changing, and indeed must change, how business engages with society, on both environmental and social levels, in the future.

Josie Morris

The vital work being done to defeat COVID-19 is sparking innovative thinking and driving change. www.ipimediaworld.com

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 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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The Challenge of Global COVID-19 Vaccine Distribution Demands a New Approach Safely and expeditiously supplying COVID-19 vaccines to the majority of the world’s adult population of more than five billion will be the most formidable logistics challenge ever tackled in peacetime. Are we ready? It is clear that the first COVID-19 vaccines will be produced in relatively low volumes with the early output being immediately transported to point of need by road and air. The priority, of course, being to protect first responders and vulnerable groups. Some of this initial distribution is likely to be fairly localised because, despite the leaders of countries knowing that this pandemic is not observant of state borders, national interest and political pressures mean that ‘me first’ policies and approaches are almost inevitable amongst the high-income countries that are the leading vaccine developers. While morally questionable and scientifically irrational, this ‘vaccine nationalism’, as it has been termed, is understandable: governments want their own people to be protected first. However, the lesson we can learn from prior mass vaccination efforts is that comprehensive administration in just a few countries is not enough. The response must be collective, with equitable distribution to all countries at the same time. After the initial ‘emergency’ consignments, and as the production of different COVID-19 vaccines ramps up for mass immunisation programmes, volume-related pressures are going to emerge accompanied, no doubt, with another cost explosion in freight rates. In these circumstances, and with so much at stake, it is patently myopic not to be considering supplementing road and airfreight with a more resilient transport mode. Weighing up the Options Airfreight has traditionally been the default mode of transport for high-value and high-risk medicines. There are a number of reasons for this; the most obvious one being, of course, speed. But speed of delivery is only important if it does not come at an unacceptable cost, either financially or in terms of safety and performance. As one pharmaceutical executive put it: 94 INTERNATIONAL PHARMACEUTICAL INDUSTRY

“Speed of delivery doesn’t matter if we can’t fully secure the requested quality of the medicine”1. The problem is that, in a globalised world, pharma airfreight is a highly complex process with products travelling thousands of miles en route to market, during which they may be exposed to widely varying ambient environments and passed between as many as twenty or more links in the supply chain. With its multiple hand-offs, its absence of failsafe protection and its direct exposure to different environments, airfreight for medicines is well-documented as being a risky process. And, as any risk analyst or insurer will tell you, it is at interfaces and handover points where the greatest risks invariably lie. Blurred responsibilities, lack of co-ordination, incompatible quality standards, inconsistent training and many other factors conspire to create endlessly recurring supply chain issues. Resilience “The resilience of a transportation network rests in its capacity to absorb the effects of a disruption and to quickly return to normal operating levels”2. There is little doubt that a lack of resilience lies at the heart of the perilous situation that the pharma industry is facing ahead of its biggest-ever logistics challenge. One area of obvious concern rests in the fact that airfreight has experienced a significant loss of freight capacity as a result of the pandemic-induced travel collapse and the concomitant loss of belly freight services. According to IATA, belly capacity for international air cargo shrank 75% in April 2020 compared with the previous year, though this was partially offset by a 15% increase in capacity through expanded use of freighter aircraft3. While strenuous efforts have been made since then to bolster cargo capacity, at the end of November 2020 the overall shortfall remains at 25% of 2019 levels and the industry is not expected to return to prepandemic capacity levels until passenger services recover4. Sea freight, on the other hand, has a surfeit of capacity largely on account of its historic focus on volume and the fact

that, whilst not immune to disruption, has been much less affected by the pandemic. As a recent article in the Financial Times reported5, the sea freight sector has weathered the pandemic storm in much better shape with its impact being more transient than structural. Ocean carriers are in a position to relatively swiftly and effortlessly adjust to the new normal. Staggering Deliveries Not all COVID-19 vaccines are the same. This means deliveries will need to be phased in line with vaccine type/stability, the availability of suitable cold-chain transport and local storage, and the preparedness and readiness of trained health staff. For these reasons it will often be necessary to conduct staggered delivery regimes. This is something that can be very effectively achieved through the use of GDPcompliant refrigerated ocean containers as temporary and mobile storage units. By adopting a ‘floating warehouse’ strategy, it is possible to achieve a sequence of phased vaccine deliveries while minimising, or even eliminating, the need for surge capacity at local cold-chain storage depots. A floating warehouse strategy is where you have product on the high seas that is spread amongst different containers on different vessels, and even on different lines. This simple expedient provides a remarkable degree of flexibility in the shipping process at the heart of a systematic replenishment cycle. A much less attractive alternative is to invest heavily in temperature-controlled warehousing and/or third-party storage, particularly for ultra-low temperature storage. But, in addition to its attendant time, cost and availability penalties, this carries a huge risk that the vaccines simply cannot be supplied safely or end up being in sub-optimal locations. Vaccine Visibility Continuous consignment tracking and monitoring is a vital part of the pharmalogistics process. In airfreight, both passive and near real-time data-logging solutions have their adherents, with the choice often Winter 2020 Volume 12 Issue 4

Logistics & Supply Chain Management coming down to cost, reliability and cellular network coverage. In the case of ocean freight, a series of large-scale sea trials, conducted in 2018 and 2019 by the Poseidon network, established, conclusively, that satellite communications are necessary for reliable data exchange at sea6. This is because GSM and other terrestrial transmission systems have limited reach and quickly lose connection with offshore devices. For land-based monitoring and in air cargo situations in which the data connection is disabled in flight, this isn’t much of a problem. However, with the longer durations and remoteness of sea travel and the inability of battery-powered devices to continuously transmit for prolonged voyage durations, reliable ship-to shore satellite communications are necessary. Satellites may seem like an expensive option but in fact this can be a relatively inexpensive option due to the fact that many reefers are equipped with inbuilt telematics. For example, the entire 270,000strong reefer fleet of shipping line Maersk is equipped with remote container management (RCM) technology. Satellite systems, including those that automatically switch to GSM when within cellular range, such as those fitted to the range of reefers from Klinge Corporation, provide doorto-door data transfer including ambient temperature, cargo temperature, running condition, alarm status, fuel levels, and power source, all in near real time. Risky Business Estimates of the drug losses attributable to temperature excursions are in the billions of dollars with some sources reckoning that up to 5% of pharma shipments involve a notifiable temperature event7. One recent survey reported nearly 45% of respondents experiencing multiple temperature excursions, with 16% having monthly occurrences8.

Reefer Model NMF-372 from Klinge Corp with dual refrigeration units and integral generator-set.

This scale of detriment is breathtaking for an industry that is tasked with saving lives, and vaccines are not exempt. One of the reasons for these extraordinary logistics failures is the fact that, despite its sustained efforts, airfreight for temperature-sensitive vaccines and pharmaceuticals remains a very risky business compared to other modes of transport. One recent paper suggests that airfreight is responsible for no less than 79% of all temperature excursion occurrences compared to 19% for road and a tiny 1% for ocean9. Some observers contend that pharma airfreight has become just too complex a process to ever be consistently reliable in practice. “Simplicity is a prerequisite for reliability”, as the celebrated Dutch mathematician and computer scientist Edsgar Dijkstra famously said.

Image shows a reefer connected via satellite when crossing the Atlantic (green symbols) then a switching to GSM near Ireland (purple symbols). When GSM connection is lost it automatically reverts to satellite. www.ipimediaworld.com

Inherent Advantages On the other hand, ocean freight comes with a number of inherent advantages which account for its much lower rate of thermal excursions. Firstly, the sea freight process involves significantly fewer touchpoints than airfreight and, crucially, vaccines and other pharma merchandise remain in a temperature-managed, GDPcompliant, storage environment all the way from the point of production to the place of delivery. Once the reefer doors are closed at the manufacturer’s premises there is no interference with the vaccines during transportation, there is practically no opportunity for opportunistic theft, and there are virtually no interruptions to the storage conditions throughout the journey. Reefers have several technological features which further render them highly advantageous for vaccines and other sensitive medicines. Reefers are available with built-in redundancy options in the form of dual refrigeration units and models such as the NMR-262 from Klinge Corp. come with in-built power generation to provide the ultimate peace of mind when shipping vaccines and other medicines. Refrigerated reefer containers are highly reliable units that are built to take the rough and tumble of many years of continuous use. Adjustable to one-tenth of one degree Celsius, the technical performance and reliability of these containers is legendary, INTERNATIONAL PHARMACEUTICAL INDUSTRY 95

Logistics & Supply Chain Management with properly serviced units typically operating for fifteen years or more without breakdown. By combining active reefer refrigeration with qualified passive pallet protection and other qualified system components, a ‘belts and braces’ transport environment can be created that is thermally stable for indefinite periods in practically all conceivable ambient conditions. This ‘duplex protection’ is highly fault-tolerant and has been successfully field-trialled by the Poseidon network over more than 50,000 reefer-kilometres in severe summer and winter conditions. Such a system is proof against the vast majority of cold-chain breakdown scenarios including temporary power-loss, ambient extremes, customs inspections, unexpected delays, deferred power hook-ups, unplanned door opening events and equipment malfunctions. Storage Boxes In theory, one very large container ship has

20-foot and 40-foot refrigerated containers are easily moved by road to place of need.

a volumetric freight capacity equivalent to more than 800 Boeing 777-200F wide body freighters, which means that just a dozen

ships could easily hold sufficient COVID-19 vaccine doses to double dose every adult in the entire world. By comparison, it will need something like 10,500 Boeing 777F Freighters to carry the same volume of vaccine. At the other end of the scale, a single 40-foot high-cube ocean reefer has the capacity to accommodate something between 350,000 and 3,800,000 individual vaccine vials depending on presentation10. So, from a capacity perspective it is easy to visualise how the ocean mode of transport can be the mainstay of a viable global logistics solution for COVID-19 vaccines. For COVID-19 vaccine distribution purposes, refrigerated containers can be uplifted from the seaport and easily transported by road to vaccine distribution points and, as we have seen, used as GDP-compliant temporary/ mobile storage units. Such moveable cold stores mean that there is no need to find, rent or build expensive fixed storage facilities. Employing a leasing strategy means there is no need to tie up huge amounts of capital. and this highly flexible approach addresses one of the biggest issues with the entire global COVID-19 vaccination programme – the availability of suitable vaccine storage in remoter locations. The only requirement is an electrical power source which, if/when necessary, can be supplied from generators or other standby sources.

The volumetric capacity of a modern container ship is prodigious compared to a dedicated widebody airfreighter. 96 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Cold Comfort Reefers can maintain stable cargo temperatures in temperatures from plus 30°C all the way down to minus 70°C and in ambient temperatures up to plus 50°C. Tests are currently underway to qualify even lower Winter 2020 Volume 12 Issue 4

Logistics & Supply Chain Management reefer operating temperatures. A major benefit with reefers rests in the fact that, having mechanical refrigeration, they are not dependent on CO2 “dry ice”, for cooling, with all its associated availability, top-up, training and safety issues. Classified as a ‘hazardous cargo’ and with current regulations restricting the maximum total volume of dry ice on board a single wide-bodied flight to “around 1 tonne”11, dry ice presents a serious limitation to the volumes of very cold vaccines that can be handled by airlines. In many regions, and in fact in some entire countries, there is little, or simply no, availability of dry ice in commercial volumes. Talking about mRNA vaccine, Dr Jarbas Barbosa, assistant director of the Pan American Health Organization, recently told broadcaster CNN: "The rural and the urban areas in any country in the world are not ready to manage this vaccine today”.12 However, the majority of COVID-19 vaccines will not need ultra-cold storage conditions. In fact, where adjuvants are used, some vaccines will almost certainly require protection against freezing which can result in loss or destruction of potency. Most COVID-19 candidate vaccines will require plus 2°C to plus 8°C and a smaller number minus 15°C to minus 25°C. These are much less challenging compared to ultracold temperature handling. In cases where there is a risk of freezesensitive vaccines being exposed to subzero ambient temperatures, it is worth noting that, unlike many active airfreight containers, refrigerated reefers come equipped with reliable heating as well as refrigeration equipment. Cost Matters Finally, we come to cost. It is easy to say that you cannot put a cost on life, but it is a hard fact that the distribution of COVID-19 vaccines needs to be performed in the most cost-efficient manner possible. Only in that way will it be possible to reach every eligible adult in every country in the world in a timely manner. The airline industry’s loss of belly capacity has not only resulted in curtailed freight services, it has provoked an inevitable surge in airfreight rates to record highs. Ocean freight rates, on the other hand, although having been volatile recently, are historically a fraction of the equivalent airfreight levels and, for now, even lower. www.ipimediaworld.com

A 2019 study13 indicated that those pharmaceutical companies that have made a serious transition from airfreight to ocean freight are consistently realising cost savings in the order of 70% or more. An even more recent (post-pandemic) analysis comparing airfreight and sea freight rates over a typical Asia to Europe freight lane, showed that temperaturecontrolled ocean freight for vaccines is now less than 8% of the equivalent airfreight rate. This suggests that, with its lower risk factor, ocean freight will be much more effective for vaccine distribution on a price/performance basis. Turbulence Ahead To expect airfreight to cope with the volumes concerned, while at the same time continuing to maintain an uninterrupted flow of non-COVID-19 related drugs, is wholly unrealistic. The ramping up of air cargo capacity may be a visceral reaction from an airline industry facing existential pressures but it is not a sustainable solution to the challenges being faced going forwards. A sole reliance on airfreight for large-scale vaccine distribution is not only physically and financially unrealistic, it will perpetuate the “all in one basket” gamble that created much of the current freight turbulence in the first place. Finally, it is important to bear in mind that where COVID-19 vaccines are being flown into place, this might be at the expense of other life-saving medicines and vaccines which will remain in demand but are potentially delayed or clinically impaired through sub-optimal distribution. This displacement of vital medicines might be a frightening ‘robbing Peter to pay Paul’ consequence of ignoring alternative distributions modes and the bigger picture. In Conclusion There is little doubt that the long-haul transportation of COVID-19 vaccines and other vital pharmaceuticals needs to be conducted in a manner that is coordinated, integrated, multi-modal, affordable, sustainable and reliable. Practically speaking, this will require a shift from airfreight to sea freight for a proportion of COVID-19 vaccines and other medicines. Already some governments are indicating that they may have to defer their vaccination programmes pending the arrival of vaccine types that are easier to store and transport14. If so, this will leave

huge expanses of the world exposed to the pandemic. As WHO chief Tedros Adhanom Ghebreyesus emphasised recently: “No-one is safe until everyone is safe”15. Disclaimer The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the authors in preference to others of a similar nature that are not mentioned. References 1.

3. 4. 5.

9. 10.

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Sandoz. Getting medicines to patients - the role of quality logistics, 2 May 2017, https:// www.sandoz.com/stories/access-medicines/ getting-medicines-patients-role-qualitylogistics T.M. Adams, F. Asce, K.R, Bekkem, et al. Freight Resilience Measures. Journal of Transportation Engineering. 138(11). November 2012. https:// ascelibrary.org/doi/abs/10.1061/%28ASCE%29 TE.1943-5436.0000415 Cargo capacity crunch, 4 Jun 2020, https:// airlines.iata.org/news/cargo-capacity-crunch https://www.flightglobal.com/strategy/cargocapacity-on-passenger-jets-key-for-vaccinerollout-iata/141305.article M. Pooler, T. Hale. Coronavirus and globalization: the surprising resilience of container shipping. Financial Times, 17 September 2020. https:// www.ft.com/content/65fe4650-5d90-41bc8025-4ac81df8a5e4 Poseidon. Migrating the transportation of high value pharmaceuticals from Air-Freight to Ocean Freight - Some Cost Considerations, (unpublished report, Poseidon, 2018) C. Amman. Handling temperature excursions and the role of stability data. Pharmaceutical Outsourcing. 25 September 2013. https:// www.pharmoutsourcing.com/FeaturedArticles/146648-Handling-TemperatureExcursions-and-the-Role-of-Stability-Data/ Pelican BioThermal. 2019 Biopharma ColdChain Logistics Survey: What matters most and what it means for the future. https://bit. ly/3mI7hnp M. Edwards. Is the tide turning? The Medicine Maker, March 2018. https://themedicinemaker. com/manufacture/is-the-tide-turning PATH/WHO. Ocean shipment of vaccines. Project Optimize. https://www.who.int/ immunization/programmes_systems/supply_ chain/optimize/ocean_shipping_of_vaccines. pdf L. Frost, I. Wissenbach. Airlines scramble to prepare for ultra-cold COVID-19 vaccine distribution. Reuters. 18 November 2020. https://de.reuters.com/article/healthcoronavirus-airlines-freight/analysis-airlinesscramble-to-prepare-for-ultra-cold-covid-19vaccine-distribution-idINKBN27Y0XO T. Lister. The world’s now scrambling for dry ice. It’s just one headache in getting coronavirus vaccines where they need to go. CNN. 21 November 2020. https://edition.cnn. com/2020/11/21/world/coronavirus-vaccine-

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Alan Kennedy Alan Kennedy is a consultant specialising in supply chain dynamics and reform and is one of the architects behind the Poseidon integrated pharma freight model which has been conceived to radically transform the long-haul transportation of vaccines and other pharmaceutical products. He currently serves as the independent Neutral Trustee in this groundbreaking distribution program. Alan has more than 25 years of supply chain reform experience and has served on many industry supply chain committees and working parties. He regularly presents, and has authored numerous papers, on bestcollaboration practice in pharma-logistics and was recently honoured with a Life-Time Achievement Award for his contributions to the pharmaceutical supply chain at the 2020 Asia-Pacific Bioprocessing Excellence Awards. Web: www.poseidon.team Email: a.kennedy@poseidon.team

Dr. Umit Kartoglu

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dry-ice-intl/index.html Poseidon. Migrating the transportation of high value pharmaceuticals from air-freight to ocean freight, (unpublished report, Poseidon, 2019). A.A. Karim. Cold Truth: South Africa won’t be able to store these COVID vaccines. Here’s why. Health24. 13 November 2020. https://www. news24.com/health24/Medical/Infectious-

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15.

diseases/Coronavirus/cold-truth-southafrica-wont-be-able-to-store-pfizers-covidvaccine-heres-why-20201113-4 WHO. WHO Director-General’s opening remarks at the media briefing on COVID-19. 18 August 2020. https://www.who.int/director-general/ speeches/detail/who-director-general-sopening-remarks-at-the-media-briefing-oncovid-19---18-august-2020

Dr. Umit Kartoglu, MD, DPH is a medical doctor and has a doctorate degree in public health. He is co-founder, President and CEO of Extensio et Progressio SARL. Umit began his career in Turkey, where he served at all levels of the national health system for over 10 years. He joined UNICEF in 1994 and proceeded to serve at the Headquarters of World Health Organization as a scientist from 2001 to 2018. Umit brought to life the WHO-UNICEF Effective Vaccine Store Management Initiative; the Global Training Network for Vaccine Management; the Performance, Quality and Safety (PQS) Initiative, and the Global Learning Opportunities (GLO) Network. He received the 2011 and 2013 Ludwig Rajchman Public Health Award for his research on shake test to differentiate aluminum adjuvanted vaccines affected by freezing. He is the author of four books and many manuscripts published in peerreviewed journals. Web: www.kartoglu.ch Email: umit@kartoglu.ch

Winter 2020 Volume 12 Issue 4

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 99

Logistics & Supply Chain Management

How Modular Passive Pharma Packaging Systems Enable Strategically Refined COVID-19 Vaccine Shipping Regimes This task is more immense, complex and time-critical than ever before. The world is waiting for the safe, reliable and rapid distribution of the approved vaccines designed to combat the COVID-19 pandemic. In our discussion with Sven Rölle, Head of Sales at the German high-tech company eutecma, we will find out what contribution this company can make towards this logistical tour de force. What policies and processes should be adopted for the optimal cold chain management of vaccines? As is always the case: Product integrity and patient safety must never be compromised, under any circumstances, and this applies even more now than in “normal times”. The vaccines will only protect patients if they remain intact. This is the only way they can suppress this pandemic and reach the high level of acceptance we need to achieve herd immunity for the entire human race. The packaging industry has a unique chance to step into the limelight with this vaccine supply chain. A much wider public is suddenly very interested in what our products can do. Because, let’s be honest here: Who else usually cares about packaging solutions for pharmaceuticals other than the specialists? What factors do you have to take into account when developing a cooling system on the scale required by a global pandemic? All vaccines are different. Where one vaccine requires extremely low transport and storage temperatures of down to -70°C in order to reach its destination in a stable form, another might only require refrigerator temperatures between +2°C to +8°C or -20°C to remain stable. Other temperature ranges may also be necessary. If we assume that, in a public vaccination centre for instance, vaccines from different manufacturers will be administered, it would be helpful to have a high-performance packaging solution that works for all temperature ranges and packaging volumes during different pandemic phases, whilst still ensuring that they are handled in the same way to avoid 100 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The PROTECT ½ Euro Pallet Shipper, with a volume of 49, 95 or 141 litres, is also modular in design. photo: eutecma any process errors. “One box fits all”– that’s how we would describe this model. Luckily, our eutecma portfolio fulfils precisely these complex requirements. How exactly does this universality function? Irrespective of whether it holds 4 or 1600 litres – our PROTECT system packaging is configured so that every high-tech box uses the same cool brick format, regardless of the box size. The design is based on a versatile lock and key principle. The ICECATCH© passive energy storage units can be smoothly inserted into predefined slots in the side walls of the PROTECT boxes. They are securely anchored in the slots during transport and provide uniform cooling energy in a precisely defined temperature range. Additionally, these ICECATCH© elements are designed for all pharmaceutical temperature ranges: Frozen (<-20°C), cool (+2°C to +8°C) and ambient (+15°C to +25°C). We use dry ice for our deep frozen range, which has recently been

qualified in one of our four in-house climate chambers. This means that the temperature can be kept constant for over 120 hours. The temperature-stable eutecma system, based on highly efficient high-tech boxes and compatible passive energy storage units, is therefore easily scalable with regard to both temperature and payload. All PROTECT boxes are modular and can transport various freight volumes, depending on how many stacking frames are added. In short, these temperature-controlled eutecma transport boxes can be expanded or shrunk according to requirements. We are not aware of any other box manufacturer that can offer such modularity. How can this modularity be of use for vaccine transport logistics? We have a box for every eventuality. I can explain this using our largest cool box, the XL PROTECT pallet box, as an example. If smaller volumes of vaccine need delivering to numerous vaccination centres during the initial delivery phase, the box can be shrunk just by adding three or even two frames, instead of the standard four frames for airfreight shipments. The result: Instead of shipping a half-filled box by truck or air, you only use the exact payload required. There is no wasted space, which enables significant weight and cost-savings, particularly with regard to air freight. When production ramps up and larger quantities of vaccines need shipping, then the maximum payload of 1275 litres can be exploited by using all four frames to reach the maximum air freight height. The shipper can select the precise number of frames needed during intermediate phases where transport is required to distant destinations with smaller

The PROTECT pallet packaging system is always the same, whether it holds 1275, 495, 333 or 172 litres. photo: eutecma/Axel Heiter Fotodesign Winter 2020 Volume 12 Issue 4

Logistics & Supply Chain Management populations or where local fine distribution only has a need for smaller quantities. If you combine this modularity with the matching cooling/heating elements – ICECATCH© Solid Insulated (+2°C to +8°C), ICECATCH© Solid Frozen (<–20°C) or ICECATCH© Solid Ambient (+15°C to +25°C) – then you have a highly innovative system. This modular packaging system therefore enables a clever, strategic approach that takes the various logistics phases required for global distribution into account. With the knowledge that this vaccine will be distributed all around the world, with products travelling thousands of miles, exposed to widely varying ambient environments, is there a need to create different packaging depending on the country of destination or means of transport? I can answer that with a definite ‘no’ when it comes to eutecma. Our PROTECT system packaging covers all pharmarelevant temperature ranges. You only need the appropriate ICECATCH© passive energy storage units for the temperature range, plus dry ice for -70°C or -20°C transport. This is how it works in practice: Our customers provide their temperature profile specifying the maximum temperature stress the cool box will be subjected to, and must withstand, on its journey to the final destination – including ramp times, ground handling, intermediate stops, etc. We test these extremes in our in-house climate chambers, so that the box is fully qualified

Products for customers are qualified in the four eutecma climate chambers. The PROTECT pharmaceutical packaging is subjected here to extreme stress tests. photo: eutecma/Axel Heiter Fotodesign for shipping. We work with empirical data from the German Weather Service entered in a transport calendar, which is used to compute the ambient temperature situations for hundreds of transport connections. We always assume and test the worst-case scenario in the climate chamber so as to provide an extra security buffer. Irrespective of whether your PROTECT box is shipped to the desert or to permafrost regions – your specific temperature range or cold chain will not be lost during transport.

TEST SCENARIO

PROTECT Frozen 8.7l · 25 plastic vials (à 20ml) · 18 kg dry ice (nuggets) below -70°C 40

The box never changes, just the quantity and type of passive energy storage units used differ, i.e., ICECATCH© elements or dry ice. This depends on the duration and prevailing temperatures during transport until arrival. In our opinion, the entire process chain should be given greater consideration in all distribution concepts. Is it possible/necessary to re-ice the boxes or are they delivered immediately? Can the packaging solutions be stored preassembled and rapidly shipped out when deliveries are required? Or are the boxes only assembled following an order? These are all questions that can positively or negatively affect supply chain efficiency and which we can optimally respond to with our PROTECT packaging solutions.

The PROTECT packaging system, when filled with dry ice, maintains a temperature of -70 °C for 120 hours. The ISTA 7D cold/hot profile was tested here. photo: eutecma

Taking into consideration that the vaccines will not all be distributed at the same time, it may be necessary to conduct staggered delivery regimes. How could this be done in practice? Staggered delivery processes are very likely as the vaccines being delivered will be correlated with warehouse availability and the number of people who can be vaccinated per day at each location X. The eutecma system is particularly suitable for such fluctuating freight volumes due to its modularity. The available interior volume varies according to how many modules are used. And our system has another advantage: When national and international vaccinations start and very large quantities of COVID-19 vaccines need transportation,

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temperature in C°

0 -13 -27 -40

120h

-53 -67 -80

-70° 0

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102

108 114

120

126

132 138

time in hours product temperature

Logistics & Supply Chain Management

“One size fits all”. These universal ICECATCH© passive energy storage units are available for all pharmaceutical temperature ranges: Frozen (<-20 °C), Cool (+2 °C to +8 °C) and Ambient (+15 °C to +25 °C). photo: eutecma/Axel Heiter Fotodesign any number of PROTECT boxes can be prepacked and stored in ambient, cool or frozen warehouse areas. Once the dispatch order comes in, the warehouse worker only needs to insert the appropriate number of ICECATCH© cool bricks in the wall slots, close the box and send it off on its journey. So, a lot can be prepared before final dispatch, which greatly accelerates the shipping process. In your opinion, what will be the biggest challenge in delivering COVID-19 vaccines? The availability of transport resources on the road, but above all in the air. Due to this corona pandemic, many planes are grounded which means there is a lack of air freight capacity around the world. Lower capacities mean higher freight prices. This also applies to normal temperature-controlled air transport of pharmaceuticals. Shipping of vaccines will worsen this bottleneck. Manufacturer and shippers must therefore be careful about pack-out, about filling the boxes as efficiently as possible so as not to waste any interior space. Our modular eutecma packaging system is designed for precisely this purpose. Additionally, the temperature-controlled eutecma cool boxes are made from EPS/Styropor. This material is both robust and resistant to ageing, but very light compared to other packaging solutions, which is a huge benefit given the strained air freight resources at present. Because every freight kilo or litre saved here is essential. And there is yet another point where eutecma can provide an efficient response to reduced air freight 102 INTERNATIONAL PHARMACEUTICAL INDUSTRY

capacities in the deep frozen sector (-70°C): In parallel with using just dry ice, we have developed concepts where this ultra-cold medium can be combined with ICECATCH© cold energy storage units. This reduces the use of dry ice by up to 30 per cent! As the amount of dry ice that can be transported in a plane is limited for safety reasons, this combination offers a very great advantage. Some governments are indicating that they may have to defer their vaccination programmes pending the arrival of vaccine types that are easier to store and transport. What storage and handling training should locations that store vaccines implement? The lack of trained personnel in the cold chain sector, capable of safeguarding the processes for storing temperaturestable vaccines in distribution centres, for instance, is in principle the second greatest challenge in this pandemic. If temperaturecontrolled transport containers are sent to interim storage or a distribution centre, they must be correctly stored and even re-cooled in some circumstances. This is particularly critical for deep frozen transportation. The logistic personnel on site must be able to handle the dry ice cooling media competently as it poses various risks and hazards. Cool bricks may also need to be replaced for products stored between +2°C and +8°C. Personnel who don’t work in this field on a daily basis therefore need to be trained. The following maxim applies in all cases: The simpler the packaging and cooling medium set-up is, the less room there is for errors.

This was precisely our guiding principle while developing the eutecma system. The PROTECT boxes are designed to be as simple and easy to use as possible and to be easily fitted with the ICECATCH© passive energy storage elements. Our ingenious trick is that PROTECT cool boxes do not need to be fully unloaded to insert new elements. The “exhausted” ICECATCH© elements can simply be removed from the insertion slots and replaced with new elements. The “exhausted” elements can then be treated in a second process so that they can be reused. This applies to all temperature ranges. So, we can certainly say that universal packaging systems, such as those made by eutecma, can minimise errors. The simple handling of our PROTECT system packaging had already been explained in two training videos, well before the COVID-19 pandemic, using the XL PROTECT pallet box and the PROTECT Euro pallet box. Both videos can be found at www.eutecma.com/movies. You can also take a look at the “Reusability Guidelines” video, which explains how our packaging solutions and ICECATCH© bricks can be used more than once. It shows the user precisely what needs to be monitored and when parts need exchanging. Good catchword, since at IPI we take an interest in supporting eco-friendly and sustainable businesses. Can you tell us more about what eutecma does to help the environment? Sustainability is playing an increasingly important role at eutecma. The main motto this year was to make existing products more sustainable, but at the same time save our customers the cost of renewed qualifications. We managed this extremely well in various areas. Example number 1: Starting from January 2021, we will successively start producing ICECATCH© elements with a composite film that consists of at least 50% sugar cane waste instead of 100% crude oil. They will bear the “I’m green” quality seal developed by Braskem, the Brazilian producer of sugarcane-based polyethylene, and a QR code leading to more detailed information. This approach is very smart, because this “green polyethylene” does not supplant any foodstuffs, instead it cleverly recycles otherwise worthless waste. At the end of the product cycle, this organic plastic can be easily recycled. Example number 2: We will also start significantly increasing the percentage of recycled Styropor in our packaging boxes in the first quarter of 2021. We are working on this project together with BASF, the world's largest chemicals Winter 2020 Volume 12 Issue 4

Logistics & Supply Chain Management

As of January 2021, eutecma will be cooperating with their partner BASF to offer high quality PROTECT packaging systems made of EPS/ Styropor® Ccycled. photo: BASF producer. In addition to conventional EPS/ Styropor, a virgin material, we will use Styropor Ccycled in a variety of PROTECT packaging boxes. This secondary material consists of pyrolysis oil recycled from plastic wastes. During chemical recycling, this material is converted into feedstock for the chemical industry and allocated to products within the BASF production network via a mass balance method. Even though Styropor Ccycled has exactly the same properties as Styropor gained from fossil fuels, it has a significantly better CO2 footprint. Both innovations are just as efficient as their predecessors and do not affect the quality of our products in any way, but improve our environmental footprint and that of our customers. Re-qualification for “I’m green” or Styropor Ccycled products is not necessary. Our message to all pharma companies who place value in sustainability along their supply chain and who also want to communicate this during their dialogue with their stakeholders: eutecma is the partner to have at your side. In contrast to the Biontech-Pfizer vaccine, which needs ultra-low temperatures, most of the potential vaccines will require a temperature of +2°C to +8°C, with some needing a slightly colder -15°C to -25°C. Does eutecma intend to participate in the global distribution of the vaccines? We belong to the lucky companies who have not suffered so far from the corona www.ipimediaworld.com

pandemic. On the contrary: Many of our customers have increased their pharmaceutical cooling packaging stocks for safety reasons. We recognised and invested in this development early on, which meant our production was increased accordingly over the course of this year. Our warehouses are well stocked with ICECATCH© passive energy storage units and PROTECT system packaging. We can ramp up our production even further for vaccination transport. With our recent qualification for deep frozen transports, and the millionfold-proven reliability of our products in all other pharma-relevant temperature ranges, we are well prepared to contribute towards this historical logistics challenge. We are already doing so in one area. Antigen tests have already provided good service during this pandemic by detecting whether a person is infectious or not in approximately 30 minutes. A study released in November 2020 by the Berlin Charité hospital, under the top virologist Dr. Christian Drosten, investigated seven antigen tests, coming to the conclusion that, although some performed better than others, they all functioned well. The specificity of the investigated tests lay between 88.24% and 100%. Five of the seven tests investigated originate from manufacturers that use eutecma products. We are proud that we can already support our customers in safely transporting these antigen tests from A to B.

Sven Rölle Since it was founded in 2008, eutecma has been researching, developing and producing passive cooling systems that are always used where the cold chain must be maintained for temperature-sensitive products. This innovative mid-sized company has shown strong growth over the years, particularly in the pharma and diagnostics sector. Sven Rölle, after holding positions in several packaging companies, including SCA, is an eutecma employee of the first hour and has contributed to many milestones in eutecma’s history. With a degree in business administration, the Head of Sales has his finger on the pulse of numerous global players in the pharmaceutical industry, many of which are eutecma customers. With a finely-developed sense for intelligent solutions driven by “outside-the-box” thinking, he and his team push the development of new, ground-breaking cooling systems and accompanying services.

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Advertisers Index

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Aurena Laboratories

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Avantor Inc

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Bachem AG

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Beneo GmbH

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Bioquell

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Chargepoint Technology

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Controlant

IBC

Denny Bros Ltd

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Eutecma GmbH

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FUJIFILM Wako Chemicals U.S.A. Corporation

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Krautz Temax

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Mikron Group

Natoli Engineering Company

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Nemera

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NResearch Inc

IFC Omya AG Page 77

Owen Mumford Ltd

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PCI Pharma Services

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Pharma Publications

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R.G.C.C. Group

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Stoelzle Glass Group

Page 57 & 85

Valsteam ADCA

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WoolCool

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

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IPI Winter 2020

Articles inside

The Challenge of Global COVID-19 Vaccine Distribution Demands a New Approach

How the War on COVID-19 is Driving Innovation in Temperature-controlled Packaging – and Beyond

COVID-19 Vaccine: Unique Distribution Challenges Call for a Unique Monitoring Approach

In Highly Regulated Industries your Labelling must Speak for your Product – Compliance is Non-negotiable!

Working Together to Beat the Drug Counterfeiters

Exploring Pharmaceutical Packaging’s Top 2020 Trends

HPMC and the Value of Vegetarian Hard Capsules

Managing the Mass-Production of Tablets with Efficient

Preserving the Parenterals of Tomorrow

Causes of Punch Tip Wear and How to Avoid Them

The Importance of Anonymised Unstructured Data in Advancing Medical Research and Patient Outcomes

Completing the Puzzle Technology in Decentralised Clinical Trials

Designing for Success: A Multi-stakeholder Approach to Clinical Development to Optimise Patient Access

What Is Preventing the Industry from Providing Electronic Product Information?

The Rabbit and the Horseshoe Crab

Powerful, Large-scale Analytics brings Single-cell Omics into Clinical Reality

Optimising Device Design for New Generation Biologics

Putting Translation Central to the MDR Shift

Editor’s Letter

Critical Challenges and Potential Solutions to Optimise Downstream Bioprocessing Production

The Heightened Case for IDMP in the Light of COVID-19

Truth Matters: Why Science Journalism Has Never Been So Important

Clinical Requirements under EU MDR: Understanding the Changes

Brexit White Paper