IPI Autumn 2020

Volume 12 Issue 3

Peer Reviewed www.ipimediaworld.com

Pharmacovigilance Why Are So Many Companies Failing their Regulated Audits?

Pre-filled Safety Syringes and the Self-administration Trend A Mutually Reinforcing Relationship Pharma’s Quantum Leap Launching New Medicine in the Age of AI Creating a Fit-for-purpose Supply Chain For the COVID-19 Vaccine Sponsor Company:

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Contents 06 Editor’s Letter REGULATORY & MARKETPLACE 08 Pharmacovigilance: Why are so Many Companies Failing their Regulated Audits?

DIRECTORS: Martin Wright Mark A. Barker 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: Ana De Jesus ana@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 Winter 2020.

ISSN No.International Pharmaceutical Industry ISSN 1755-4578.

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This publication is protected by copyright.

2020 PHARMA PUBLICATIONS / Volume 12 issue 3 – Autumn – 2020

When EU legislation on pharmacovigilance came into force in July 2012, it established the clear legal requirement that marketing authorisation holders must perform audits of their pharmacovigilance systems, including risk-based audits of their quality systems. So why then are so many life sciences companies struggling with associated audits and inspections? Summarising the 10 aspects of PV covered by the formal requirements, Vanessa Fachada Oliveira, Pharmacovigilance Manager & EU QPPV at Arriello, discusses where companies are falling short and where they need to focus their attention to stay on the right side of inspectors.

10 Building Solid Foundations for Regulatory Data Automation Automating regulatory processes delivers undeniable benefits, ranging from accelerating time to market to reducing error. But life sciences companies are widely grappling with the basic issue of getting up-to-date and consistent data to talk to each other across functions and systems. Duncan van Rijsbergen at Iperion offers five practical starting points to build a solid data quality foundation.

12 Barriers in Medical Device Innovation Every day innovative new technologies can and do transform industries, and due to the massive technological innovations like the web, smartphones, and communication technology, the rate of change has increased. The healthcare industry is extremely complex, and due to rising costs and patient demands, the medical care delivery environment is under growing pressure. To break through the complexities of medicine and drive science forward, inventors, medical testing, and production firms must first resolve the many obstacles to the creation of healthcare products. Knowing how medical devices interact with humans is a critical problem as discussed by Tarun Nag S S, Balamuralidhara V and M P Gowrav at JSS College of Pharmacy, which influences both the design and acceptance of innovative new technologies and regulation.

18 Ensuring the Pharmaceutical Industry is Prepared for a Future Pandemic The COVID-19 pandemic has stretched healthcare suppliers, organisations, governments, and healthcare professionals to their very limits, locking down the world like never before. Healthcare industries, which were already under huge strain across the world have been placed under unprecedented pressure. Despite this, Vladimir Tkachenko at Amaxa Pharma believes that we are starting to see positive signs and sees a light at the end of the tunnel.

20 The Patent Landscape Behind COVID-19 Vaccines The development of vaccines to prevent COVID-19 has become a fascinating story, especially for those with an interest in life sciences. In the development of COVID-19 vaccines, there has been a surprising uptake in the use of a relatively new vaccine platform.

In this article, Dr. Leena Contarino and Ellie Purnell at HGF look at the patent landscape covering some of the platform technologies

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 1

Contents that are being exploited by researchers in the race to develop an effective COVID-19 vaccine.

24 Agile and Flexible – A Fitness Check for the Pandemic Era The COVID-19 pandemic era is shaking up the pharma supply chain.

Heavily regulated processes that used to take years are speeding up as existing drugs are repurposed as therapeutics for COVID-19 patients, and new drugs and vaccines are under development. Gurdip Singh, CEO at Kallik, provides a health check for pharma businesses who are straining every sinew to meet changing market demands.

26 Successful Marketing of Medicinal Cannabis and Cannabis-derived Products – Part II In June, the first part of this article was published, describing differences in the legal background of some of the European Union countries, which need to be known for successful marketing. The second part of the article, by Barbara Siebertz and Ute Hegener at PharmaLex, describes hurdles and requirements regarding the growing, import, and distribution of medicinal cannabis or cannabis-derived products, as well as the potential of this market concerning the development of finished medicinal products as a next step of product development in this evolving market segment.

DRUG DISCOVERY, DEVELOPMENT & DELIVERY 30 Pre-filled Safety Syringes and the Self-administration Trend: A Mutually Reinforcing Relationship Under growing pressure resulting from staff shortages, overburdened funding, an ageing population and most recently a global pandemic, healthcare systems across the world are supporting the drive towards self-administration of injectable medication for patients with chronic diseases. The number of people worldwide aged 60 and over is projected to nearly double by 2050. By shifting the administration of certain therapies towards the home and away from the traditional clinical setting, hospitals are exporting a lower-risk medical procedure. George I’ons at Owen Mumford Pharmaceutical Services explores how this helps to manage occupancy pressures within their facilities and encourages patients to be more involved in their own medication regime.

34 Optimising HPAPI Value Chain to Achieve Maximised Product Value In the quest to find new and more effective treatments against severe diseases, researchers are increasingly moving towards active pharmaceutical ingredients (APIs) with increased potency and more targeted delivery mechanisms. These powerful compounds may help treat life-threatening and so-far incurable diseases, including cancer, diabetes, Parkinson’s disease, and others. Maurits Janssen at Lonza Pharma & Biotech showcases why sustainable manufacturing of highly potent APIs (HPAPIs) requires specific precautions to operator health and safety on the one side and to product quality on the other.

40 The Role of Connected Inhalers in Improving Usability and Adherence in Respiratory Disease Recent data suggest that 339M people globally have asthma, resulting in 425,000 deaths annually, many of which would be 2 INTERNATIONAL PHARMACEUTICAL INDUSTRY

preventable with access to medication and appropriate healthcare.

Even in countries with high standards of living, well-established healthcare systems, and proper medication availability, unnecessary deaths still occur. In fact, a recent report suggests that around twothirds of asthma deaths are preventable in the UK. Although several factors contribute to a failure to manage treatment effectively, Iain Simpson at Phillips-Medisize states why failure to take medication as prescribed is a key issue.

46 Respiratory Drug Delivery – What has Happened and What Might the Future Hold?

Recent decades have seen vast technological developments all over the world, particularly in respiratory drug development. Respiratory drug delivery has equally been defined by the development and approval of new drugs and treatments. Brennan Miles at Team Consulting looks back at some of the recent defining moments for the respiratory drug delivery sector and looks at what the future holds for the industry.

52 Regeneron v Kymab: Transgenic Mice Claims Found Insufficient A patent reflects a bargain between the inventor and the public. The inventor gains a time-limited monopoly over the making and use of a product. In return, the public gains the ability to make the product after the expiry of the monopoly. Regeneron obtained two patents with a priority date of 16 February 2001, EP(UK) 1 360 287 (“the ’287 Patent”) and EP (UK) 2 264 163 (“the ’163 Patent”, a divisional of the 287 Patent). Kymab’s challenge to validity arose in defence to an infringement action brought by Regeneron against Kymab’s commercialisation of its own transgenic mice, “Kymouse”. Martin MacLean and Andrea Hadfield at Mathys & Squire demonstrate how transgenic mice claims have been found insufficient by the Court of Appeal.

56 Returning to Basics of siRNA Design to Fulfil Therapeutic Potential The recent FDA approval of siRNA therapeutics has re-energised the RNA interference (RNAi) field. The discovery of RNAi-mediated silencing in mammalian cells and parallel availability of the whole human genome sequence allowed for creation of research tools to study gene function using siRNA. However, due to challenges in siRNA delivery and pharmacokinetics, its potential as a therapeutic was not realised until the FDA approval of the siRNA therapeutics ONPATTRO® (patisiran) and GIVLAARI® (givosiran) in 2018 and 2019, respectively. Annaleen Vermeulen and Amanda Haas at Horizon Discovery discuss how the success of these therapeutics builds on almost two decades of siRNA design and encourages the field to pursue additional gene targets for therapeutic intervention.

CLINICAL & MEDICAL RESEARCH 60 Diagnostic Techniques for COVID-19 SARS-CoV-2, or the pathogen which causes COVID-19, is a virus containing a positive-sense RNA as its genetic constituent.

Morphologically, it contains spike-like projections on its surface and is hence named as ‘The Coronavirus’. On March 11, 2020, the disease was declared a ‘pandemic’ by the WHO and since then, the search for an effective diagnostic tool was the key to controlling the Autumn 2020 Volume 12 Issue 3

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 3

Contents devastating repercussion of the viral outbreak. Subhajit Hazra, an experienced medical writer, reviews the current array of techniques available for the detection of SARS-CoV-2.

mouth by swallowing. Sven Stegemann at ACG Capsules discusses the history of therapeutic products, which can be considered as the first attempt at a gelatine capsule development.

TECHNOLOGY

90 Automated Quality Control of Pharmaceutical Packaging Materials

64 Pharma’s Quantum Leap: Launching New Medicine in the Age of AI The pharmaceutical industry has long been squeezed by tight regulation, cost controls on medicines, and the necessarily extensive drug discovery and research process. There is some hope, however, as we are on the cusp of a change across the sector. In February 2020, a team at MIT discovered a new antibiotic in record time using a machine learning algorithm. Robert Weissgraeber at AX Semantics questions whether AI technology will usher in a quantum leap in pharmaceuticals and solve some of pharma’s long-standing structural problems.

68 Trapped Ion Mobility Mass Spectrometry (TIMS) Drives High-throughput Phosphoproteomics Research Unlike genomic and transcriptomic research, the measurement technologies for proteomics are still evolving, and the complete analysis of a proteome has not yet been achieved. The end goal of proteomics studies is not just to identify all the proteins that can be expressed, but also to uncover cellular protein events.

Yasushi Ishihama at Kyoto University gives examples of cellular protein events such as protein expression / degradation, protein localisation, protein interaction, protein post-translational modifications (PTM), and protein processing/splicing.

MANUFACTURING

Inspection systems help print shops perform a 100% print inspection and save time at the implementation of new jobs, due to automated job setups and high-speed inspections. The customer proof is loaded and used automatically based on the entered job data. Even composite jobs, for instance front and back labels, can be checked against corresponding PDFs in one click. Nico Hagemann at EyeC explores how the information contained in the PDF is used to define priority regions and adjust inspection sensitivity automatically.

LOGISTICS & SUPPLY CHAIN MANAGEMENT 94 Creating a Fit-for-purpose Supply Chain for the COVID-19 Vaccine The race is on amongst the international scientific research community to develop a vaccine that will prevent infection by SARS-CoV-2, the virus that causes COVID-19. There is also the very real risk of a second wave of Coronavirus infection in countries that have already been badly hit earlier in 2020, as autumn looms.

By the end of 2021, the World Health Organisation (WHO) plans to deliver over 2 billion doses of a Coronavirus vaccine internationally to accelerate herd immunity and wipe out the highly infectious virus. Rich Quelch at Origin explains why this ambitious timeline presents a huge challenge for pharmaceutical supply chains and healthcare systems.

72 Calcium Bioavailability is Key

98 End-to-end Visibility – The Foundation of Addressing Today’s Challenges in Pharmaceutical Distribution

For the first time in history, most people can expect to live into their 60s and beyond. According to the World Health Organisation, one in five people will be 60 or over by 2050. Yet while there is no doubt that a longer life brings great opportunities, the extent to which they can be enjoyed depends on an individual’s physical and mental state. Healthy ageing is the process of maintaining the functional ability that enables wellbeing in older age, beyond merely prolonging life. Lalit Sharma at Omya believes that how you look and feel is more important than your actual age.

Over the last few years, challenges in the distribution of pharmaceuticals have grown with the need to have better visibility along the entire chain to act fast due to disruptions or to prevent them from happening at all. Thankfully, technology in recent years has provided more than just visions on how to address these challenges. Carl Spörri at Modum explains how this provides solutions to connect and synchronise the flow of physical goods with the flow of information, therefore reducing the manual effort to handle information.

76 Using Phase-appropriate Delivery to Accelerate Inhaled Product Development Different inhaled product development programmes can use different platform delivery technologies at various stages of development. Sandy Munro at Vectura shows why careful thought must be given as to what will work best at any given stage due to the broad choice of options.

PACKAGING 80 Advanced Capsule Development for Today’s Needs: HPMC+ The use of compounds (from biologic or chemical origin) as therapeutics is as old as mankind. Traditionally, the administering of such therapeutic products to the body occurred through the 4 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2020 Volume 12 Issue 3

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 5

Editor's Letter We are now eight months into the pandemic in Europe and is there a light at the end of the tunnel for delivering a vaccine? Well, Bill Gates says that “the rich world could be close to normal by late 2021”, but what does this say for world equality?

With any disease or infection diagnosis, it is so important to ensure a patient understands why they are feeling the way they are. Subhajit Hazra, an experienced medical writer, reviews the current array of diagnostic techniques available for the detection of SARS-CoV-2 (COVID-19).

How we are going to be able to receive drugs in the future is also an interesting question, as there are many patients who are unable to swallow medicine. Brennan Miles at Team Consulting looks back at some of the recent defining moments for the respiratory drug delivery sector, and The COVID-19 pandemic has stretched healthcare suppliers, organisations, governments, and healthcare professionals to their very limits, locking down the world like never. Healthcare industries, which were already under huge strain across the world, have been placed under unprecedented pressure. Sadly, when the pandemic hit, we quickly discovered that many nations and their health services were underprepared when it came to having the right equipment and infrastructure in place to respond rapidly.

Demand change, supply shortages, panic

looks at what the future holds for the industry.

COVID-19 really has been a wake-up call to the world on what our future may hold for humanity, but surely we can’t keep going down the same path each time this happens. That’s why we need to ensure the pharmaceutical industry is prepared for a future pandemic.

Vladimir Tkachenko at Amaxa Pharma talks about ensuring that we are prepared, and he believes that we are starting to see positive signs, and sees a light at the end of the tunnel.

Vanessa Fachada Oliveira, Pharmacovigilance Manager & EU QPPV at Arriello, discusses where companies are falling short and where they need to focus their attention to stay on the right side of inspectors.

One of the challenges that the industry faces is the barriers in medical device

innovation. Knowing how medical devices interact with humans is a critical problem that needs to be discussed. Tarun Nag S S, Balamuralidhara V and M P Gowrav at JSS College of Pharmacy look at this issue, which influences both the design and acceptance of innovative new technologies and regulation.

We must also ensure we create a fitfor-purpose supply chain for the COVD-19 vaccine. This means that every patient who needs a vaccine, whatever country they live in, should be vaccinated. Rich Quelch at Origin explains why this ambitious timeline presents a huge challenge for pharmaceutical supply chains and healthcare systems.

I hope that you enjoy reading this edition of the magazine and keep well.

Lucy Robertshaw CEO LucyJRobertshaw

buying and stocking, regulation changes and shift of communication and promotions to remote interactions through technology and research and development (R&D) process changes can be seen as short-term impacts of COVID-19 on the pharmaceutical market.

However, while the pandemic continues, it is beginning to ease out, and pharma is becoming more adept at responding to the crisis. Companies are collaborating with each other to form partnerships to help accelerate the global effort to develop a vaccine to protect as many people as possible from COVID-19.

Others have donated a variety of crucial medical supplies including advanced surgical equipment, antibiotics, disinfection equipment, masks,

gloves and more. In addition, antibacterial medicines that have been approved to treat secondary infections such as pneumonia are being used.

Companies have also donated compounds with the potential to treat coronavirus for emergency use and clinical trials, including compounds formerly tested on other viral pathogens such as Ebola and HIV. While the fight is far from over, we as a pharma industry can work together to beat COVID-19 head on and forge a better future for our people.

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

Virginia Toteva Editorial Manager – IPI

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

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 Autumn 2020 Volume 12 Issue 3

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 7

Regulatory & Marketplace

Pharmacovigilance: Why Are So Many Companies Failing their Regulated Audits?

But although other strong standard operating procedures (SOPs) may have been documented as part of general quality systems, there is often nothing relating specifically to PV – about procedures for managing deviations; what happens if a new qualified person responsible for pharmacovigilance (QPPV) is appointed; how external service partners are qualified; what the business continuity plan is and how this is tested, etc. These omissions can result in inadequate integrity and management of pharmacovigilance data; difficulty identifying and implementing corrective/preventative actions (CAPAs); and incomplete oversight/compliance management of a PV service provider.

When EU legislation on pharmacovigilance came into force in July 2012, it established the clear legal requirement that marketing authorisation holders must perform audits of their pharmacovigilance systems, including risk-based audits of their quality systems.

So why then are so many life sciences companies struggling with associated audits and inspections? Summarising the 10 aspects of PV covered by the formal requirements, Vanessa Fachada Oliveira, Pharma-covigilance Manager & EU QPPV at Arriello, discusses where companies are falling short and where they need to focus their attention to stay on the right side of inspectors.

2.

The way life sciences companies run, check and document their pharmacovigilance (PV) activities is as important as the function itself, because regulating authorities need to be confident that standards are being upheld and that nothing is being missed. So it is vital that pharmaceutical organisations get this right and can provide evidence of strong standard operating procedures on demand.

Yet, although eight years have elapsed since EU legislation on PV came into force, a majority of companies are still struggling to fulfil their obligations, potentially causing marketing authorisation holders (MAHs) to fail inspections, incur fines and see products withdrawn from markets.

One of the reasons for common failings in PV process documentation is that the EU has not set out clear guidelines about how or where companies should go about this. Here are some of the problems this can cause and what can be done to rectify the situation: 1.

Failure to implement an adequate quality management system. EU PV legislation makes clear that quality systems should form an integral part of an organisation’s PV system.

8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

3.

Insufficient or poorly documented training. This can occur firstly because it is not obvious who is responsible for or who actually needs PV training.

Depending on the organisation, the remit for organising training could fall to the HR department, the quality leadership, or the PV function itself.

What’s less obvious is that everyone in the company will need PV training – from the most senior managers to manufacturing teams. That’s because anyone could find themselves the recipient of safety feedback, which means everyone needs to know what action to take next – and how quickly.

To ensure that no training needs are missed, there should be a clear training plan, and formal records showing which employees have attended which sessions and when. The QPPV in particular must attend regular training and have up-to-date certificates.

Quality people who perform audits must have at least some PV training too, yet this is often found not to be the case.

Failure to make contractual provision for PV along the supply chain.

Manufacturers as well as MAHs and distributors could find themselves the first port of call for a safety report.

A safety data exchange agreement should set out the respective PV

responsibilities of each party, who the QPPV is, who will manage actions relating to adverse reactions and associated reporting. For a distributor, the obligation might simply be to forward all relevant information to the MAH – unless that company also has a remit for local PV activities. Lesser failings, but nonetheless important to put right, include the omission of situation reports, and provision for archiving, retention periods and exchange of information following the termination of an agreement.

4.

Inadequacies relating to the pharmacovigilance system master file (PSMF).

This is one of the main documents of the company’s PV system, which should provide a very clear overview of all critical PV processes and procedures for managing adverse events and safety signals; the key stakeholders; full details of the QPPV and their experience and contact details; documentation showing how the organisation will manage compliance with the legal requirements; KPIs and the rationale behind these. The PSMF must be kept up-to-date at all times, so there must be a process for ad-hoc revisions as well as periodic updates.

If the competent authority asks to see a copy of the file, the company must be able to deliver a fully updated document within seven days. Failings can be for something as simple as poor formatting or omitting an index to allow easy navigation. If the PSMF preparation is subcontracted, another oversight inviting a penalty might be the lack of MAH involvement in any document revisions.

5.

Inadequate QPPV oversight. If the qualified PV person – who carries personal liability for PV failings, in addition to any company penalties – does not have sufficient oversight of the process for safety variations preparation, submission and implementation, or over KPIs and ICSR adverse event reporting, this could also result in a failed inspection and potential fine.

Autumn 2020 Volume 12 Issue 3

Regulatory & Marketplace

6.

7.

8.

Lapsed attention to risk management. This is one of the topics with the largest number of critical findings over time during inspections, and includes findings related to poor maintenance of product information (routine risk management) or to implement additional risk minimisation measures (aRMM), such as educational materials or pregnancy prevention programmes.

Inconsistent or inadequate collection and management of safety information. Often the breakdown here is a failure to identify and track all potential sources of spontaneous safety data, or to reconcile adverse event monitoring activity with medical information and product quality complaints.

This can lead to safety signals being missed. Failing to properly validate the database for ICSR management can also lead to a fine, especially for SMEs which can’t justify the cost of a top-of-the-range PV database.

Using spreadsheets or other tables to manage validation is not acceptable, but there are affordable options to formalise activity here. Failure to transfer safety data from previous MAHs during an acquisition can also catch companies out.

Ongoing safety evaluation failings.

These concern benefit-risk and signal management and aggregate reports

www.ipimediaworld.com

(PSURs). Common mistakes include inaccurate sales and patient exposure figures; the inclusion of unrelated adverse event reports; failure to include relevant cases in the benefitrisk analyses; and late updating of product information. Other issues include failure to discuss all sources of potential signals; and a lack of rationale for the report frequency.

9.

Poor integration/interfaces between departments or with external parties to support complete and timely safety information. It’s important to include teams monitoring MAH websites for comments/safety reporting, and keep tabs on any general company email addresses that people might use to report safety data.

10. Failure to ensure safe archiving/ backups and business continuity planning. This includes validating controls over access to sensitive patient medical information and, if fireproof/ waterproof filing cabinets have been swapped for digital archiving, that such systems meet all required parameters.

With so many elements to get right, it is unsurprising that PV departments are getting some of this wrong – and feeling daunted by the responsibility.

It is worth seeking unbiased feedback on current provisions from professionals

with experience of a diverse range of approaches and systems, who can bring to bear the latest best practice – or perform a gap analysis that can help target remedial action.

In due course, the EU should clarify and update its guidance, so pharma companies understand more of what to aim for. But it’s important not to wait until then: competent authorities are starting to perform remote inspections, which is likely to lead to increased coverage and frequency as auditors’ capacity is increased.

Vanessa Fachada Oliveira Vanessa Fachada Oliveira is a Pharmacovigilance Manager & EU QPPV at Arriello. She is a qualified pharmacist with deep knowledge of pharmacovigilance legislation, and extensive experience in PV, quality management and medical information. Based in Lisbon, Portugal, Vanessa supports clients both as a PV consulting specialist and as a global EU QPPV/ deputy QPPV or LPPV for the local territory.

Email: vanessa.fachada@arriello.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 9

Regulatory & Marketplace

Building Solid Foundations for Regulatory Data Automation Automating regulatory processes delivers undeniable benefits, ranging from accelerating time to market to reducing error. But life sciences companies are widely grappling with the basic issue of getting up-to-date and consistent data to talk to each other across functions and systems.

Iperion’s Duncan van Rijsbergen offers five practical starting points to build a solid data quality foundation.

Life science companies are increasingly focused on the need for digital transformation in the pharmaceutical industry.

But data quality issues are impeding systems integration and automation. Regulatory systems contain data on products and their licences. There is also procedural data, recording interactions with the authorities about a licence, from the initial application through to post-authorisation changes to the licence.

Elsewhere, expert functions from manufacturing to clinical teams generate the basic data that feed the regulatory dossier that supports the licence. Typically, there is no direct communication between regulatory systems and expert functions systems. Manufacturing or clinical teams collate their data into a summary document and send it to the regulatory function. The regulatory team then takes that data and pulls it together in a submission dossier, ready to send to competent authorities for approval.

In manufacturing and the supply chain, the enterprise resource planning (ERP) system typically holds data about products and materials. Meanwhile, in the regulatory function there will be a regulatory information management (RIM) system which also contains data about the same products, but from the perspective of regulatory approval. Those systems are most often in completely separate worlds, with little or no interoperability.

Yet, a change made in the manufacturing world must be reflected in the licence.

Similar issues apply between the systems for management of clinical trials and 10 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the regulatory tracking of clinical trials applications. Currently, sharing that information is done through lots of forms and maybe even an intermediate system, which stores those forms. If these processes were automated, changes made post-authorisation would not delay product delivery or clinical trial start-up, enabling products to be brought to market and made available for patient treatment rapidly.

It is particularly important to get back to basics when it comes to structured, regulatory chemical, manufacturing and control (CMC) data. In just one instance, the process of inputting specification testing data into the laboratory information management system (LIMS), extracting it, entering it into regulatory documents, sending to regulatory bodies and then reversing the process for implementation can easily take a year or more.

Start with Data A data-first starting point is key. If companies store clean and consistent data, rather than documents, they will be in a much better position to automate processes and share this data efficiently with regulatory bodies.

Yet, companies continue to struggle with basic data quality issues.

First, there is the compliance issue, where licences must accurately reflect activity relating to clinical trials or manufacturing.

In a regulated environment, compliance failure could lead to product recall, licence suspension or fines. Datasets in operational settings may not align with datasets shared with the authorities. While the data is essentially the same, the way the data is presented may not be aligned exactly across the two systems. The granularity of the data, how it is worded or linked, might be slightly different.

Secondly, there are issues tracking changes in data over time. Drugs that are produced over many years will experience changes in, for example, composition or manufacture. These must be reflected both in regulatory systems and in the company’s operational systems. There is a need to change the data but also to keep it in sync. That synchronisation becomes

much more difficult if there is a long-winded process, with multiple steps in it, where the data changes form multiple times, going from structured to document, and back to structured again, with manual copying along the way.

Ideally the syncing process should be integrated with the regulatory process.

That way, when the company introduces improvements to the product, testing data can be shared with the regulator much more quickly, accelerating the time it takes to get product enhancements to market.

Reducing manual processes also eliminates the potential for human error and reduces costs.

Practical Action Points Commonly, compliance has become a goal in itself. Ideally, though, compliance should be effortless, a by-product of a company’s activities, not the focus of them. When data is aligned and kept in sync automatically, through a proper aligned process, then compliance is secondary – it will just happen by itself.

Here are five practical action points to help get companies started on their data quality journey: 1.

Communicate with all the stakeholders involved in the process. Together, identify the use cases for data flow continuity and agree on how best to measure the benefits of automating data integration. Getting everyone’s buy-in and developing solutions collaboratively drives transparency and improves trust among functions.

This approach enables people within a fairly long process chain to know how their data affects their predecessors and successors. It provides confidence that predecessors have done things correctly and successors get data they can work with.

2.

Develop a shared vocabulary to talk about data held in common across functions. Presenting product data across the organisation in a way that everybody understands, with commonality of language, also builds Autumn 2020 Volume 12 Issue 3

Regulatory & Marketplace trust as well as driving operational excellence and innovation.

3.

Standardise data descriptions. Once use cases have been identified and a common vocabulary agreed, consider how best to standardise data relating to complex products. The IDMP model is a valiant effort to find a common way to describe product data. The quality and consistency of individual data is also key to data standardisation initiatives, such as the US FDA’s drive to standardise Pharmaceutical Quality CMC (PQ-CMC) data elements for electronic submission. The more widely

accepted a product model is, the easier it is to share with external parties. This includes regulators, and also partners such as labs, manufacturers and research organisations.

4.

Ensure processes are properly aligned.

There needs to be a robust process for capturing and sharing changes over time – and making sure that systems keep in sync and that there is as little time lag as possible. Focus on bottlenecks. There may be one process in an operational setting and another in the regulatory function. Where do they meet? Where does the data gets

exchanged and how could that be improved?

5.

Identify suitable technological solutions. The initial focus should not be on finding the right software, but on the system architecture and how and where to connect systems. One approach could be to build a bridge between two systems, a point to point connection. The issue is maintaining the link and upgrading functionality in two discrete systems that talk to each other. A better option would be to develop a looser coupling, and this is where the common language model comes in. It is important not to take a static approach – how do I solve the problem now – but to also consider maintaining the solution and innovating over time. This is not about individual systems but about a system of systems.

Ensuring data quality and integration won’t in itself generate innovation but it will provide a platform on which to innovate. The core business of a pharma company is to get the best medicines to its patients. Data processing should be a hygiene factor.

Technology, systems and software are not, on their own, the answer to data quality issues. They are secondary to a good understanding of the data and data flows within the business. The first steps are to map then standardise data. This will provide a solid foundation for life science companies to put in place technology to integrate and automate data processes, joining the regulatory dots and speeding time to market.

Duncan van Rijsbergen Duncan van Rijsbergen is Associate Director Regulatory Affairs at Iperion, a globally-operating life sciences consultancy firm which is paving the way to digital healthcare, by supporting standardisation and ensuring the right technology, systems and processes are in place to enable insightful business decision-making and innovation.

Email: duncan.vanrijsbergen@iperion.com

www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 11

Regulatory & Marketplace

Barriers in Medical Device Innovation Introduction: Abstract: Every day, innovative new technologies can and do transform industries, and due to the massive technological innovations like the web, smartphones and communication technology, the rate of change has increased. But not all companies are created equal as regards creativity. The healthcare industry is extremely complex and due to rising costs and patient demands, the medical care delivery environment is under growing pressure. Such stresses and the industry's inherent existence itself make healthcare development more complex than it is in the consumer products market.

To break through the complexities of medicine and drive science forward, inventors and medical testing and production firms must first resolve the many obstacles to the creation of healthcare products. Knowing how medical devices interact with humans is a critical problem that influences both the design and acceptance of innovative new technologies and the regulation.

The FDA classifies medical devices into three classes: the first two classes do not have much regulatory requirement, but class three has a main hurdle which should pass the regulatory requirements for marketing of the product. During the early generations, the regulatory requirement for marketing of medical devices was much less compared to the present situation; now it requires to pass many regulatory hurdles which is a very big barrier for medical device innovation because there is no proof that it will pass through the regulatory hurdle.

Keywords: Medical device, Innovative Barrier

body; or a tool intended for internal or Barriers in innovation of medical devices A medical device is described as a medical product which, via pharmacological, external use in human or animal disease cause a massive problem globally. For immunological or metabolic achieves its primary intended effect in on or the on or disorder, diagnosis, treatment,means, mitigation example, if a medical device is not 2 or market the treatment for someordisease or theprevention. human body; or a tool intended for internal orand external use in human animal disorder is not available; most barriers relate disease or disorder, diagnosis, treatment, mitigation prevention.

(2) Example to medicalor efficacy review, distribution of the Substances used for in vitro diagnosis product, and manufacturing of the medical Example: and surgical dressings, surgical bandages, device with good quality, regulatory oversight. surgical staples, surgical sutures, ligatures, blood and blood component collectionand surgical Anotherdressings, hurdle is surgical questions relating Substances used for in vitro diagnosis bandages, bag with or without anticoagulant and to intellectual property rights (IPRs). The surgical staples, surgical sutures, ligatures, blood and blood component collection substances like mechanical contraceptives extensive testing that the US Food and (condoms, devices, tubal rings), Drug Administration (FDA) or the European bag with intrauterine or without anticoagulant and substances like mechanical contraceptives disinfectants and insecticides.

Notified Bodies require represents large (condoms, intrauterine devices, tubal rings), disinfectants and insecticides. and risky financial commitments. The final History financial outcome of investments may History: The first “medical device” invented was be uncertain even after positive clinical the thermometer in 1603 by Galileo. In 1819 testing, as payments for products and Thestethoscope first “medical device” thermometer in 1603 Galileo. In the (wooden) wasinvented invented was by the services are not assured by by reimbursement Rene, real breakthrough when mechanisms. may require 1819 and the the stethoscope (wooden)was was invented

by Rene,Reimbursements and the real breakthrough there was the discovery of X-rays in 1895, more research, recording a beneficial cost was the when there was of X-rays in 1895, thenforthe invention of the then invention of thethe ECGdiscovery in 1903, which / benefit analysis patients, healthcare is still used in all hospitals.

There are more providers, or even for the broader society.

ECG in 1903, which is still used in all hospitals. There are more than 14,000 than 14,000 different products, according to The cost of such studies is often the liability different products, according to Global Medical Nomenclature.

Global Medical Device Nomenclature. of theDevice fabricators of products.5

There are four types of classification of medical devices in India and Japan: (4)

There are four types of classification of medical devices in India and Japan:4

But according to some countries like Europe and the USA, there are only three classes:1

ButInnovation according to some countries like Europe and the USA, thereadding are only three Innovation isisnot about introducing something new but also value to notonly only about introducing something new but also adding value to it. classes: (1) it. It should be useful and feasible. Innovation and new product development are It should be useful and feasible. Innovation the lifeblood of thedevelopment R&D department of an industry. and new product are the lifeblood of the R&D department of an industry.

Ideas for change also come from consumers and experts who are most familiar

with the issues that need to be addressed. Most ideas are received from clinicians

Introduction A medical device is described as a medical product which, via pharmacological, immunological or metabolic means, achieves its primary intended effect in or on the human

Ideas for change also come from and healthcare solve consumers andproviders experts to who aretheir mostproblems by innovating new products. familiar with the issues that need to be addressed. ideas are received devices from cause a massive problem globally. For Barriers in Most innovation of medical clinicians and healthcare providers to example, if a medical device is not on the market and the treatment for some solve their problems by innovating new products. disease or disorder is not available; most barriers relate to medical efficacy

12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Regulatory & Marketplace Barriers in Medical Devices6 The following topics will be discussed herein in an attempt to give a brief overview of barriers in medical device innovation:

Medical Practice Patterns and Education While medical practice is changing rapidly, there is an underlying tradition in medicine which supports the status quo. New methods are often, and often correctly, adopted only after the "medical establishment" has completed and accepted controlled studies. Randomised trials and metaanalysis are needed for new procedures and technologies to become a standard of care. Even upon completion of such studies, years can pass before a tool or procedure is commonly used. This is a challenge for designers of devices who spend enormous resources to sell a product. The duration of the new product's high-income potential may be short, making it less desirable for new technology to be the first out. The method of introducing new technologies in hospitals is often difficult and relies on physician-administrative consensus.

Market Size and Penetration The global market for medical devices is rising, but substantial maldistribution exists between rich and poor countries.

The disparity is apparent and important as applied to the consumer technology industry such as mobile phones. Although cell phones are available to most people, there are few cardiac pacemaking agents, and the number of patients killed each year by a lack of pacemaker and defibrillator care is estimated at 1–2 million. While ordinary Africans can afford a cell phone and pay the subscription services, a lifesaving pacemaker and the requisite charges for implantation and monitoring cannot be managed. This can be partially understood as an inefficiency for medical devices firms in emerging markets and a lack of healthcare services and skills. Device manufacturers 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

may be hesitant to offer the emergent market lower-priced products, believing their own goods could be cannibalised and profit margins eroded.

Research and Development (R&D) and Device Failures Medical device R&D and sales are highrisk projects. It's a long and expensive process from proposal to practical medical implementation. Traditionally, early research is conducted in educational institutions, while in the corporate environment software creation, evaluation, and development occurs. Systems are expensive and often drag on for years.

Despite extensive product evaluation both ex vivo and in vivo, the manufacturer's risk of later failure of new products will cause severe medical problems for the consumer and economic disaster. The Christiansen hip prosthesis and the “Björk–Shiley” heart valve, as well as the silicone breast implants in France, are the leading examples of failed products. The future legal and financial consequences of such failures represent a major investment risk. As an example, with the “Björk–Shiley valve”, where welded valve struts split and caused embolisation of the leaflet, the production company went bankrupt because of allegations of personal injury. The “Björk–Shiley” experience has resulted in more stringent testing practices and medical follow-up for heart valve products, which is helpful to patients, but acts as an innovation barrier as new claims will emerge more than 20 years after medical devices barriers to product development implantation. Initial acceptance and successful implantation of a device is definitely not a guarantee against future complications. It may be unrealistic

for developed and poor countries to assume the same degree of complexity and safety features of medical devices as those requested by Western regulatory bodies. Most poor countries' gross domestic product could not afford the implantation of costly implants even for life-threatening diseases for the people, and it may be fair to permit simple, perhaps even less stable devices in such markets. At present, advanced computer therapy is open only to the wealthy and government leaders in poor countries. Implantable devices pose risks to patients and are known as Category III products, requiring premarket approval.

In the US, the FDA, a government agency, oversees this procedure.

IPRs, Patent Issues, and Publication New medical technologies are often the product of academic-commercial collaboration. This may create contradictions between the willingness to publish and the interest in patenting and obtaining IPRs. Previously, researchers and healthcare employees' IPRs may have been poorly secured, leaving the scientist with the choice of keeping or publishing an invention secret, risking the latter's loss of privacy. Technology transfer organisations, while increasing this obstacle, promote collaboration between companies and institutions. Small businesses, creating new technologies, may be in an adverse position to protect their IPR from enormous legal and financial assets from corporations.

Big companies often use large and general patents to protect their goods and services, preventing new development. Medical professionals are essential contributors to product innovation, and insufficient IPR regulations pose yet another obstacle to advanced innovative development unless technology transfer organisations actively help protect IPRs. A double-edged sword may be the question of patent law and practice. Gaining a patent will promote creativity by granting exclusivity to the patented item for the length of the patent.

Patents, on the other hand, raise product costs dramatically and may reduce creative efforts in the relevant field. Gold et al. provide a careful analysis of the importance and drawbacks of existing patent law practices. The consumer limitations on modern devices or drug therapies in the developing world is a particularly serious problem that has been proposed as an alternative to the current patent procedure.

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 15

Regulatory & Marketplace

classification in many countries and may not include the cost of new advanced tools. Methods involving new devices for healthcare providers can pose a financial pressure or loss. The lack of innovative technology payments will hamper the implementation of new technologies and thus product innovation. Legislation can vary considerably in different countries, and the lack of predictability is an apparent obstacle to innovation. Reduced payment options on emerging markets are seriously obstructing the introduction of new technologies. As noted earlier, patent regulations may further hinder the growth of low-income countries, even though these countries may be able to use the reversing design technique to manufacture out-of-patent products.

16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Ethical Considerations The World Health Organization considers access to healthcare to be a human right, but this right remains a myth for most of the global population. Although the health problems are different, the richest countries are also struggling with delivery and access to care. Transplantation and use of existence-support equipment, such as dialysis and circulatory aid devices, should be in theory open to everyone in need, but provision, in fact, is severely restricted globally. In many countries, insurance may not cover existence-supporting devices such as pacemakers, and treatment is thus restricted to monetary rather than clinical indications.

Conclusion As the world is moving very fast, innovation of medical device will provide a better lifestyle to patients. Innovation in medical devices has given enormous benefits to patients, particularly in the developed world, while there has been much less benefit to the population in emerging and poor countries. Because of the obstacles to technology, the production and adoption of novel medical devices was slower than for some consumer goods. The combination of medical and technical expertise will contribute to faster and more efficient growth, thereby enhancing investment capital availability. Early R&D will take place across consortia like education, manufacturing companies, and government Autumn 2020 Volume 12 Issue 3

Regulatory & Marketplace agencies, thus increasing shareholder aversion to risk. Streamlining clinical trials, including a more consistent method to the process of evaluating health technology, can accelerate the implementation and spread of price-effective devices. While the current business model for computer manufacturers may be threatened by lower prices, increased sales may make up for them economically by establishing a real global market. Medical devices often have excessive pricing, and it is undoubtedly

true that this innovation will make it much easier for the medical field to stick to its basic moral principles when interacting with medicine and technology. Changes in patent laws and the way such laws are practised may decrease cost and increase competition.

Internet: Classification of medical devices in USA is available at https://www.fda.gov

Tarun Nag S. S.

4.

5.

REFERENCE 1.

2.

3.

6.

medicaldevices deviceregulationandguidance/ overview/classifyyourdevice/ucm2005371.html [citation 13 May 2019] https://en.wikipedia.org/wiki/Medical_device https://www.who.int/medical_devices/full_ deffinition/en/ https://cdsco.gov.in/opencms/opencms/en/ Medical-Device-Diagnostics/Medical-DeviceDiagnostics/ https://www.theguardian.com/healthcarenetwork/2015/jan/23/barriers-healthcareinnovation https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4063798/

Balamuralidhara V.

M. P. Gowrav

Tarun Nag S S is pursuing a Masters in Pharmaceutical Regulatory Affairs, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India.

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

M P Gowrav is Lecturer in the Department of Pharmaceutics in JSS College of Pharmacy, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India.

Email: tarunnag9844@gmail.com

Email: baligowda@jssuni.edu.in

Email: gowrav@jssuni.edu.in

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Regulatory & Marketplace

Ensuring the Pharmaceutical Industry is Prepared for a Future Pandemic The COVID-19 pandemic has stretched healthcare suppliers, organisations, governments and healthcare professionals to their very limits, locking down the world like never before. Healthcare industries, which were already under huge strain across the world, have been placed under unprecedented pressure. But, as the saying goes, there’s always light at the end of the tunnel and we’re beginning to see positive signs. While there is still a threat of a second wave on the horizon, deaths and infection rates are declining and the recent discovery of dexamethasone as a viable treatment for the sickest patients has been greeted with enthusiasm by the scientific community. Similarly, Oxford University appears to be making some progress on the vaccine front, with a drug developed that’s safe and triggers an immune response.

With such a focus on drug development and also on searching for existing drugs that can help the fight against COVID-19, the pharmaceutical industry has been central and will continue to play a leading role in the months to come. However, it’s not been without difficulty. COVID-19 has had a significant impact on all sectors of the economy, including pharmaceuticals.

On the one hand, new opportunities have opened up; first of all, the involvement of companies in the development of new drugs for the treatment of COVID-19, as well as in the clinical trials of these drugs and in the future in production and distribution.

Like many other industries, pharmaceuticals are often not a vertically integrated business. In order to create, properly register, produce and subsequently market a medicine, the efforts and involvement of many companies, sometimes located in different countries and on different continents, are needed.

breakneck pace to reach a solution, it is fair to say times have been tough.

For example, we produce a generic drug at a factory in India, buy raw materials for this drug in Japan and after production, the drug goes to a distribution warehouse located in Europe. After that, the drug is delivered to different countries, including via air delivery, all whilst bearing in mind that the drug has a rather short shelf-life and in some countries it is impossible to deliver the drug with a residual period of less than, for example, one year. This example on one specific drug shows how vulnerable the pharmaceutical business is.

2. Speed and Collaboration are Key The scientific community has come together to discover ways to protect against the virus at a speed never seen in our lifetimes. The virus having originated in China, much of the essential groundwork was also completed by the Chinese, ensuring the rest of the world at least had some degree of preparedness before the virus reached their shores.

Preparing Ourselves Undoubtedly, the way we have approached this pandemic will become a case study which will inspire our response to future global disease outbreaks. So, with this in mind, what are the lessons that can be learnt to ensure that the pharmaceutical industry can respond quickly and definitively to the next pandemic? The answers are many, but finding them will be key to saving lives.

Secondly, the state budgets allocated to healthcare in many countries were significantly increased and a fairly large part of this funding was directed to the procurement of medicines.

1. Applying Unique Approaches to a Unique Virus Scientists and pharmaceutical experts have faced myriad challenges, as is to be expected from COVID-19’s status as a novel coronavirus. While similar in ways to the viruses that caused the SARS outbreak of 2002–2004 and the MERS outbreak that began in 2012, COVID-19 has proven to be much more transmissible, with its presence in the vast majority of countries now confirmed.

But on the other hand, despite the stereotypes that pharmaceuticals are one of the few industries for which the pandemic and subsequent quarantine have brought certain benefits, the pharmaceutical industry has suffered from quarantine no less than other industries.

Essentially, those charged with coming up with effective treatments or a vaccine have had to start from scratch, while contending with the various restrictions brought about by global lockdowns. Combined with a growing sense of panic amongst the general public and the subsequent need to move at

18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

However, there have been a number of success stories that underline the vital work that the pharmaceutical industry does, and it is these that should serve as examples of how to approach the future.

The pace of developments since then has been relentless. Teams around the world are working furiously to develop an effective vaccine, with promising results seen already.

As far as viable treatments are concerned, the evidence of remdesivir reducing patient recovery times shows significant promise, and the discovery of dexamethasone – an affordable, widely available steroid in use since the 1960s – in improving survival rates has led to the UK government approving it for immediate use.

The bottom line here is that speed and collaboration have been hugely beneficial in turning the tide against COVID-19, and will continue to be so in the ongoing battle.

It is necessary that state regulators, together with relevant organisations and with the involvement of other players in the pharmaceutical industry, develop principles for the work of the healthcare industry in general and pharmaceuticals in particular in a pandemic and other possible scenarios.

In this case, everyone will understand how they act in certain conditions and procedures should be simplified, including clinical trials and drug registration. Any future pandemic will only be successfully beaten if pharmaceutical companies, experts, scientists and governments are willing to spring into action and work together for the common good.

3. Analysing Big Data Data gathering and analysis have grown Autumn 2020 Volume 12 Issue 3

Regulatory & Marketplace in importance in recent years for all businesses, aiding everything from customer interactions to HR functions. For a company in the retail sector, for example, unifying a range of disparate datasets and drawing insight from them can give an organisation that all-important competitive advantage. The situation is no different for the pharmaceutical industry: when it comes to identifying the right treatments and approaches in a future pandemic, data will play a leading role.

Of course, data already provides the basis for the treatment of many diseases.

Before a new medicine is approved for use, huge amounts of data from clinical studies will be examined and compared, before a final decision is made.

However, there is more we can do to make data analytics processes stronger.

When independent studies on a particular drug are carried out in one country, experts in other nations may be unaware that these studies exist if they do not have the ability to find and process vast amounts of data.

This is where emerging technologies such as artificial intelligence (AI) and machine learning will make their mark. By automating data analytics and applying AI capabilities where possible, the management of large datasets becomes considerably easier, and insights can be drawn from this information much more readily. Finding ways to conquer data – coupled with the aforementioned collaboration between experts – will revolutionise the industry.

4. Optimising Logistics Sadly, when the pandemic hit, we quickly discovered that many nations and their health services were underprepared when it came to having the right equipment and infrastructure in place to respond rapidly.

Testing for Covid-19 took a long time to get fully off the ground in the UK, and the early scramble for ventilators underlined the fact that the country had been caught off guard.

Logistically, the production of medicines is a major operation even outside of a pandemic. For example, a drug may be produced in India with raw materials developed in Japan, before being sent to a warehouse in Europe from which it is then distributed. This all needs to be carried out with the medicine’s short shelf-life in mind.

Currently, there are still problems with the supply of raw materials and with www.ipimediaworld.com

production. Interestingly, prior to the pandemic some organisations didn’t pay attention to the geography of where they buy raw materials, where they produce and where they deliver. Geography has always been important, mainly in terms of cost and delivery time, but the possibility of delivery not happening would never be in question. What we are seeing now is that the more geographically concentrated production activity, API, packaging production, laboratories, production sites, location of employees; the less vulnerable the business, at least from the point of view of today.

To prevent these struggles from becoming a major issue in a future outbreak, the pharmaceutical industry needs to be prepared to act quickly to scale up production of key resources – such as specialised testing kits and new medicines as soon as they are needed. Maintaining healthy stockpiles of established treatments is also key as there is always a possibility that an older medicine might be effective against a novel disease – as has been seen with dexamethasone.

This will also require governments and international health bodies to be much quicker in future in developing and implementing emergency procedures to scale up production when the need arises.

5. Regulatory Considerations The pharmaceutical industry, by necessity, is a heavily regulated one. While the challenges of the pandemic have created a need for regulatory processes to be expedited in many cases, lockdown restrictions have made it more difficult for this to be done efficiently. There are also inconsistencies across geographies in terms of if and how a state regulator will approve a particular treatment. For these problems to be ironed out, the pharma industry and the agencies responsible for regulation need to work more closely together to ensure responses can be better coordinated in future.

Increased flexibility and efficiency are the name of the game, both in terms of regulatory approval for new treatments, and logistical considerations that ensure that medicines can be manufactured and delivered in double-quick time.

Learning from What We’ve Witnessed With no end in sight to the COVID-19 crisis, it is time to take a fresh look at national laws and start discussing possible changes.

Governments around the world are taking unprecedented measures to support the economy and, in particular, healthcare.

The scale is amazing – today in Western countries, support packages range from 10% to 30% of GDP and huge amounts of money are being allocated to support health systems and to develop drugs to treat COVID-19.

Any pandemic leads to increased cooperation between countries both at the government level and at the industry level, and just cooperation between pharmaceutical companies and governments should give significant progress in the fight against the pandemic.

In the months and years to come, we will most likely see pharmaceutical companies together with governments developing a ‘plan B’, in case of the closure of a number of industries or countries.

Although we hear that many governments are talking about the need to establish national research centres and local pharmaceutical industries, in general, the pandemic crisis has shown the value of globalisation in the pharmaceutical field.

Ultimately, if and when we face another pandemic, it’s crucial that the pharmaceutical industry has learnt from the lessons taught by COVID-19: innovation, efficiency, data analysis and collaboration will be key, and leaders in the sector should be focusing their efforts now on how to ensure the processes are in pace to facilitate this should we find ourselves amidst another worldwide pandemic.

Vladimir Tkachenko Vladimir Tkachenko, a pharmaceutical sciences expert, is general manager of Amaxa Pharma, a UK-headquartered pharmaceutical company focused on life-threatening therapeutic areas such as oncology and neonatology in the CIS countries. Within this role, Vladimir is responsible for the general management and success of the company, developing sales strategy, implementing managerial accounting strategy, preparing operation budgets and licensing.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 19

Regulatory & Marketplace

The Patent Landscape Behind COVID-19 Vaccines

Development of vaccines to prevent COVID-19 has become a fascinating story, especially for those with any interest in life sciences. The speed in development and diversity of strategies that have arisen all around the world involve a vast patchwork of private companies, public institutions, and private-public partnerships such as CEPI (the Coalition for Epidemic Preparedness Innovations) and Gavi, a Geneva-based vaccine procurement organisation. However, most of the novel vaccines are being built using previously developed vaccine platform technologies. By vaccine platform technologies we refer to those techniques or methods that typically comprise multiple components or a common “recipe” and are used or have been proposed to be useful for producing more than one different vaccine1. Some platform technologies are older than others. For example, viral vectors carrying an antigen of choice have been used for longer and are more established than nucleic acidbased vaccines. In the development of Covid-19 vaccines, there has been a surprising uptake in the use of relatively new vaccine platforms. The choice of the less-tested platforms likely stems from the fact that the more traditional vaccine platforms have not been particularly successful in attempts to develop vaccines against coronaviruses, and also because many of the novel strategies promise a faster development timeline compared to the traditional platforms.

20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Given that most of the newer vaccine platforms, or at least some components of them, will have been developed within the past 20 years, many of them are likely to be still covered by patent protection. In this article, we took a look at the patent landscape covering some of the platform technologies that are being exploited by researchers in the race to develop an effective COVID-19 vaccine.

The WHO reported that as of July 14, 2020, there were 23 vaccines in clinical development and 140 vaccines in preclinical research2. Of this total of 163 vaccine candidates, 51 are reported as being developed using previously used platforms for vaccines against non-coronavirus targets.

That leaves 112 vaccines that use a platform that has not previously been used for any approved vaccine. For the vaccines in clinical development, the number of vaccines that have been developed using a completely novel approach is surprisingly high, at roughly 50% (11/23). It is worth noting that vaccines that have been in development based on recent next-generation vaccine platform technology against other coronaviruses, such as SARS or MERS, have not yet resulted in clinically successful vaccines.

On the topic of platform technologies, the EPO has recently published a variety of search statements to help in identifying the most relevant documents in various technical fields3. This is fairly similar to the WIPO coronavirus search tool that we described in our previous article 4, however the EPO tool includes a specific section that is focussed only on vaccines.

The vaccine platform categories listed

are fairly broad, but include some of the specific platforms we will look at here, such as virus-like particles, nucleic acid based vaccines, nanoparticles and adjuvants used in formulating the vaccines.

New Patent Coverage?

Based on prior experience in patent filings for vaccines at the time of epidemics, it is clear many patents have been and will be filed for the new COVID-19 vaccines. We cannot yet evaluate most of the claims that have been filed to cover the novel vaccines themselves or see by whom they have been filed, because patent applications are typically published no earlier than 18 months from the filing.

Having said that, the first patent application that specifically covers a COVID-19 vaccine was reportedly published on June 2nd, 2020 by China National Intellectual Property Administration5. The application No. CN202010193587.8 was only filed on March 18th by the Institute of Military Medicine, Chinese Academy of Military Sciences in conjunction with CanSino Biologics, a Chinese vaccine manufacturer. The patent application seems to describe the use of a human replication-deficient adenovirus as a vector encoding a specific S-protein sequence antigen. The description set forth that the claimed S-protein encoding nucleic acid sequence was optimised by reducing the content of rare codons to 3%, increasing the content of high-frequency codons to 81%, and increasing the GC content to 58%. The description further notes that the homology of the engineered S-protein antigen coding nucleic acid sequence with the original S-protein gene sequence was

Autumn 2020 Volume 12 Issue 3

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

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

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 21

Regulatory & Marketplace The following table provides a look at some of the patent families covering components of platforms that are being used to develop candidate COVID-19 vaccines:

tiveness/non-obviousness of any specific vaccine will also likely require some results that show that the particular approach surprisingly results in producing antibodies, and preferably neutralising antibodies against the SARS-CoV-2 virus.

While the complete genetic sequence of SARS-CoV-2 was published on January 11, 2020, public information on the specific SARS-CoV-2 antigen(s) used in the vaccine development is limited8. Like the published Chinese patent application with claims that identify a specific sequence ID as the antigen, we anticipate that other patent applications are likely to be filed to cover the specific, effective antigenic fragment(s) and their potential modification(s) and/or combination(s). In view of the uncertainty in biology, we further envisage that the specific vector constructs and/or specific formulations that elicit in vivo neutralising effect on the SARS-CoV-2 virus could be patented. Furthermore, the development process of these vaccines may also uncover some unexpected tweaks to the existing platforms that may make the platform perform better for future projects and therefore provide patentable claims. Any such advances that may be utilised in some form for possibly speeding up other vaccine development or manufacturing, targeting new or previously difficult to target pathogens, and making potentially safer and/or more effective vaccines could lead to further patent filings. Such follow-on filings will create a larger portfolio of patent documents sitting over and around each platform technology, with specific filings directed towards use in preventing and/or treating COVID-19.

70.4%. The published claims as filed and re-produced in the INSERT as they were translated in the ESPACENET database, are illustrative of the types of claims one can anticipate to be included in other applications. The claims cover an isolated and optimised nucleic acid sequence for the specific antigen6, a specific vector or delivery method or vehicle delivering the antigen as a vaccine, and methods of use of the antigen as a vaccine, as well as methods of making the vaccine. The Chinese media reported that the Chinese Patent Office (CNIPO) granted the patent on August 17th, 2020, and it was issued on September 11th, 2020 as CN111218459B with claims that were identical to those published with the application. Interestingly, the claims are limited to use of spike protein of SEQ ID NO: 1 only.7 22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

We anticipate the claims in patent filings for other specific COVID-19 vaccines to be relatively narrow in order to establish novelty over the early platform technology filings. This is clear, not only from the published Chinese patent application claims but also from our review of the patents covering the basic platform technologies, where other specific follow-on patent filings directed towards the use of the platform in making vaccines for preventing/treating other diseases have been filed.

The global story of the struggle in developing a vaccine against coronaviruses in general, and for COVID-19 specifically, should provide a backdrop for establishing inventiveness/non-obviousness that the patent offices around the world could acknowledge. However, establishing inven-

What about Freedom-to-operate?

As with any technology that utilises multiple components covered by multiple patent claims, clearing the right to make, use and sell a product that utilises the components can become a challenge. While collaboration initially appeared to be the popular route for COVID-19 vaccine development, the potential for significant commercial gains has already begun to brew some patent battles.

For example, the much talked about mRNA-platform-based vaccine under development by Moderna is facing headwinds from Arbutus. Arbutus claims that the delivery system, based on lipid nanoparticles (LNP) that are essential for delivering Moderna’s vaccine, infringes patents covering the original LNP technology Autumn 2020 Volume 12 Issue 3

Regulatory & Marketplace

CANSino Biologics patent application publication No. CN111218459A claims as published: 1.

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A polynucleotide for coding a Sprotein of the 2019 novel coronavirus is characterised in that the sequence of the polynucleotide is shown as SEQ ID NO: 1.

A vector comprising the polynucleotide of claim 1.

The vector of claim 2, wherein the vector is pDC316.

A human replication-deficient recombinant adenovirus capable of expressing the polynucleotide of claim 1.

The recombinant adenovirus of claim 4, wherein the recombinant adenovirus is derived from an admax adenovirus system.

patents owned by Arbutus9 (see above table for some of the relevant LNP filings held by either party). While Moderna’s battle over rights to use the Arbutus LNP technology began before the development of COVID-19 vaccine by Moderna, there is no doubt the

7.

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The use of the recombinant adenovirus of claims 4 and 5 in the preparation of a vaccine for the prevention of 2019 novel coronavirus.

The method of claim 6, wherein the recombinant adenovirus is formulated as an injection, nasal drop, or spray.

The use of claim 7, wherein the recombinant adenovirus is prepared as an intramuscular injection.

A method of preparing a recombinant adenovirus according to claim 4 or 5, said method comprising the steps of: (1) constructing a shuttle plasmid vector comprising a polynucleotide encoding a 2019 novel coronavirus s protein; (2) transfecting the shuttle plasmid vector and the skeleton plasmid

stakes have gotten significantly higher in light of the initial development successes of Moderna’s vaccine candidate.

We will continue to follow the developing landscape of COVID-19 vaccines once a more complete picture of the filings emerges. It will be fascinating to observe how much of the collaborative spirit remains when the intellectual property positions are clarified.

2.

https://www.centerforhealthsecurity.org/ourwork/pubs_archive/pubs-pdfs/2019/190423OPP-platform-report.pdf https://www.who.int/publications/m/item/

Dr. Leena Contarino Leena is a member of the HGF Life Sciences Team and also a member of the HGF Microbiome IP Team. She advises clients in creating strategies to capture, protect and commercialise inventions mainly in the areas of biologics, including DNA, RNA, peptides, and proteins, such as antibodies and enzymes, as well as cells and microbes. She also has considerable experience in diagnostics utilising biomolecules, particularly for personalised medicine applications. www.ipimediaworld.com

11.

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REFERENCES 1.

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of step (1) into the host cell; (3) culturing the host cell in step (2); (4) harvesting the human replication-deficient recombinant adenovirus released from the cells of step (3); (5) amplifying and culturing the recombinant adenovirus in step (4); (6) purifying the culture product in step (5).

The method of claim 9, wherein the vector of step (1) is pDC316.

The method of claim 9, wherein the backbone plasmid of step (2) is pBHGlox_E1, 3Cre. The method of claim 9, wherein the cell of step (3) is an hek293 cell.

The method of claim 9, wherein the amplification culture method of step (5) is suspension culture.

The method of claim 9, wherein the purification method of step (6) is source 30q chromatography.

draft-landscape-of-covid-19-candidate-vaccines https://www.epo.org/news-events/in-focus/ fighting-coronavirus.html http://www.hgf.com/updates/news/2020/06/alook-at-the-wipo-coronavirus-tools/; https:// patentscope.wipo.int/search/en/covid19.jsf https://www.natlawreview.com/article/ chinese-patent-application-coronavirusvaccine-published https://worldwide.espacenet.com/patent/ search/family/070813158/publication/ CN111218459A?q=CN111218459 https://www.chinadaily.com.cn/a/202008/16/ WS5f391566a31083481726099a.html https://www.nature.com/articles/d41573-02000073-5 https://www.evaluate.com/vantage/articles/ news/patents-and-litigation/covid-19vaccine-battle-just-got-interesting

Ellie Purnell Ellie is a member of the HGF Life Sciences team and also a member of the HGF AgBio and Industrial Biotechnology teams. She has developed a breadth of experience extending across a variety of technologies in life sciences and has a keen interest in biochemistry, cell biology and plant sciences. Ellie has specific experience working with multinational clients in the antibody, microbiology and plant genetics sectors.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 23

Regulatory & Marketplace

Agile and Flexible – A Fitness Check for the Pandemic Era The COVID-19 pandemic era is shaking up the pharma supply chain. Heavily regulated processes that used to take years are speeding up as existing drugs are repurposed as therapeutics for COVID-19 patients and new drugs and vaccines are under development. Kallik CEO Gurdip Singh provides a health check for pharma businesses who are straining every sinew to meet changing market demands.

Many global pharmaceuticals companies are struggling to meet demand, while some are experiencing dramatic drops in demand and pressure to cut operational costs.

Every major manufacturer is experiencing disruption across supply chains, driven by volatility in the supply of parts and raw materials. The requirements for social distancing and employee safety measures add an additional level of pressure.

Across the globe, countries have stopped elective surgery to create capacity for treating COVID-19. Medical device suppliers supporting hospitals with procedures such as hip replacements and even elective cardiac surgery have seen a huge impact on their revenue streams. Some have diversified their product ranges to meet the demand for PPE and ventilators. As countries re-open the doors to elective surgery, there is huge pent-up demand for product. The need to able to ship different product lines rapidly has forced changes in manufacturing shift patterns and logistics.

In the pharmaceutical sector, many players have pivoted their operations to join in the race to develop a vaccine or repurpose existing drugs to treat COVID-19.

The need to repurpose patient information labelling rapidly to meet regulatory requirements is an immediate challenge.

Normal has fundamentally shifted.

Leaders in pharmaceuticals, medical devices, chemicals and cosmetics who understand and act on this new normal will have ample opportunities for growth.

The possibility of future pandemics is very real. From now on, suppliers must be 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

mindful that they may have to diversify from mainstay revenue streams at short notice. The dynamic of the supply chain has changed. Traditional, smooth processes will need to adapt to peaks and troughs.

Diversification is key to responding to changes in buyer behaviour and the macro economic environment – and avoiding massive dips in conventional revenue streams. A centralised view of data and insights across the whole manufacturing operation will become a standard component of running a manufacturing organisation.

Diversify to Survive For the survival of many organisations, it is vital to accelerate diversification and boost speed to market. Data analytics, harnessing the power of data that companies already have, can help organisations understand their customers’ fast-changing needs at a granular level. Getting information about the product to the right stakeholders so they can use it safely and effectively is key. Patient information need no longer be produced only in the form of a label or a leaflet. Consider what is the most effective means for people to consume that information – an online video may be a useful supplement to traditional paper information.

If patient information data is stored at component level, separated into symbol, text, or phrase, right through to adaptations for different languages, it will enable faster change. That way, when a company has to diversify rapidly, it is easy to reuse existing data to create new labelling using confirmed branding, logos and phrases.

A medical device company that produces predominantly orthopaedic surgical devices might be able to produce ventilators.

Reusing existing data, it can get a new product line labelled and out very rapidly.

Anyone selling a drug that can be used to treat COVID-19 can repackage and deliver it within a matter of days.

Addressing Staffing Issues Social distancing measures have had a huge impact on staffing. Many organisations have been forced to put in place remote

working access for office staff – that meets regulatory requirements – at short notice.

Manufacturers may lose up to 50% of their on-site personnel1. To address this, some manufacturers have adjusted shift patterns to reduce the number of staff on site at any one time. Longer term, increasing process automation is more effective.

In the scramble to pivot business models to address fast-changing supply challenges, it is difficult to look ahead to the likely long-term changes to the sector.

Some things won’t change. We don’t need a pandemic for organisations to know they need to focus on driving efficiency. That is something that is always at the heart of business. Automation, supported by the Internet of Things (IoT), is increasingly looking like a sensible way of achieving greater and sustainable efficiency.

Analyst firm McKinsey highlights how the manufacturing sector, where physical distancing can be challenging, is tapping into the IoT: “In the recent past, there was some scepticism about applying the Internet of Things (IoT) to industry.

Now, many industrial companies have embraced IoT to devise safety strategies, improve collaboration with suppliers, manage inventory, optimise procurement, and maintain equipment. This virtual shift will help digitise and scale much-needed expertise across the organisation to enable the extended and often virtual workforce to become more focused, effective, and more productive.”2 Remote Management and Reducing Costs Significantly accelerated deployment of industrial IoT is already contributing more data visualisation and insights across operations. Remotely managed virtual solutions can help companies adjust to a very different future by reducing costs, enabling physical distancing, and creating more flexible operations. Increased automation of all processes can support business resilience across pharmaceutical businesses. Automation underpins business agility, making it easier and quicker to gain business insights and respond by changing processes more quickly than was previously possible.

Autumn 2020 Volume 12 Issue 3

Regulatory & Marketplace Pharma businesses looking to evaluate supply chain robustness and build resilience for the future have a number of urgent considerations. These include, how ready is your business to work with a reduced or variable supply chain headcount? How are your product information, labelling and work processes affected by employees working from home or reduced headcount? It might well be possible to address some issues with better labelling automation.

Are you prepared in case of another lockdown? Local lockdowns are already beginning to happen and it is important to consider how this scenario would impact staffing, manufacturing and the supply chain. Critically, can you still get product out the door as easily and profitably as before and can you easily offer new essential product lines? It is vital to identify and address all the bottlenecks. In the new reality of the Covid-19 pandemic, pharmaceutical leaders must be ready at all times to diversify product lines and update product information to meet regulatory requirements as quickly as possible.

REFERENCES 1.

2.

https://www.industryweek.com/technologyand-iiot/article/21129334/what-will-manufacturings-new-normal-be-after-covid19 https://www.mckinsey.com/industries/ healthcare-systems-and-services/ourinsights/beyond-coronavirus-the-path-tothe-next-normal

Gurdip Singh Gurdip Singh is CEO of Kallik, the marketleading enterprise labelling company, and a deeply experienced practitioner and leader in life sciences industry transformation. He previously held senior life sciences industry leadership roles at CSC, then DXC Technology. He is passionate about the user experience.

Over his career he has also worked extensively in the healthcare, life sciences and banking industry, giving him an insight into transferable/crossindustry best practice.

Email: gurdip.singh@kallik.com

www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 25

Regulatory & Marketplace

Successful Marketing of Medicinal Cannabis and Cannabis-derived Products – Part II Abstract In June, the first part of this article was published, describing differences in the legal background of some of the European Union countries, which need to be known for successful marketing.

The second part of the article describes hurdles and requirements regarding growing, import and distribution of medicinal cannabis or cannabisderived products, as well as the potential of this market concerning development of finished medicinal products as a next step of product development in this evolving market segment.

Keywords: medicinal cannabis, Cannabidiol, GMP, GDP, GACP, safety, efficacy, clinical data Import of Medicinal Cannabis – More Complex than Expected With the implementation of the Cannabis Law in Germany and Germany being the biggest European market for these medicinal products, the country was flooded with an overwhelming interest of cannabiscultivating companies from abroad, mainly from non-EU countries on importing cannabis to Germany/EU, securing market shares as early as possible. In many cases the processes were investor-driven with the idea of quick business in Europe, but reality was slower. A lot of companies failed to see the pitfalls, based on missing knowledge on the broad legal background on medicinal products in general and on medicinal cannabis in particular, especially with its different national requirements by different European countries. It took quite a while to find a path through the legal and regulatory jungle on narcotic drugs and their exemptions, including such requirements as the establishment of qualified persons for narcotic drugs, wholesale licenses, GACP, GMP, underlying QM systems, import licences and radiation protection ordinance for marketing approval of irradiated cannabis. By now this path became a road with “mainly” clear directions for all stakeholders. New stakeholders on the market were in the 26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

beginning not aware of the significant and pivotal role of “legal and regulatory affairs” for medicinal cannabis, which was necessary for a successful implementation of products for marketing approval. Every strategic decision of a company should be based on deep knowledge of national legal and regulatory requirements to turn a marketing strategy into a success. In addition, in such a regulated market as the one for medicinal cannabis, it is of intrinsic importance to find the right partnerships for all steps, from cultivation, storage, import, product analysis and release in the European country as well as delivery to the pharmacy at the very end.

For new stakeholders it was extremely important to find supporting companies, being able to search for partners on any level in this very specialised area by using their network.

GMP / GPP – What´s the Difference?

Opening the German market for medicinal cannabis in 2017 led to huge interest from cannabis-cultivating companies from outside of the European Union. In contrast to their expectations, import to Europe in general or Germany more specifically was a complex path of regulatory requirements from different authorities.

Strong quality control underlies production of any medicinal product; the same is true for cultivation and harvest of medicinal cannabis, reflected by compliance to Good Agricultural and Collection Practice (GACP) and compliance to Good Manufacturing Practice (GMP).

Companies from outside of the European Union were confronted with the European requirements to cultivate and harvest cannabis according to Good Agricultural and Collection Practice (GACP) and to possess a certificate on Good Manufacturing Practice (GMP) issued by the concerned supervising authority. The first companies entering the European market were Canadian companies, who presented their licence on “Good Production Process” (GPP) – issued by Canada Health, based on the Canadian Cannabis Act reflecting compliance to the Good Production Practices (GPP) requirements of the Cannabis Regulations.

What is the difference between Canadian GPP and European GMP? Canadian GPP describes requirements for production of cannabis herb but covers only parts of the European GMP processes and their requirements, like standard operating procedures (SOPs), sanitation programmes, recall procedures. GMP has additional requirements, such as staff qualification and additional testing for stability, pesticides and others.

With reference to Eudralex Volume 4, Good Manufacturing Practice, Part II, European GMP is bindingly applicable with physical processing of the plants. The distinct processing steps from which the GMP requirements have to be met depends on the final product which is intended for the application in patients. All steps during cultivation, advancing this GMP-starting definition must show compliance with Good Agricultural and Collection Practice (GACP). The basis of GMP-compliance is the understanding of the whole production process regarding potential risk to product quality and patient safety. Setup of quality risk management, including measuring control steps and activities reducing these risks is an important requirement.

A company´s GMP certificate is one of the most important prerequisites for receiving an import licence of medicinal cannabis to a country of the European Union.

Cannabis-based Medicinal Products on the Market – Current Situation in the European Union and in Germany Within the European Union, the German medicinal cannabis market is the biggest.

Due to this circumstance we focus on this market in the following.

According to the German legislation, social insurance code 5, article 31 subarticle 6, the following medicinal products are legally on the market in Germany: Sativex, Epidiolex, Canemes, Nabilon, Dronabinol, cannabis flos and cannabis extracts.

Cannabis flos (flowers), extracts of cannabis and Dronabinol are delivered to the patient based on a patient’s individual prescription.

These products are produced by the pharmacist as magistral formulations.

Sativex®, Epidiolex and Canemes® are Autumn 2020 Volume 12 Issue 3

Regulatory & Marketplace was conducted by several authors with the result that Sativex (Nabiximol, GW Pharmaceuticals) is available in most of the European countries, while Dronabinol and Nabilone are only available in a third of all EU countries4,5,6. The latest product, which just received a European-wide marketing authorisation by the European Medicines Agency (EMA) in September 2019, is Epidiolex for treatment of patients, aged two years and older, who suffer from Lennox-Gastaut syndrome or Dravet syndrome and rare types of epilepsy that begin in childhood and can continue into adulthood. It contains Cannabidiol (CBD) as active substance.

Fig. 1: Medicinal cannabis products and the number of prescriptions per product (data from Germany, 20191,7)

finished medicinal product, delivered to the patient, in the pharmacy, off the shelf without any additional manufacturing step in the pharmacy. Finished product hereby means that these products are approved by competent authorities, confirming a positive benefit to risk ratio concerning efficacy and safety of the product, with data that has been derived from pre-clinical and clinical studies.

The German Authority (BfArM) analysed the prescription situation1 for magistral formulations and finished products in Germany regarding the indication chronic pain (Fig. 1). The result shows a ranking of the number for prescriptions and products in decreasing order: Dronabinol, cannabis flos, Sativex, cannabis extracts and Nabilon (Canemes®) (Dr Cremer-Scheffer,

Symposium Medicinal Cannabis, Frankfurt, November 2019; status of data is March 2019).

Numbers on sales show a similar picture for product scaling. Data on sales between September 2018 and September 2019 was published in December 2019 by the German social health insurance information service (GAMSI, 2019, see Fig. 2), indicating that sales of medicinal cannabis2 increased during the year, while sales of Sativex are more or less on a constant level. In April 2019, Germany introduced additional Retaxgroups for cannabis-pharmacy products, leading to a change from three groups originally to five retax-groups3.

An analysis on availability of cannabisbased medicinal products in the EU

Fig. 2: Monthly gross profit of cannabinoid-containing finished products and magistral preparations [turnover in mio €], published by the German Social Insurance Information Service (GAMSI, 2019). www.ipimediaworld.com

Future Potential of the Medicinal Cannabis Market Marketing medicinal cannabis products is strictly legally regulated throughout Europe and the market is highly competitive. As can be seen by the short overview on different national legislation in European countries (Part 1 of this publication) and implemented during the last years, the European market is highly diversely regulated. Companies planning the import of cannabis from outside of the EU, being unfamiliar with the different legal background directing marketing opportunities, are confronted with this complex situation. Sound and extensive expert knowledge is necessary to understand the national requirements, not to lose time to market.

A keyword for the basis of the diverse national legislation is for sure “missing data on safety and efficacy” to which the different countries react by using different strategies regarding patients’ safety. Opening the doors for medicinal cannabis was an answer to the need of patients being without alternatives in treatment, e.g. regarding chronic pain or during chemotherapeutic treatment. For sure cannabinoids are effective in treatment of certain disorders, but pre-clinical and clinical data is still missing for different indications for which medicinal cannabis is used today.

The clinical trial library “ClinicalTrials. gov”, provided by the U.S. National Library of Medicine, lists about 900 trials conducted with cannabis or cannabisrelated substances as drug substance.

Just to mention some of the different indications, there are 53 trials concerning cancer using either cannabis or cannabisbased medicinal products as drug substance, 10 trials on epilepsy, 29 on multiple sclerosis, 13 trials on insomnia, INTERNATIONAL PHARMACEUTICAL INDUSTRY 27

Regulatory & Marketplace 36 trials on stress, one trial on appetite disorder, five trials on dementia, one clinical trial on neuroprotection, 32 trials on chronic pain, 14 trials on drug addiction, 14 trials on attention deficit, 49 trials on schizophrenia, 35 trials on depression, one trial on Alzheimer´s disease, three trials on osteoarthritis and two trials on psoriasis.

Up to now only a few cannabinoid prescription medicinal products were developed, e.g. Sativex and Epidiolex.

Filling the lack of clinical data with results on toxicology, safety and efficacy in specific indications will strongly raise the interest of pharmaceutical companies in developing new products. This in turn will enlarge the market potential of cannabinoid-based medicinal products on prescription and will raise overall trust in the cannabis-based products and therapies. Clinical data might probably also help to distinguish responderpatients, who benefit from medicinal cannabis-based products in dosage form of inflorescences and tinctures, from nonresponders, needing indication-specific cannabinoid prescription medicines.

With this vision in mind, it becomes quite clear that the market for medicinal cannabis

is not just a market bubble but a true new developing pharmaceutical area with a broad field of applications.

REFERENCES 1.

2.

3.

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5.

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7.

Dr. Cremer-Scheffer, Symposium Medicinal Cannabis, Frankfurt, November 2019 GAMSI: Sonderbeilage zur GKV-ArzneimittelSchnellinformation für Deutschland, Dezember 2.12.2019 Neue Sonder-PZN für Cannabis ab 1. April, DAZ-online, 28.03.3019 Abuhasira R, Shbiro L, Landschaft Y, Medicinal use of cannabis and cannabinoids containing products - Regulations in Europe and North America. Eur J Intern Med. 2018 Mar; 49: 2-6. doi: 10.1016/j.ejim.2018.01.001. Epub 2018 Jan 10 Bramness JG, Dom G, Gual A, Mann K, Wurst FM. A Survey on the Medicinal Use of Cannabis in Europe: A Position Paper. Eur Addict Res. 2018;24(4):201-205. doi: 10.1159/000492757.

Epub 2018 Aug 22.

Krcevski-Skvarc N, Wells C, Hauser W. Availability and approval of cannabis-based medicines for chronic pain management and palliative/supportive care in Europe: A survey of the status in the chapters of the European Pain Federation, Eur J Pain 22 (2018) 440-454 Cremer-Scheffer P. Cannabis als Medizin - Erste Erkenntnisse aus der Begleiterhebung (PDF, 1MB, barrierefrei ⁄ barrierearm), 09.05.2019

Barbara Siebertz Barbara Siebertz, Dr. rer. nat. graduated at the Albertus-MagnusUniversity of Cologne with a diploma degree in Biology. She received her PHD and worked at the Max-PlanckInstitute for Plant Breeding Research in Cologne up to 1992. The topic of her thesis was the elucidation of a molecular regulatory mechanism in wounded plants. In 1995 she joined Sandoz Pharma in Basel in the Department of Immunology, followed by an additional time of research at the Rheinisch-Westfälische Technische Hochschule in Aachen in the department of Pathological Biochemistry. In 1998 she joined Biofrontera Pharmaceuticals GmbH and started her activities in Regulatory Affairs activities. From 2013–2015 she was engaged in Regulatory Affairs studies at the University of Bonn and joined Sträter Life Science GmbH in 2015. Since 2018, she has worked as a consultant at PharmaLex and holds the position as Senior Manager, Regulatory Affairs and Special Projects.

Ute Hegener Ute Hegener, Dipl. Biol. graduated at Heinrich-Heine-University of Düsseldorf with a diploma degree in Biology in the subject of elucidation of plant secondary metabolism by molecular biology methods. In 2003 she started her professional career with the development of a pharmaceutical wholesale company in Turkey for phytopharmaceutical products. In 2004 she joined JanssenCilag GmbH were she held different positions before starting in the Regulatory Affairs department at Janssen-Cilag GmbH. She then joined Axcount Generika (axicorp) GmbH in 2009, where she led the Regulatory, Quality Assurance and Scientific Affairs department until 2016. In her current position at PharmaLex she holds the position of Director, Regulatory Affairs.

28 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2020 Volume 12 Issue 3

Micronization for Inhaled Medication

Patented 4th generation MC DecJet® spiral jet mills for DPI production > Improved internal mill geometry using CFD > Special carved version for sticky products > Easy scale-up maintaining the same narrow PSD > Constant temperature – no heat generation > Integration of particle size analysis (PAT) > High containment isolator integrated mills > SIP/CIP systems www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 29

dec-group.net

Drug Discovery, Development & Delivery

Pre-filled Safety Syringes and the Self-administration Trend: A Mutually Reinforcing Relationship Under growing pressure resulting from staff shortages, overburdened funding, an ageing population and most recently a global pandemic, healthcare systems across the world are supporting the drive towards selfadministration of injectable medication for patients with chronic diseases.

The number of people aged 60 and over worldwide – a demographic that disproportionally requires treatment for chronic conditions – is projected to nearly double from 962 million in 2017 to 2.1 billion by 2050.1 By shifting the administration of certain therapies towards the home and away from the traditional clinical setting, hospitals are exporting a lowerrisk medical procedure, helping to manage occupancy pressures within their facilities and encouraging patients to be more involved in their own medication regime. This is a particularly welcome development during this unprecedented time of demand for healthcare.

Typically administered via subcutaneous injection, a wave of biological therapies for patients with chronic conditions has entered the market since the late 1990s.

These therapies often are the only ones to provide best outcomes for patients suffering from chronic conditions such as neurological, cardiovascular, and autoimmune diseases. They are particularly wellsuited to self-administration through prefilled safety syringes because they require regular injections, for which it would be impractical and not cost-effective to visit a clinic or call out a nurse each time. Patients who self-administer their treatment are not only empowered by the responsibility of managing their own drug administration but can also alleviate some of the pressure on hospitals and healthcare professionals.

Today, over two-fifths of registered nurses are now employed in non-hospital settings in the USA,2 and an estimated 7.5 billion syringes are used in the homecare environment every year.3 While this migration may be cost-effective and practical for both 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

parties, needlestick injuries still present a significant risk within hospital settings, let alone in non-clinical sites where there is no presiding professional. In this context of growing home-administration, it is vital that equal attention be given to the safety of sharp devices and best practice injection procedures both within the confines of hospitals and outside.

While the introduction of the US Needlestick Safety and Prevention Act (NSPA) almost two decades ago has led to a 30% decline in sharps injuries, they continue to occur – averaging 1000 reported sharps injuries per day in US hospitals.4 Beyond the clinical setting, it is currently estimated that over 50% of non-hospital settings are in violation of Occupational Safety and Health Administration (OSHA) laws.5 In the EU, compliance levels for safety-engineered injection devices are at 70% across EU economies, a number which falls to 60% in the homecare environment.6 Non-compliant settings have a much higher risk of needlestick injuries occurring, leaving patients, carers and non-users at risk of potentially contracting unwanted infections. Family members and other residential non-users are particularly vulnerable to exposure for they are often unaware of the extent of the risk presented by a potentially contaminated sharp. This makes them unlikely to report needlestick injuries and get proper treatment when required – in fact, studies show that up to half of sharps injuries may go unreported.7 As the administration of drugs and its associated risks migrate into the homes of chronic patients, manufacturers must take on some of the responsibility of guarding non-professional users against the dangers of needlestick injuries.

Amidst this evolving healthcare landscape, it comes as no surprise that demand for pre-filled safety syringes has taken off in recent years. With some reports stating that 80% of needlestick injuries can be avoided by using safer needle devices,7 disposable safety-engineered delivery devices have become instrumental in the prevention of sharps injuries and recent figures confirm this growing trend. In fact,

the global safety syringe market is expected to reach $1.137 billion by 2023, up from $772 million in 2018 – representing an impressive CAGR of 8.1%.9 In a context of mounting self-care, one of the main driving forces behind the growth of pre-filled safety syringes is therefore ensuring convenience and safety for the patient and/or their carer. The design of a drug delivery device determines the level of its needlestick injury prevention capabilities, with certain designs potentially making some devices less safe than others.

For instance, devices with hollow-bore needles or syringes that retain an exposed needle after use carry a greater risk.10 Many of the new biological drugs are designed to treat inflammatory conditions such as rheumatoid arthritis – meaning that self-administering patients may be debilitated and yet still need to be able to securely hold and operate the injection device. Similarly, older patients are often less dextrous than their younger counterparts and could struggle with handling and administering an accurate dosage. It is therefore crucial that selfadministration devices should be as simple as possible to use, require a minimum amount of force to activate and include passive safety mechanisms to reduce additional activation steps. Pre-filled safety syringes as well as auto-injector devices fulfil both ease-of-use and safety device requirements at the same time.

The increase in scrutiny on medical administration from health authorities further to medication error scandals in the US and Europe11 is another driver for growth of the pre-filled device market. Biological drugs often have low-volume, specific dosage requirements, which explains the preference for pre-filled syringes as delivery devices for these types of drugs. Pre-filled syringes not only reduce the potential for inadvertent needlestick injuries and exposure to contamination that can occur while drawing medication from vials, but also help ensure that the correct drug is accurately delivered, significantly reducing the risk of medical errors. Pre-filled devices and syringes also have time-saving Autumn 2020 Volume 12 Issue 3

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Drug Discovery, Development & Delivery devices contribute to providing patients with the independence that comes with self-administration, while reducing the risks associated with unsupervised selfcare.

REFERENCES 1.

2.

3.

4.

potential, helping overburdened healthcare staff accurately deliver medication more rapidly, speeding up clinical pathways and procedures.

Similarly, safety syringes as well as other needle-safe devices help protect hospital and non-hospital healthcare workers against infection through sharps.

The risk of unsafe injections as a result of contamination with blood-borne viruses is a concern in the spread of HIV, hepatitis B, and particularly hepatitis C among healthcare workers. For instance, although modern treatments that eliminate the hepatitis C virus mean that infection through sharps no longer ruins healthcare workers’ careers, expensive and disruptive treatment periods are still required. Introducing safety devices is a proven strategy to remove unnecessary risk from the healthcare professional’s working environment, including home visits.

Further driving this growth in demand for pre-filled safety syringes is the large number of original biologics continuing to come out of patent protection and the

32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

associated emergence of biosimilars. This host of new drugs entering an increasingly competitive market is reducing cost to patients, boosting the use of biosimilars and encouraging home-based selfadministration. Between 2018 and 2020 alone, seventeen original biologics have reached their patent expiration date in Europe, opening the market to biosimilar competitors.

5.

The demand for safety-engineered devices and pre-filled syringes is growing around the world in parallel to the rise of self-administration. Pre-filled safety syringes are not only safer than those without needle protection but also more convenient and well-adapted to the self-administration trend. In particular, retracting and needle shielding mechanisms used in pre-filled safety syringes and autoinjectors allow both ease-of-use and safety device requirements to be met all at once, while also potentially reducing the risk of dosage errors. Allowing older, debilitated and less dextrous patients to securely hold and operate them, these safety-engineered

9.

6.

7.

8.

10.

11.

UN, Department of Economic and Social Affairs, World Population Ageing, 2017 Montana State University, Proportion of Registered Nurses Employed in Hospitals Falls Below 60% in 2013, May 2014 Gold K (2011). “Analysis: The impact of needle, syringe, and lancet disposal in the community”.

Journal of Diabetes Science and Technology. 5 (4): 848–50.

OSHA, http://www.osha.gov/SLTC/etools/ hospital/hazards/sharps/sharps.html Medical Devices: Evidence and Research, Vol 10, Clinical, economic, and humanistic burden of needlestick injuries in healthcare workers, 2 May 2017 European Biosafety Network, Sharps Safety Survey 2016 Centres for Disease Control and Prevention, Stop Sticks Campaign, February 26, 2019: https://www.cdc.gov/nora/councils/hcsa/ stopsticks/sharpsinjuries.html World Health Organization, Needlestick Safety and Prevention, Independent Study Market Data Forecast, Safety Syringes Market

by Technology, Oct 2018 World Health Organization, Needlestick Safety and Prevention, Independent Study e.g. Nursing Times, College warns short staffing is key factor in medication errors, February 2018: https://www.nursingtimes.net/news/ reviews-and-reports/college-warns-shortstaffing-is-key-factor-in-medication-errors23-02-2018/

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.

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 33

Drug Discovery, Development & Delivery

Optimising the HPAPI Value Chain to Achieve Maximised Product Value In the quest to find new and more effective treatments against severe diseases, researchers are increasingly moving towards active pharmaceutical ingredients (APIs) with increased potency and more targeted delivery mechanisms.

These powerful compounds may help treat life-threatening and sofar incurable diseases, including cancer, diabetes, Parkinson’s disease and others. Simultaneously, due to these compounds having a physical and clinical effect at very low dose, they carry potential risks in terms of occupational health hazards.

Personnel in manufacturing facilities must be protected at all times from the products they are making. Sustainable manufacturing of highly potent APIs (HPAPIs) therefore requires specific precautions to operator health and safety on the one side and to product quality on the other.

However, while protecting workers is perhaps the most important element of HPAPI development and production, biopharma innovators need access to many other specialised capabilities to take their HPAPI innovations from concept to commercialisation. Other steps in the development process include chemical synthesis, intermediate development, sampling, logistics, waste management and beyond – on top of the critical work of keeping people safe. By creating a true value chain that spans all unit operations of HPAPI product development, based on extensive experience and driven by a safetyfirst philosophy, contract development & manufacturing organisations (CDMOs) can play a pivotal role in bringing innovative HPAPI-based drug products to market that improve or even save patients’ lives.

Three Focus Areas are Key Sustainable HPAPI production is centred around three principles: 1.

Operators’ Health: With the product already active at low dose, and with the certainty that manufacturing

34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

operations often have situations where production equipment has to be opened (e.g., for adding reagents, taking samples or isolating product), it is conceivable that product exposure via the air can reach manufacturing operators and thereby result in measurable effects on their health.

Thus, occupational health & safety precautions are required to ensure safe operations.

2.

Product Quality: Besides the normal GMP regulations related to product quality, the same activity at low dose requires having additional precautions regarding adequate cleaning and decontamination procedures to minimise product carry-over into the next product (especially in multipurpose facilities). With high potency products, it is no longer sufficient to work with a general and fixed-limit (e.g. 10ppm) for all products produced within the facility, but ideally a cleaning strategy based on the product’s permissible daily exposure (PDE).

3.

Containment Strategies: These are implemented in most organisations that handle HPAPI, but there may be differences in the level at which they are being practised. In most countries, a legal framework exists to guide organisations in adequate employee protection. A general best practice example follows three main principles: 1) Engineering controls 2) Organisational measures 3) Personal protective equipment (PPE)

Not all companies follow the same priorities and order of the above measures. Therefore, one can observe facility conditions ranging from HPAPI being handled seemingly without special measures (in case engineering controls and organisational measures are proven to suffice), as well as facility conditions where the employees are fully gowned, including breathing protection and/or complete gowning.

Personal protective equipment (PPE), including powered purifying air respirators (PAPR) and powered respirator protective suits (PRPS), should only be used in exceptional cases (e.g., non-routine unit operations such as cleaning or troubleshooting including the opening of equipment) and cases where engineering and organisational controls cannot be adequately implemented.

Some organisations implement PPE as a permanent measure to safeguard employees. This practice often provides a false sense of safety; in case of a spill or incident where HPAPI is dispersed, the operator needs to find a place to decontaminate himself without further spreading HPAPI within the facility. The PPE will protect the operator short-term, but it is not addressing the overall safety of operations – therefore, engineering controls are always the preferred approach for safe HPAPI handling. This is often the reason for implementing airlocks and air pressure cascades to trap airborne matter in a well-defined and controlled place (i.e., the airlock). This measure is certainly a musthave in multi-product facilities but is also recommended for dedicated lines.

For remote observers not necessarily familiar with handling HPAPI, observing such different operations can make sustainable HPAPI handling seem mysterious and complex. In addition, when developing drugs and handling both drug substance and drug product operations, the variety of unit operations employed can be so wideranging that containment solutions can vary broadly. Well-designed HPAPI facilities require a good understanding of the product, its toxicological and physical properties, the unit operations executed during manufacturing, its containment engineering and limitations and ultimately PPE. Elements of a Secure and Safe HPAPI Manufacturing Process Typically, optimal HPAPI handling setup in a manufacturing process involves the following dimensions (related professional terms in italics): •

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Drug Discovery, Development & Delivery human body and at what levels? Hazard assessment (toxicology), occupational exposure limits (OELs), occupational exposure bands (OEBs), permissible daily exposures (PDEs).

•

Unit Operation Properties: What handling is required and to what extent?

Dry or wet material? Risk assessment based on exposure pathways, mass transport, exposure potential

•

Full Process Design: How do unit operations connect – via closed connection, or separated unit operation?

Integrating drug safety into the manufacturing process design (e.g. equipment selection)

•

Engineering of Control & Containment (preferably at source): Now knowing all of the above, how would we contain the product optimally? Barrier containment (e.g. hard vs. flexible walled), ventilation-based controls, connection points (valves, etc.)

•

Definition of Organisational Measures: When we will be operating the facility, what special procedures or precautions must be defined to handle the HPAPI responsibly with the actual manufacturing setup, without endangering operators and others?

Considerations include procedural controls, specific work instructions, operator education, cleaning and dismantling of equipment (e.g., maintenance-related) and defining higher-risk groups: operator screening and exclusion from specific unit operations.

•

Personal Protective Equipment (PPE): What additional protective aids are needed at what specific unit operation in the process?

When all of the above are in place, it is important to monitor the performance of the process and its containment design before, during and after actual operations.

Toward this end, an occupational hygiene group typically ensures: •

•

Containment Design performs as required: Smoke testing or surrogate testing to monitor air flows and containment performance.

Control and Containment Performance Verification: Measurements are taken

36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

at strategic positions within the facility/operation in order to monitor HPAPI product levels to confirm these are at acceptable levels.

•

Worker Exposure Assessments: Similar measurements are taken at strategic positions on the operator him/herself (e.g., breathing zone, hands, others) in order to monitor if the actual operation is executed safely, where the weak spots of containment are and if further measures are required.

•

Incident Preparation: Although it is difficult to foresee where calamities might happen, it is good practice to thoroughly evaluate this topic in advance with a robust risk assessment.

Spill management, personnel evacuation and decontamination, calamity cleaning procedures and other potential crisis responses must receive an appropriate level of attention in an effort to minimise the negative impact in the event that such a mishap occurs.

•

Management System: A management system needs to be in place to repeat or review the above measurements on a regular basis, and to ensure the procedures defined are actually executed as they should be. In addition, the management system defines educational requirements, i.e. how often is training of operators needed and when does it need to be repeated.

Ultimately, the management system will define on what frequency medical surveillance of employees handling HPAPI is needed to prevent longerterm effects from the products they have handled.

In many cases, HPAPI will be handled in a dedicated HPAPI facility. In most cases, the design of the facility is a given, and we must recognise that many containment measures are a compromise between safety, design, operational and financial parameters. In the exceptional situation where a new facility is being designed, it is key to involve EH&S (environmental, health & safety or occupational health professionals) as early as possible in the design phase in order to influence the design optimally for the handling of HPAPI products. The EH&S team is critical in supporting the definition of facility layout, people and material flows, HVAC, airlocks and air pressure zoning (cascades), containment and control measures. In addition, they can

drive optimisations to the facility regarding cleaning, opening of equipment and possible temporary containment solutions to handle such events. Most organisations will require external support from an architect and one or more engineering companies in the realisation of the new facility. For such situations, it is worthwhile to dedicate resources to facilitate flawless communication and to avoid sub-optimal alignment between the involved parties (e.g., dedicated project management).

Ultimately, the business leaders will decide on the required capital and operations budget, timeline, etc., but this should not distract from the main goal, which is to realise an HPAPI facility that is sustainable and can answer to the business needs in the long term.

Building on Safety and Containment to Create an Optimised HPAPI Value Chain These safety principles can help inform the entire value chain of HPAPI development and manufacturing. Firstly, in the process of making a drug substance (DS), a chemical process generally leads from a number of starting materials, through several intermediates, to the API. The intermediates involved are not necessarily of identical potency as that of the API. Often one starts from non-highly potent starting materials that become highly potent once the API core structure is being formed. There are also examples where highly potent materials are converted to non-potent materials, or where potency varies largely throughout the chemical pathway. The required efforts also depend largely on whether or not a certain intermediate needs to be isolated in pure form.

As a consequence, not all steps require measures of the same kind and one can thus execute non-HPAPI steps in a nonHPAPI facility. On the other hand, not all companies can afford to have different types of facilities and thus often (temporary) containment measures are implemented to normal facilities to handle HPAPI in situations where a large capital investment to create HPAPI-dedicated facilities is not considered viable. This introduces risk not only to the safety of personnel, but also to the overall timeline for bringing the HPAPI programme from early development to the next clinical stage, or even to market.

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so that containment measures can be defined for a specific band. Based on the potency of the compound and on the quantity to be handled, the most appropriate laboratory is selected to run a specific project.

Drug Discovery, Development & Delivery

OEB (OEL)

“Normal” lab 3 (100 – 10 µg/m3)

High-potent lab 4 (10 µg - 0.1 µg/m3)

High-potent lab 5 (0.1 µg – 1 ng/m3)

Quantity Max. reactor

mg - kg 6L / 250L

mg - kg 6L / 50L Limited Badge-controlled Normal lab

mg - kg 6L / 50L Dedicated Badge-controlled 10-20x, qualified

Access

Open Normal lab

Air exchange Pressure zoning Wet chemistry

No

No

Yes, incl. airlocks

Normal hoods

RABS

Product drying

Separated dryers

Normal hoods & RABS Separate dryer & connected to RABS

Powder handling

VBE, RABS, isolator

Equipment on workbench, special hood sample preparation Packaging Double plastic bag sealing * RABS = restricted access barrier system / VBE = ventilated balance enclosure.

Analytical

Equipment on workbench, standard hood sample preparation

Connected to RABS Isolator (RABS up to g scale) Equipment in enclosure (hood/isolator) Double plastic bag sealing

Table 1: Overview of the types of API laboratories at Lonza, demonstrating differentiation across key criteria and capabilities.

Table 1: Overview of the types of API laboratories at Lonza, demonstrating differentiation

limit) is an upper limit on the acceptable across key criteria capabilities.substance concentration ofand a hazardous in workplace air for a particular material or class of materials, and these limits help define molecular potency. When handling many compounds with different OEL, companies often define occupational exposure bands (OEBs) so that containment measures can be defined for a specific band.

Based on the potency of the compound and on the quantity to be handled, the most appropriate laboratory is selected to run a specific project.

In all HPAPI laboratories, it is helpful to be able to run the widest possible set of unit operations. For specialist operations (e.g., micronisation, encapsulation), equipment can be placed inside an isolator, in order to keep the unit operations as unchanged as possible.

upfront and “cradle-to-grave” waste considerations in line with responsible care considerations; cleaning and maintenance, e.g., required engineering controls.

Dedication of equipment may sometimes be an expensive option, but for cases where cleanliness of equipment cannot be proven (e.g., OEB5), this might be the only option to create a sustainable manufacturing environment. Disposable (single-use) glass equipment is also utilised routinely in laboratories.

Lastly, process automation should be considered wherever possible, although this is less practical for multi-purpose facilities running campaigns with a limited number of batches. When implementing

automation in a multi-purpose facility, the key is to find the right balance between flexibility and automated robustness.

Manufacturers may explore several levels of automation, such as manufacturing execution systems (MES), in-line process analytical technologies (PAT) or real-time release-testing (RTRT). Avoiding paperbased documentation in OEB5 facilities is considered a final step in containing the HPAPI to where it is desired.

For larger-scale production, some facilities have a modular setup, with technology for wet chemistry for reactor sizes customisable up to 50L, and isolator technology for product isolation and dry powder handling. Facilities may be optimised for high output, potentially running up to three large reactors and two drying operations in parallel (filter dryer or lyophiliser). Some facilities have high levels of automation and potential for 24/7 operation, as well as capabilities for a high level of compliance with electronic batch records. Large-scale facilities may be used for development of highly potent payloads for antibody drug conjugates or ADCs (see Figure 1). At larger scales, the containment measures do look different, but comply to the same principles as described above.

Conclusion – Optimising the Value Chain When looking into pharmaceutical development in a bit more detail, the necessity of having different types of

The sampling of wet or dry material from the production (or laboratory), and subsequently the sample preparation, typically happen in smaller laminar flow type of enclosures such as ventilated balance enclosures or laminar flow cabinets.

Preferably, sampling is done at the source for OEB4 compounds. For OEB5, there is an additional and dedicated laboratory for sample preparation and analytics including the above-cited requirements. The analysis for OEB4 compounds typically can be performed in normal analytical laboratories as the quantity being handled is small, yet exceptions for specific techniques exist where increased containment is needed.

Besides laboratories and their setup, one has also to consider related activities, such as logistics, e.g., special precautionary requirements for transportation of material; waste management, i.e., hazard analysis 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 1: Multi-purpose, kg-scale facility for highly potent payloads for antibody drug conjugates at Lonza’s Center of Excellence for HPAPI development and manufacturing at its Visp, CH site Autumn 2020 Volume 12 Issue 3

Drug Discovery, Development & Delivery Acknowledgement The author wishes to thank Mr Conrad Roten, R&D API Chemical Services at Lonza in Visp, for his open discussions about this topic and his support in final proof corrections.

REFERENCES 1.

kilogram-scale laboratory facilities can be explained by the increasing demand in HPAPI projects, as well as an increasing pressure on development timelines. Flexibility to perform projects in the most appropriate asset and keeping sufficient capacity in HPAPI facilities increases the options for a CDMO partner to meet customer timeline requirements. In addition, flexibility to perform any kind of unit operation in the contained environment allows for quick transition from typical drug substance activities into drug product activities (e.g., micronisation, encapsulation, etc.).

Challenges in the drug product area may differ and introduce new dimensions, such

as very low yet uniform dosing requirements for a highly potent active ingredient in the final product. For ADC products, this has introduced aseptic biologic manufacturing as an additional challenge. However, the general principles of containment, facility & operational design and occupational health principles relevant for drug substance will also apply to the drug product. Combining these skills and experiences to integrate all unit operations into one optimised value chain will help CDMOs support customers even further in reducing drug programme risk and complexity, as well as meeting the increasingly accelerated timelines required for bringing novel and highly effective drug products to patients that need them.

2.

3.

“Lonza Expands HPAPI Development and Manufacturing Capacity for ADC Payloads.”

Lonza. October 8, 2018. https://www.lonza. com/news/2018-10-08-13-30 “Antibody Drug Conjugates: Precision Cancer Care.” Lonza. February 3, 2020. https://www. youtube.com/watch?v=KkAKgU2A6qo “Lonza to expand HPAPI development and manufacturing capacity.” Lonza. June 17, 2019. https://www.lonza.com/news/2019-06-13-1535

Maurits Janssen Maurits Janssen, Sr. Director, Strategic Business Development, Lonza Pharma & Biotech.

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 39

Drug Discovery, Development & Delivery

The Role of Connected Inhalers in Improving Usability and Adherence in Respiratory Disease Recent data suggest that 339M people globally have asthma, resulting in 425,000 deaths annually, many of which would be preventable with access to medication and appropriate healthcare1. Even in countries with high standards of living, well-established healthcare systems and proper medication availability, unnecessary deaths still occur. In fact, a recent report suggests that around two-thirds of asthma deaths are preventable in the UK2. Although several factors contribute to a failure to manage treatment effectively, failure to take medication as prescribed2 is a key issue. An estimated 50 per cent of people with asthma fail to do this – a figure that may well understate the problem – and is well below the 75-80 per cent adherence levels required to improve asthma control significantly3.

Furthermore, many users who intend to take their medication fail to do so because of poor inhalation technique.

Studies suggest that at least a third of inhaler users have a technique that adversely affects the delivery and/or absorption of the drug in the lung4, and that this rate has not changed over the past 40 years. This article aims to consider why patients don’t take their respiratory medication and how adherence to inhaler medication can be improved.

medication when experiencing asthma symptoms, rather than regularly taking their prevention medication. Failureto-use is a complex issue but, as discussed below, developments both in technology and understanding human behaviour may offer the potential to address this.

•

Second, it is well known that inhalers are prone to use errors5, notably dose preparation errors (where the user fails to load or prime the device) and inhalation errors (where the user fails to perform the correct inhalation technique for effective delivery of the drug to the lung). So even when a patient intends to take their medication, they may not receive an effective dose. These factors make inhaler use more challenging than the use of other drug delivery devices such as insulin pens and autoinjectors. The reduction of use errors has therefore been a particularly important theme in the evolution of inhaler design. In a presentation made more than 10 years ago at RDD (a leading respiratory conference), Dixon and Simpson5 summarised the literature reporting on inhaler use errors. They suggested

that the majority of use errors should be addressable through application of the principles and methods of usability engineering and inclusive design.

These, combined with the adoption of novel deaggregation/aerosolisation technologies, can enable better inhaler designs to fit with users’ typical behaviour. While use errors continue to be an issue for inhaled therapy, more recent dry powder inhaler designs such as the Ellipta device developed

by GSK, the NEXThaler developed by Chiesi and breath-actuated pressurised metered-dose inhalers (pMDIs) such as the Teva Easi-Breathe have come close to optimised designs, showing lower use errors than comparable device types6,7,8. Open-Inhale-Close designs such as Chiesi NEXThaler and Sun Pharma Starhaler represent an idealised design, with the fewest user steps and the ability to avoid errors such as double dosing or dose loss, if inhalation does not take place.

Wider adoption of these newer device designs should reduce the overall use error rate observed.

With a strong focus on the use of human factors engineering to guide device design

Medication Non-adherence: Two Key Factors For asthma, there are two primary aspects of medication non-adherence to consider: •

First, patients may fail to take their medication for a variety of reasons.

There may be a lack of belief in the efficacy of the drug, concerns about real and perceived side-effects, high out-of-pocket costs or simply forgetting to take the medication. As asthma symptoms are often episodic, many patients may feel they can skip doses to save money or reduce sideeffects. Furthermore, patients may rely too much on using their reliever

40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 41

Drug Discovery, Development & Delivery (notable since the FDA published guidance in 20009), there has been a reduction in use errors for many drug delivery devices, as predicted by Dixon and Simpson. Now, more attention can be paid to addressing failure-to-use and as Sheldon Moberg from Amgen commented at a conference in 2012 “To address adherence, [we] need to focus on ‘want to use’ as well as ‘can use’10.” In their work, Dixon and Simpson made little consideration of failure-to-use. They assumed that the principles of inclusive design might influence willingness to use, but overall, this was a different and more complex challenge that goes beyond inhaler design.

Subsequent years have seen two significant developments that might help address the issue of failure-to-use: 1.) the arrival of connected devices and digital health; and 2.) the development of psychological models that allow a better understanding of human behaviour and the interventions that can influence behavioural change. As discussed below, connected devices and associated digital services provide a useful means of supporting behavioural change.

The Impact of Behaviour Change on Medication Adherence At its core, non-adherence is a behavioural issue, which can be addressed by designing interventions that influence behaviours that support or hinder medication use.

However, focusing solely on the patient misses a large part of the issue, as it is essential to consider other factors that influence their behaviour and their capacity to adhere to their treatment regimen.

Sabate (2003)2 identified five interacting dimensions that affect adherence: 1.) social and economic factors; 2.) healthcare team and system-related factors; 3.) conditionrelated factors; 4.) therapy-related factors; and 5.) patient-related factors. These dimensions can influence adherence in many different ways – i.e. not having the financial means to pay for medication, the knowledge to understand the importance of medication use, or the right training and support and motivation from healthcare

professionals or other caregivers. To be effective in improving adherence, an intervention needs to target one or more of these factors.

Although behaviour change models are in everyday use, the COM-B model has gained popularity in recent years.

It was developed by the Centre for Behaviour Change at University College London from a rigorous assessment of existing behavioural change research and frameworks. It proposes that the performance of a particular behaviour requires someone to have the capability, the opportunity, and motivation to do so.

•

Capability includes both the psychological and physical capacity to engage in an activity, including knowledge, skill and memory.

•

Motivation relates to the neurological processes that operate both consciously and subconsciously to direct behaviour, including habits, emotions and analytical decisionmaking such as goal setting.

•

Opportunity refers to the factors that lie outside an individual that make the behaviour possible or trigger its performance. Opportunity includes physical environment and resources as well as social and cultural aspects of life such as stigmas, taboos and beliefs that might encourage or discourage behaviour.

As shown in Figure 2, these components of the framework interact to stimulate or modulate behaviour, and conversely, enacting a response might then influence these components to create a virtual or vicious circle. The model has been applied to a range of situations, including smoking cessation, encouraging testing for transmittable diseases, use of hearing aids and medication adherence.

Although COM-B was developed as a model of behaviour, its power in situations

Figure 2: The COM-B Model of Behaviour 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

such as addressing non-adherence is that it provides a basis for designing interventions targeting behaviour change. With this in mind, Michie et al.12 developed a Behaviour Change Wheel that links the COM-B model to nine intervention functions and seven policy categories identified in the assessment of existing behavioural change frameworks, as shown in Figure 3.

Jackson et al. describe how the COM-B model can be applied to medication adherence13. They used three comprehensive reviews of medication adherence studies to identify and map the different factors associated with adherence. They found most factors mapped directly onto a subcomponent of COM-B, but depression, substance abuse, marital status and forgetting show a more complex association impacting several areas of the COM-B model. This complexity is to be expected as marital status, for example, can impact social support, cost and access. The authors suggest a three-step process to developing an adherence intervention: •

First, the use of secondary and primary research to identify the factors associated with non-adherence within the target population and map these to the sub-components in the COM-B model.

•

Second, identification of intervention types and behaviour change techniques appropriate for the sub-relevant components, for example using the taxonomy developed by Michie et al.14

•

Third, as an understanding of the effectiveness of different BCTs in influencing the COM-B sub-components is better established, the intervention can be optimised.

In other published research, COM-B has been applied to adherence in several disease areas, including asthma15, COPD16, hypertension17, oncology18, and growth hormone deficiency19.

Digital services provide an ideal service structure to support medication adherence.

They allow support to be delivered to patients remotely via apps and portable devices, information to be gathered and shared between key stakeholders including the patient, HCP, and lay caregiver, and – if they include connectivity – allow reliable and timely monitoring of medication use.

A digital service can facilitate many of the Autumn 2020 Volume 12 Issue 3

Drug Discovery, Development & Delivery but was not a head-to-head controlled study.

Figure 3: The Behaviour Change Wheel

behavioural change techniques described in the Behaviour Change Wheel.

Digital approaches to disease management should be backed by substantial evidence, have a reliable infrastructure, be designed collaboratively as clinically- and cost-effective systems, and reflect the needs of patients and healthcare providers. Given the challenges in supporting adherence for inhaled drugs in respiratory disease, it is not surprising that there has been increasing interest in the development of smart inhalers combined with digital services, in recent years as technology has become available.

Smart Inhalers and Connected Health Blakey et al.20 conducted a review of digital intervention used in respiratory medicine, aiming to improve adherence. Between 2007 and 2017, they identified more than 25 studies, many of which were randomised controlled studies. Although many of the studies showed improved adherence for the intervention group compared to the control group, fewer showed improved outcomes.

The authors concluded that the use of digital technologies in respiratory diseases offers great potential in improving adherence, raising its importance and also supporting better inhaler technique. However, to achieve success requires a focus on the end-user to support long-term use, and to ensure uptake

by HCPs, the solutions need to be better integrated into healthcare systems.

Developments around smart inhalers and digital services in respiratory diseases continue to gather pace. At this year’s RDD conference, which was rather aptly presented in online format due to the COVID-19 situation, a significant part of the plan was given over to advances in inhalers, www.ipimediaworld.com

particularly around the use of connectivity – a topic that hardly merited mention 10 years earlier. Bonham et al. described how the addition of sensors to inhalers, connectivity and data analytics could improve inhaler use, encourage better dialogue between patients and clinicians and improve the health-related decision process, for example, to predict exacerbations. Results were presented from a study that used an add-on device (Turbu+ monitoring device developed by AstraZeneca in partnership with Adherium) with a standard Turbuhaler dry powder inhaler. The research conducted in Italy showed good adherence compared with that typically observed in the country,

In another paper, Chrystyn et al. described the ProAir Digihaler®, the first connected inhaler with integrated sensors to measure inhaler use and inspiratory flow. Inhalation information is presented on a patient app that allows the patient or their caregiver to monitor usage and identify potential inhalation errors. Data was presented that showed an accurate measurement of inhalation, and the authors anticipated that as more data is gathered from the devices in real use, this can potentially be used to develop algorithms that might predict the risk of exacerbation. The authors also recognised that more work is required to ensure digital inhalers are adopted in the market and the case for reimbursement developed. Moore presented adherence data gathered from patients using both connected maintenance and rescue therapy inhalers. There were several intervention groups ((1) access to maintenance therapy adherence data for patients only, (2) for patient and HCP, access to maintenance and rescue therapy adherence data for patients only (3), for patient and HCP) and one control group.

Results showed a statistically significant increase in adherence in months 4–6 for all the intervention groups compared to the control group for the use of maintenance therapy. Overall adherence was higher

Figure 4 INTERNATIONAL PHARMACEUTICAL INDUSTRY 43

Drug Discovery, Development & Delivery

Figure 5: Summary of adherence intervention type and effects on outcomes [from Wilhelmsen and Eriksson]20 for all groups than levels seen in routine clinical practice, highlighting the problem of the “Hawthorn Effect” when participants know they are being observed. Giving HCP access to the data (for use in an interim consultation) and access to the adherence data from the rescue medication did not seem to influence adherence. In another paper presented at the conference, Tweedie described user research to establish the minimal viable product for a connected inhaler. This research found a high level of enthusiasm for connectivity of an inhaler to an app, preference for a screen on the device to provide the necessary information, and a longer battery life. The importance of ensuring good environmental sustainability for the product was also strongly highlighted.

Discussion There continues to be increasing interest in connected smart inhalers with more products in development likely to enter the market in the coming years. But the RDD papers discussed above also show there are challenges in realising their potential. Moore showed the difficulties of the challenges of gathering adherence data in clinical studies that are representative of the real world. Tweedie pointed out the challenges in explaining the economic value of connected devices, and Bonam stated the need to move from pilot studies to more extensive real-world studies. With the arrival of products such as Digihaler in the market, this is becoming a reality. However, it is also clear that for a good effect to be achieved, the right interventions need to be designed that can influence behaviour towards better adherence.

However, systematic reviews of interventions such as dose reminders do 44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

not provide compelling results in terms of improvement in adherence and/or clinical outcomes. Wilhelmsen and Eriksson conducted a comprehensive review of systematic reviews of medication adherence interventions and their impact on various health outcomes. Their review included data from 28,600 participants in 37 randomised controlled studies21. The results shown in Figure 5 show negative results for most adherence interventions against a range of outcomes. Focusing on the treatment of asthma using inhaled steroids, Normansell et al. performed a meta-analysis on data from 39 RCTS and a total of 16,303 participants22. They saw an increase in adherence for interventions targeting adherence education, electronic trackers or reminders, and simplified dosing regimens, with the former showing the most significant effect of 20 percentage points overall in the control group. However, this increase did not translate into improved outcomes for exacerbation requiring oral steroids, asthma control, unscheduled healthcare visits and quality of life. As pointed out by Moore, they noted that participation in a trial affects adherence, confounding results, and that studies would have benefited from better blinding, use of objective measures and validated questionnaires.

timestamp of when an inhaled medication event took place and ideally, whether it was free from inhalation errors, is a significant step forward. However, if the technology is to bring real benefit in improving adherence, attention to the design of the intervention needs to be given. The work being done

by Michie et al. to catalogue BCTs and encourage consistent application in the development of BCIs is an important step forward. Improvements to study designs, as pointed by Normansell and Moore, are also critical. But, as was the case in reducing inhaler use errors (“can use”), user research will continue to play a key role in developing an understanding of how device and app features can support “want to use”. In everyday life, such as in e-shopping, we have experienced the value of good web and app design which encourage use, as well as the frustrations of poorly designed solutions that achieve the opposite.

As pointed out by Michie et al., consistent application of BCTs needs to be ensured if study data is to be compared, and optimal interventions are to be designed to support adherence.

REFERENCES

Conclusion As more smart inhalers and associated digital services enter the market, the opportunity to gather more real-world data and test out different interventions will increase. The ability to collect an accurate

In some cases, the technical difference between the two extremes is small, but the difference in outcomes is immense. As Michelangelo said, “Perfection is not small, but it is made up of small things”. If digital interventions are to succeed in improving the adherence of inhaled drugs, such attention to detail is going to be critical.

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The Global Asthma Network. The Global Asthma Report 2018, http://www.globalasthmanetwork. org/Global%20Asthma%20Report%202018.pdf.

Retrieved May 26 2020 Asthma UK 2017. Smart asthma: Real-world implementation of connected devices in the UK to reduce asthma attacks, https://www.asthma. org.uk/591e6f4b/globalassets/get-involved/ external-affairs-campaigns/publications/ smart-asthma/auk_smartasthma_feb2017.pdf.

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Systematic Review of Errors in Inhaler Use: Has Patient Technique Improved Over Time?

Chest. 2016;150(2):394-406. doi:10.1016/j. chest.2016.03.041 Dixon J and Simpson I, Appealing to Users – Designing Inhalers to Maximize Compliance and Minimize Misuse In RDD Europe 2009 Respiratory Drug Delivery (Dalby, R.N., Byron, P.R., Peart, J., Suman, J.D., Young, P.M., eds), pp.

57–61, Davis Healthcare Int’l Publications Voshaar T, Spinola M, Linnane P et al.

Comparing usability of NEXThaler(®) with other inhaled corticosteroid/long-acting β2-agonist fixed combination dry powder inhalers in asthma patients. J Aerosol Med Pulm Drug Deliv.

2014;27(5):363-370. doi:10.1089/jamp.2013.1086 van der Palen J, Thomas M, Chrystyn H et al.

A randomised open-label cross-over study of inhaler errors, preference and time to achieve correct inhaler use in patients with COPD or asthma: comparison of ELLIPTA with other inhaler devices [published correction appears in NPJ Prim Care Respir Med. 2017 Mar 23;27:17001]. NPJ Prim Care Respir Med. 2016;26:16079. Published 2016 Nov 24. doi:10.1038/npjpcrm.2016.79 Chapman KR, Love L, Brubaker H. A comparison of breath-actuated and conventional metereddose inhaler inhalation techniques in elderly subjects. Chest. 1993;104(5):1332-1337. doi:10.1378/chest.104.5.1332 U.S. Food and Drug Administration, Applying Human Factors and Usability Engineering to Medical Devices, Guidance for Industry and

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Retrieved May 26 2020 Moberg S. Essential Parts of Innovation in Combination Products: Improving Patient Outcomes, presented at PDA Universe of Prefilled Syringes 2012, Las Vegas Sabate E. World Health Organization (2003): Adherence to long-term therapies: Evidence for action https://www.who.int/chp/knowledge/ publications/adherence_full_report.pdf.

Accessed May 26 2020 Michie S, Atkins L, West R. (2014) The Behavior Change Wheel: A Guide to Designing Interventions. London: Silverback Publishing. www.behaviorchangewheel.com Jackson C, Eliasson L, Barber N and Weinman J . Applying COM-B to medication adherence: A suggested framework for research and interventions. Eur Health Psychol 2014;16:1 Michie S, Richardson M, Johnston M, Abraham C, Francis J, Hardeman W, Eccles MP, Cane J, Wood CE. (2013). The Behavior Change Technique Taxonomy (v1) of 93 hierarchically clustered techniques: building an international consensus for the reporting of behavior change interventions, Annals of Behavioral Medicine, 2013;46(1): 81-95. doi: 10.1007/s12160-013-9486-6 Harris K, Mosler G, Grigg J. Theory-based self-management intervention to improve adolescents’ asthma control: a cluster randomised controlled trial protocol.

BMJ Open 2019;9:e025867. doi: 10.1136/ bmjopen-2018-025867 Smalley KR, Aufegger L, Flott K et al. Which behavior change techniques are most effective in improving healthcare utilisation in COPD self-management programmes? A protocol for a systematic review. BMJ Open Respiratory Research 2019;6:e000369. doi: 10.1136/ bmjresp-2018-000369

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Implementation Sci 12, 25 (2017). https://doi. org/10.1186/s13012-017-0553-4 Heneghan MB, Hussain T, Barrera L et al.

Applying the COM-B model to patientreported barriers to medication adherence in pediatric acute lymphoblastic leukemia.

Pediatr Blood Cancer. 2020; 67:e28216. https:// doi.org/10.1002/pbc.28216 Graham S, Weinman J, Auyeung V. Identifying Potentially Modifiable Factors Associated with Treatment Non-Adherence in Paediatric Growth Hormone Deficiency: A Systematic Review. Horm Res Paediatr. 2018;90(4):221227. doi:10.1159/000493211 Blakey JD, Bender BG, Dima AL, Weinman J, Safioti G, Costello RW. Digital technologies and adherence in respiratory diseases: the road ahead. Eur Respir J. 2018;52(5):1801147. Published 2018 Nov 22. doi:10.1183/13993003.01147-2018 Wilhelmsen NC, Eriksson T. Medication adherence interventions and outcomes: an overview of systematic reviews. Eur J Hosp Pharm. 2019;26(4):187-192. doi:10.1136/ ejhpharm-2018-001725 Normansell R, Kew KM, Stovold E. Interventions to improve adherence to inhaled steroids for asthma. Cochrane Database Syst Rev. 2017;4(4):CD012226. Published 2017 Apr 18. doi:10.1002/14651858.CD012226.pub2

Iain Simpson Iain Simpson is a Director of FrontEnd Innovation at Phillips-Medisize, a Molex company. He is part of a global team of engineers, designers, researchers, and business analysts developing industry-leading solutions for drug delivery, digital medicine and connected health systems. Dr Simpson has more than 25 years of experience in multi-disciplinary technology and product development in the US and European markets, with an increasing emphasis on the use of devices and digital technologies to create product differentiation, improve patient engagement, and better measure clinical outcomes in real-world settings.

He has a degree in physics and a PhD in experimental solid-state physics from UCL (London, UK) and an MBE in Technology Management from the Open University (UK).

Email: iain.simpson@phillipsmedisize.com

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Drug Discovery, Development & Delivery

Respiratory Drug Delivery – What has Happened and What might the Future Hold?

Recent decades have seen vast technological developments the world over. Here we look back at some of the recent defining moments for the respiratory drug delivery sector and take a look forward at the areas that are set to define the industry in years to come.

In the era of Pac-Man, big hair and Whitney Houston, a defining moment for respiratory science was the signing of The Montreal Protocol by 167 countries in 1987. Introduced to protect the ozone layer by phasing out harmful substances, this international treaty forced a pivot in the type of gases used in millions of asthma inhalers.

The chlorofluorocarbon (CFC) propellants widely used in pressurised inhalers at the time were phased out and replaced by newly-developed hydro-fluorocarbon- (HFA) based propellants. The effect of the move away from CFCs also kickstarted investment by pharma companies into alternative propellent-free drug-delivery methods, like dry power inhalers which have now become commonplace alongside more traditional press-and-breath inhalers.

Respiratory drug delivery has equally been defined by the development and approval of new drugs and treatments.

1990 saw the launch by Glaxo (now GSK) of Salmeterol, one of the most widelyused medications for asthma and COPD management today. Salmeterol was the very first long-acting beta-agonist (LABA), to be taken regularly to control chronic symptoms and prevent asthma attacks. This was followed by Seritide/Advair in 1998 – a combination of salmeterol and fluticasone propionate – which remains the best-selling asthma treatment of all time, generating annual revenues of over $7 billion.

Another ground-breaking drug introduced in recent decades is TOBI (tobramycin solution for inhalation); approved by the FDA for the treatment of cystic fibrosis (CF) in 1997. It was the very first inhaled antibiotic for the treatment of CF and has been credited with significantly extending the life expectancy of CF patients. Uniquely, 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

this drug was deemed to be so important to health that it was developed by PathoGenesis Corporation in collaboration with the academic inventors, the National Institutes of Health, the U.S. Food and Drug Administration, and the CF Foundation.

While there is a lot to be learnt from successful products, there is perhaps more to be learnt from failed ones. My final key milestone is Pfizer’s Exubera; the first ever inhaled insulin drug/device combination to be approved by the US FDA in 2006. At the time, the use of the pulmonary pathway was considered a major breakthrough in diabetic treatment. However, for Pfizer it ultimately ended in disappointment when they withdrew the therapy after less than two years. Part of the therapy’s shortcoming for patients was the inconvenient size and complexity of the delivery device. Pfizer wrongly believed that the inadequacies of the device would be outweighed by the benefit of not needing to self-inject insulin, but this didn’t play out as they had expected. Most diabetics ultimately favoured a small and discreet injection to a cumbersome inhalation device.

For device developers, Exubera remains one of the most interesting examples in recent history of how a poor understanding of patients’ needs resulted in a difficult-touse delivery device which contributed to a major failure to gain market acceptance, at the estimated loss of $2.8 billion to Pfizer.

But what about 2020 and beyond?

Looking ahead, for me there are three key areas which will define the future of respiratory drug delivery. The first is adherence, and efforts to improve patient compliance with therapies. Secondly, I think we will see much greater focus on prevention and management of diseases like asthma and COPD, as preferable to intense treatments. And last is the topic of sustainability; the environmental impact of this industry and our responsibility to limit it. But how and why will these three things impact drug delivery?

Patient Adherence The challenge of improving patient adherence remains a major theme for the

delivery of inhaled medicines. Worldwide, non-compliance is a major challenge to the delivery of healthcare. This is because consistent patient adherence to medication and treatment therapies is both crucial to successful disease management, and extremely difficult to ensure.

In 2003, the WHO estimated that only 50% of patients successfully take their medication as prescribed; non-adherence is not only detrimental to patient health, but also has vast cost implications for healthcare providers. Adherence is also directly linked to sustainability because the better patients follow their medical instructions, the less wastage and overuse of medicines and devices there are.

Julian Dixon, Director of Human Factors at Team Consulting, tries to explain the difficulties.

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Drug Discovery, Development & Delivery "We humans often don't do what we know we should. Perhaps it is one of the things that makes us human. Unfortunately, many medicines still depend on us as part of their delivery system, and most of us aren't that dependable when it comes to adherence with our medication. Nonadherence is an elephant of a problem: it is in every room where pharmaceuticals are talked about and it will be tackled one step at a time. We can attempt to tackle the nonadherence elephant by reducing the burden on users, by making administration less unpleasant, by eliminating ways of going wrong and by providing memory aids and reminders."

"Those measures make it easier to adhere – e.g. fewer, easier administrations – but don't address the non-adherence 'hard problem', which is that it is rooted in our human capacity to not do what is in our interests. Adherence with medication is one human challenge amongst many hardnuts-to-crack: smoking cessation; adequate exercise; healthy diet."

Thanks to the importance of ‘good adherence’ to patient health and recovery, there are significant efforts across the industry to make improvements. Recently, there have been attempts to tackle nonadherence through new technologies, such as companion apps that give patients reminders to take their drugs and device training instructions. These apps may be specific to a certain therapy or device, but there are now also many versatile ‘virtual pillbox’ apps – such as Medisafe and Dosecast – which can log patients’ doses and symptoms for any condition. These apps send push notifications to remind patients to take their medication, and will even notify a friend or family member if the patient forgets.

These companion mobile apps can also work alongside increasingly common ‘smart’ devices that actively assist a patient to inhale correctly, to improve the drug delivery effectiveness. One example is Teva’s ProAir Digihaler, which is the first FDA-approved connected inhaler. However, new technology also has a downside; it increases the device cost and complexity, so the technology gains need to be carefully weighed and balanced against the therapy’s benefits.

Greater Focus on Prevention ‘Prevention is better than cure’. It is neither a new or novel concept, but nor is it one that has been well championed in the respiratory 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

health space. In recent years, we’ve finally seen a shift in perspective to see diseases like COPD and asthma as intrinsically linked to our environment, lifestyle and overall health.

Using technology to make more regular check-ups accessible will help respiratory health problems to be identified early, or even pre-empted. Nowadays there are more devices and technologies than ever to encourage people to stay healthy. In the consumer world, sensor technologies are being increasingly utilised to track heart rate and pulse, body temperature, glucose and blood oxygen levels. Devices such as FitBit and Apple Watches record activity and fitness levels and accompanying smartphone apps help users track their fitness, and act as motivation.

Using technology in the respiratory health sector for preventative measures is less common but not unheard of. Recently, GSK have partnered with the Weather Channel, utilising data on upcoming weather events to improve effectiveness of respiratory care solutions. There also now exist smartphone apps available to help measure and monitor lung health and function, such as the Aria: Spirometry and Lung Health app.

These types of innovative solutions provide individuals and healthcare providers with more information about individuals’ health – important information that can improve diagnosis and treatment, keeping them healthier longer, allowing them more control of their respiratory health.

Sustainability There is increasing demand for more sustainable product design in the medical device industry. Whilst sustainability has been on the agenda for several years, the medical industry moves slower than our consumer counterparts, many of whom have already made serious changes to reduce the environmental impact of products and packaging.

There remains the complex underlying issue of finding a balance between ‘patient health’ and ‘environmental health’, especially when each affects the other. Typically, major shifts in the medical devices industry only come about when pushed by regulation; there will certainly need to be adaptions in the respiratory industry to reduce our environmental impact and we should expect some developments in this area soon. We think that it can be tackled right now in several key ways: Autumn 2020 Volume 12 Issue 3

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Drug Discovery, Development & Delivery 1.

2.

3.

4.

By working on manufacturing processes to reduce production waste and reduce the need to ship materials, components and sub-assemblies to different manufacturing sites.

By specifying materials with a reduced carbon footprint during the development of new devices.

By reducing the amount of device packaging that is delivered to the patient; for example, by combining packaging and instructions for use or by using simple cardboard support trays.

By setting up and supporting programmes that deal with the collection and recycling of used devices.

The environmental impact of modern inhaler devices is the key area of debate when it comes to sustainability in the industry. The vast majority of the 10 million asthma patients in Europe use pressurised metered dose inhalers (pMDI). These plastic devices, produced in mass, release propellants which are damaging to the atmosphere. They are also not reusable and are very difficult to recycle; most are incinerated, releasing more harmful gases.

At the beginning of this article I mentioned the impact that the Montreal Protocol has had on inhaler devices; by phasing out CFC gases and triggering the development and use of HFA-based propellants. However, HFAs, while not as damaging to the ozone layer – with a carbon footprint one-eighth the size of that of CFCs – still represent a potent greenhouse gas, and calls for discontinuing or at least limiting their use are growing. The problem with this is that, whilst current propellantbased inhalers may be detrimental to the environment, they are also an important part of the lives of millions of patients worldwide. This raises a big question; should we potentially sacrifice patients’ disease management by withdrawing or changing devices that are environmentally damaging? Or, should patient health take priority over environmental protection?

There is no easy answer, but significant effort is being spent to find a reasonable solution, including the development and approval of more environmentally-friendly HFA propellants and other inhalation technologies with reusable elements.

Speaking of other inhalation technologies, the second key impact of the

Montreal Protocol for the respiratory industry was the growth in research effort into other device-reliant drug-delivery methods such as dry powder inhalers (DPIs).

DPIs work without propellants, instead using patients’ respiratory effort to aerosolise the drug, and their carbon footprint is less than a tenth of that of pMDIs. Because of this, government and healthcare bodies continue to encourage the shift away from pMDIs towards dry powder alternatives. However, where the environment is concerned, there are still issues around the overall sustainability of single use devices.

More thought is also being given to how devices are managed at the end of their lives, recovering devices to recycle the materials used (rather than incinerating them as usually happens). Inhaler recycling schemes have been introduced in many areas – Teva recently launched one such scheme in Ireland, and GSK have recycled 1.2 million inhalers since 2010 as part of their ‘Complete the Cycle’ recycling and recovery scheme. Unfortunately, these schemes only recycle the gas and metal canisters; the plastic elements that make up the bulk of the devices are still being incinerated.

There are areas where incineration is used to generate power, but the industry is in need of a more sustainable recycling

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solution for such vast numbers of plastic inhalers.

Making products reusable is one such solution which is gaining traction in the market. For example, Boehringer Ingelheim’s Respimat® inhaler is now reusable, with patients receiving with each inhaler up to six replaceable cartridges containing their medicine. This alternative approach

drastically cuts down on the amount of plastic used and then disposed of, without having to significantly change the core drug delivery mechanism.

In my career I have worked on various dry powder inhalers, including a concept for a novel inhaler that is essentially a cardboard tube with a simple piercing mechanism to release the drug from an

innovative single-dose blister. This approach is novel not only because it uses advanced blister technology, but also because it vastly reduced the complexity and physical mass of the device; another approach to more ecofriendly product design. It has generated a lot of positive interest; pioneering solutions like this should be seriously considered in the next few years to supplement current respiratory device offerings and encourage more sustainable product design.

Brennan Miles Brennan Miles is an experienced respiratory drug delivery consultant.

Prior to joining Team Consulting, Brennan spent several years with the pharmaceutical giant Pfizer. He has been involved with and led the development of a range of respiratory devices, as well as surgical, injector and ophthalmic devices for a wide variety of therapies. He is the named inventor on a number of patents and has also had several papers published. Team Consulting is an award-winning medical device design and development consultancy. For over 30 years we have worked closely with our clients at the world’s leading pharmaceutical and device companies to develop better medical devices.

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Regeneron v Kymab: Transgenic Mice Claims Found Insufficient The Supreme Court judgment (24 June 2020) sends a clear “no” Brexit message to any big pharma contemplating corporate muscleflexing of excessively broad patent claims. This ruling overturned the position held by the Court of Appeal that, for patents relating to “a principle of general application”, there was no requirement to teach how to make the full range of claimed products. In this regard, the Court of Appeal held that Regeneron’s contribution to the field extended beyond the products (transgenic mice) that could be made back in 2001, and instead related to the general principle of providing ‘better’ mice (thereby overcoming a prior art immuno-sickness problem inherent to mice transfected with human DNA).

With hindsight, the Court of Appeal allowed too much weight to be given to the relative contribution the ‘better’ mice aspect provided in producing a(ny) mouse having commercial utility.

In sum, the Supreme Court considered the Court of Appeal had incorrectly watered down the “sufficiency of disclosure” requirement of patent law and, in doing so, this judgement maintains a sensible balance between patent law enforceability and invalidity and provides guidance on what might constitute a ‘principle of general application’ for which broad claim scope might be held valid.

Background to the Case Regeneron obtained two patents with a priority date of 16 February 2001, EP(UK) 1 360 287 (“the ’287 Patent”) and EP (UK) 2 264 163 (“the ’163 Patent”, a division of the ’287 Patent). At the priority date, there were two main problems associated with the use of mice as a platform for antibody development. First, use of murine antibodies in humans typically resulted in a host rejection response. Secondly, the transfection of mice with human antibody genes was associated with the mice developing a reduced immune response function (and thus reduced antibody titres). Regeneron’s solution to this reduced 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

antibody production capability was to develop a hybrid (chimeric) antibody gene structure, consisting in part of human and in part of murine elements, created by insertion of ‘human variable regions’ into the genome of the mouse, whilst retaining the ‘mouse constant regions’. The ‘variable’ regions are primarily responsible for antibody recognition of its target antigen.

In both mice and humans, the variable regions consist of V (variable) and J (joining) segments, with additional D (diversity) segments in the heavy chain but not the light chains. Evidence in the proceedings confirmed that a typical human heavy chain locus has around 125 different V segments, 27 D segments and nine J segments, and that one of each (V, D, and J) is found mature antibody. Including the light chain V and J segments, about 1.5 million different combinations are possible. Selection from a pool of V, (D) and J segments provides the rich diversity which is essential for generating antibodies against new targets.

Kymab’s challenge to validity arose in defence to an infringement action brought by Regeneron against Kymab’s commercialisation of its own transgenic mice, “Kymouse”. In the first instance (Patents Court), Mr Justice Henry Carr [[2016] EWHC 87 (Pat)] found that the difficulties in producing a hybrid gene structure where the whole of the human variable region was combined with the murine constant region were not taught (enabled) by the technical disclosures offered by the Regeneron patents (even when combined with the common general knowledge at the time of the priority filing), concluding that “at the priority date, the skilled person would not have been able to perform the invention over the whole area claimed without undue burden and without needing inventive skill”. This decision was overturned by the Court of Appeal [[2018] EWCA Civ 671], holding that Regeneron’s patents contained enough information to insert some of the human material into a mouse’s genes.

Whilst this would have created a hybrid mouse (as claimed), the prevailing genetic manipulation techniques available imposed a significant limitation on the amount of human DNA that could be transferred.

Indeed, said limitations would, at best, have

permitted the transfer of up to six out of 125 of the human variable region V segments into a mouse genome and an unspecified number of D and J segments. Moreover, the necessary transfection techniques required for transfer of the full human repertoire, and, therefore, necessary to put into effect the full breadth of the claim, were not invented until 2011. Thus, the Regeneron patents taught how to make a transgenic mouse having up to 5% of the necessary human repertoire, which as such simply had no meaningful commercial utility. Despite this, however, the Court of Appeal upheld the Regeneron patents on the basis they related to a “principle of general application”, and did not, therefore, require any teaching of how to make products commensurate with the scope of the claims. Kymab appealed to the Supreme Court.

The Claim in Question Covers a Range of Mice The validity of claim 1 of the ’163 Patent was central to the case. Both previous courts concluded that that claim covered all and any replacement of mouse VDJ regions with human VDJ regions in the heavy chain and replacement of mouse VJ regions with human VJ regions in the light chain, where replacing all equates to entirely replacing the mouse variable domains with human variable domains.

Thus, the case turned on the relevance or otherwise of the existence of a very narrow range of mice having amounts (up to 5%) of the human variable domain repertoire, to the question of sufficiency.

The appellant submitted that the range was of the highest importance because of its effect upon the ability of a particular type of mouse to produce a wide variety of B cells, and hence its potential to deliver a broad stream of useful antibodies (and thus have a meaningful commercial utility).

The respondent/patentee submitted that the existence of this range was irrelevant, because the unique advantage conferred by the use of a reverse chimeric locus, namely a cure for the immunological sickness of the recipient mouse, worked across the whole range, regardless of the amount of the human variable region DNA inserted into the murine genome, because it retained the murine constant region genes.

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Drug Discovery, Development & Delivery Sufficiency at the EPO Exxon/Fuel Oils (T 409/91) (1993) directly addressed sufficiency in a claim for a range of products: “the disclosure... is only sufficient if it enables the skilled person to obtain substantially all embodiments falling within the ambit of the claims…”

The Board of Appeal (BoA) considered the relevance that the invention disclosed as general principle, and decided it made no difference, stating that the claim must fail “regardless of whether or not the alleged ‘principle’… would be novel and inventive”, leading Lord Walker in Generics v Lundbeck (Generics (UK) Ltd v H Lundbeck A/S [2009] RPC 13) to describe the requirement that the invention be enabled across the whole scope of the claim as the ‘Exxon principle’. In Unilever/Detergents(‘Detergents’) (T 435/91) (2008) the BoA confirmed that “the whole subject matter of the claims, not only a part of it, must be capable of being carried out by the skilled person without the burden of an undue amount of experimentation or the application of inventive ingenuity” (emphasis added) and that a patent which enables an invention across a broad claim must disclose “a technical concept fit for generalisation which makes available to the skilled person the host of variants encompassed by the respective ‘functional’ definition of the ... claim.” Lord Briggs contrasted these cases considering product claims with Genentech I/Polypeptide expression (T 292/85) 1988 (‘Polypeptides’), which the respondent relied on in their defence. In Polypeptides, the claims (e.g. claim 1, a recombinant plasmid suited for transformation of a bacterial host comprising a homologous regulon … and claim 9, a bacterium transformed with the cloning vehicle of claim 1 …) were framed by reference to function, and sought to protect products and processes that achieved that

function when applied to a broad range of input variables, none of which were themselves embodiments of the claim.

Specifically, the terms bacteria, regulon and plasmid covered (e.g. bacteria, or plasmids which may not even have been identified), but the process would work for bacteria not yet discovered, and would produce the same result: an expressed polypeptide. In contrast, in the (later) Detergents case, the patent failed to disclose any general technical principle by which the skilled person could achieve the desired result across the whole range of claimed embodiments.

Why Does the Current Case Follow ‘Detergents’ not ‘Polypeptides’?

In the present case (claim 1), the whole of the human variable region gene locus had already been mapped, and could be inserted into mice, and had been, but only when attached to the human constant regions, giving rise to murine immunological sickness. The problem facing the skilled person at the priority date was that there was no known way, either using the teaching in the Regeneron patents or using the common general knowledge, to combine more than a very small part of the human variable region gene locus with the endogenous murine constant region gene locus, in the same hybrid gene structure.

The ‘inventive shortfall’ lay not in the range of possible inputs to which the invention could be applied, but in the inability to actually put the invention into effect for anything other than a very small part of the scope of the claim.

Sufficiency in the UK Lord Briggs found that the UK cases follow a similar approach to the existence and nature of the exception to the ‘Exxon

Heavy chain

Light chain Mouse constant regions

Human antibody

Reverse Chimeric antibody

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principle’ illustrated by Polypeptides for ‘principles capable of general application’. In considering UK cases (Biogen Inc v Medeva plc [1995] RPC 25 and [1997] RPC 1, KirinAmgen Inc v Hoechst Marion Roussel Ltd [2005] RPC 9 Generics (UK) Ltd v H Lundbeck A/S [2008]); Lord Briggs found that the UK case law provides clear guidance for product claims, in contrast to the situation for a process such as described in ‘Polypeptides’, reciting Hoffmann on insufficient disclosure: “The patent may claim results which it does not enable, such as making a wide class of products when it enables only one of those products and discloses no principle which would enable others to be made.” “In the case of a product claim, performing the invention for the purposes of section 72(1) (c) means making or otherwise obtaining the product. In the case of a process claim, it means working the process. A product claim is therefore sufficiently enabled if the specification discloses how to make it” (emphasis added).

Lord Briggs Set Out Principles for Determining Sufficiency The following principles for determining sufficiency were outlined [56]: i)

The requirement of sufficiency imposed

by Article 83 of the EPC exists to ensure that the extent of the monopoly conferred by the patent corresponds with the extent of the contribution which it makes to the art. ii) In the case of a product claim, the contribution to the art is the ability of the skilled person to make the product itself, rather than (if different) the invention. iii) Patentees are free to choose how widely to frame the range of products for which they claim protection. But they need to ensure that they make no broader claim than is enabled by their disclosure. iv) The disclosure required of the patentee is such as will, coupled with the common general knowledge existing as at the priority date, be sufficient to enable the skilled person to make substantially all the types or embodiments of products within the scope of the claim. That is what, in the context of a product claim, enablement means. v) A claim which seeks to protect products which cannot be made by the skilled person using the disclosure in the patent will, subject to de minimis or wholly irrelevant exceptions, be bound Autumn 2020 Volume 12 Issue 3

Drug Discovery, Development & Delivery V segments VH 1

VH 2

VH 3

VH n

Variable region

n= ̴27

n= ̴9

DH1-DHn

JH1-n

Application of those principles to the current case shows that claim 1 fails for insufficiency, because only a small range of the products could be made, and mice at the more valuable end of the range could not be made.

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Constant region exons CH1-3

Constant region

to exceed the contribution to the art made by the patent, measured as it must be at the priority date. vi) This does not mean that the patentee has to demonstrate in the disclosure that every embodiment within the scope of the claim has been tried, tested and proved to have been enabled to be made. Patentees may rely, if they can, upon a principle of general application if it would appear reasonably likely to enable the whole range of products within the scope of the claim to be made. But they take the risk, if challenged, that the supposed general principle will be proved at trial not in fact to enable a significant, relevant, part of the claimed range to be made, as at the priority date. vii) Nor will a claim, which in substance passes the sufficiency test, be defeated by dividing the product claim into a range denominated by some wholly irrelevant factor, such as the length of a mouse’s tail. The requirement to show enablement across the whole scope of the claim applies only across a relevant range.

Put broadly, the range will be relevant if it is denominated by reference to a variable which significantly affects the value or utility of the product in achieving the purpose for which it is to be made. viii) Enablement across the scope of a product claim is not established merely by showing that all products within the relevant range will, if and when they can be made, deliver the same general benefit intended to be generated by the invention, regardless of how valuable and ground-breaking that invention may prove to be.

•

J segments

D segments

n= ̴125

Interesting Observations (Unusual Nature of the Court of Appeal Order) Kymab obtained a stay of the injunction, the order for delivery up and the order for disclosure pending resolution of their appeal to the Supreme Court. Under the terms of the stay, Kymab’s collaborative work with humanitarian bodies, including the Bill & Melinda Gates Foundation and the International AIDS Vaccine Initiative to treat diseases with unmet clinical need, was allowed to continue. Specifically, Kymab was permitted to ‘dispose or export’ antibodies or mouse serum for the purposes of: •

•

Kymab’s collaborations with the Bill & Melinda Gates Foundation and the International AIDS Vaccine Initiative and Heptares Therapeutics Limited; and Preparing and conducting pre-clinical or clinical trials, antibody producing CHO cells for use by Kymab’s manufacturing CRO Lonza (and which will remain under Kymab’s control) solely for the purposes of manufacturing antibodies under GMP conditions for use in preclinical or clinical trials.

The Court of Appeal considered that in the absence of a stay, Kymab’s loss would include serious disruption, putting an end to Kymab’s work and outweighed Regeneron’s loss. A requirement for Kymab to ring-fence damages was also rejected – the Court of Appeal considered that there was a real prospect that it would drive Kymab out of business, frustrating any further appeal and leading to a termination of the humanitarian work that Kymab was undertaking.

Summary A patent reflects a bargain between the inventor and the public. The inventor gains a time-limited monopoly over the making and use of a product. In return, the public gains the ability to make the product after the expiry of the monopoly. As part of this bargain, the inventor must publish

sufficient information to enable a skilled member of the public to make the product.

This ensures that patent holders only gain legal protection which is proportional to their actual technical contribution to the art, and encourages inventors to conduct research for the benefit of society. The decision makes a clear distinction between the requirements for a product claim (that the product can be made across the breadth of the claimed range at the effective date of the patent), and a process claim capable of general application, where the process can be applied to a range of inputs, and will always provide the benefit. Whereas the Court of Appeal gave the patentee a tantalising glimpse of a world where the patentee might receive the benefit for having a good idea, even though they could not make it work across the board, this decision puts the balance back firmly with the public.

Martin MacLean Martin has over 20 years of IP experience with particular expertise in patent portfolio management for corporates and government. With a strong biotech background, he specialises in technologies such as the protein therapeutics, antibodies, vaccines, expression systems, diagnostic assays, and ‘green’ agrochemicals. Martin’s expertise is recognised by his Band 1 ranking in Chambers UK, recommendation in The Legal 500, and his rankings as a leading individual in IAM’s Strategy 300 and Patent 1000 directories.

Andrea Hadfield Andrea works in all areas of the life sciences and has experience working for a wide range of clients, including universities, spin-outs, SMEs and multinational corporate clients. She has experience in drafting and the prosecution of patent applications in the UK, Europe and worldwide, as well as post-grant opposition and appeal proceedings before the EPO.

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Drug Discovery, Development & Delivery

Returning to Basics of siRNA Design to Fulfil Therapeutic Potential The recent FDA approval of siRNA therapeutics has re-energised the RNA interference (RNAi) field. The RNAi mechanism was first proposed with the discovery of microRNA in 19931,2 and soon after it was demonstrated that microRNAs regulate gene expression in normal cellular biology and disease.

In a Nobel prize-winning discovery in 1998, RNAi was described in C. elegans, where small interfering RNA (siRNA) caused sequence-specific gene knockdown3. The discovery of RNAi-mediated silencing in mammalian cells4 and parallel availability of the whole human genome sequence allowed for creation of research tools to study gene function using siRNA. Manufacturing siRNAs using chemical synthesis was straightforward and the prevailing thought was that siRNA could be used to silence any target gene in any cell. In fact, siRNAs targeting the whole human genome were synthesised in 2006 and whole genome screens have shown them to be a powerful genomics research tool5. However, due to challenges in siRNA delivery and pharmacokinetics, its potential as a therapeutic was not realised until the FDA approval of the siRNA therapeutics ONPATTRO® (patisiran) and GIVLAARI® (givosiran) in 2018 and 2019, respectively. The success of these therapeutics builds on almost two decades of siRNA design and encourages the field to pursue additional gene targets for therapeutic intervention.

Mechanism To design a functional and specific synthetic siRNA therapeutic, the RNAi mechanism must be considered. The endogenous RNAi mechanism uses transcribed microRNA to regulate gene expression (Figure 1).

Synthetic RNA can enter the RNAi mechanism at different steps to effect gene knockdown. Longer double-stranded RNAs [>19 base pairs (bp)] can enter the pathway as Dicer substrates which are cleaved into siRNAs by Dicer, or synthetic siRNAs (<19 bp) can enter the cell and be loaded directly 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 1: Synthetic siRNA can enter the endogenous RNAi mechanism to specifically downregulate gene expression. Primary microRNAs are transcribed in the nucleus and processed by the Drosha-containing complex (microprocessor) to yield the precursor microRNA, which is then shuttled out of the nucleus into the cytoplasm by Exportin-5. The Dicer complex cleaves the pre-microRNA hairpin into a double-stranded microRNA duplex. The double-stranded microRNA is unwound, and one strand is selected for incorporation into the RISC. RNA-programmed RISC binds to target mRNA with imperfect (seedmediated) or perfect complementarity, respectively. Seed-mediated complementarity causes transcript destabilisation and subsequent downregulation of protein expression while perfect complementarity causes catalytic mRNA cleavage and robust gene silencing.

into the RNA-induced silencing complex (RISC). These synthetic siRNAs must be able to enter the cell and interact with RNAi machinery including: Dicer to cleave the molecule into siRNA, RISC components for unwinding, loading, and then finally WatsonCrick base pairing one strand to the mRNA target to result in gene silencing.

RNA Synthesis and Chemical Modifications This discovery that siRNAs can cause robust gene knockdown excited the field because now it is possible to easily knock down the expression of a gene by delivering a complementary RNA sequence. siRNAs are comprised of two strands (active and passenger) that form a helical duplex (Figure 2). Compared to traditional organic molecule therapeutics, siRNAs do not have drug characteristics. They are relatively large in size, the backbone contains many negative charges, and the molecule is hydrophilic. Fortunately, the short length of

siRNA allows almost any sequence to easily be synthesised by various chemistries: TBDMS (tert-butyldimethylsilyl), ACE (5'-silyl-2'-acetoxyethylorthoester), and TOM (2'-O-[(triisopropylsilyl)oxy]methyl) chemistries have all been used6. In addition, chemical modifications can be introduced to the siRNAs at multiple positions (nucleoside base, phosphate backbone, 5’ or 3’ ends, demonstrated by the coloured ovals in Figure 2) to alter the therapeutically relevant properties of the molecule. The advantage of siRNA is that its pharmacokinetic properties are primarily defined by the molecular structure, while the targeting properties are defined by the RNA sequence. This means that a successful molecular structure can be applied to a different target sequence and the development time to therapeutic can be substantially shortened. In theory, it should be possible to target any gene, making previously undruggable proteins amenable to therapeutic approaches.

Autumn 2020 Volume 12 Issue 3

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PowdAir Plus is an innovative, discreet, patented capsule based dry powder inhaler designed for advanced simplicity, ease of use, affordability and consistent medicine dose delivery.

PowdAir Plus, with a transparent chamber for visual dose delivery feedback, automatically activates the capsule as the tray is closed and is suitable for all capsule types in size 3.

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 57

Drug Discovery, Development & Delivery strands so strong that unwinding is impaired and siRNA functionality is impacted. Data have shown that thermodynamic stability of the duplex requires the 5’ end of the guide RNA to be paired more weakly, followed by a higher affinity region through the seed sequence and finally a lower affinity region toward the 3’ end to promote strand release during unwinding. The thermodynamic stability of the duplex can easily be tuned through application of chemical modifications. For example, 2’-F and 2’-OMe modifications increase the local melting temperature, while PS modifications reduce melting temperature.

A 5’-phosphate on the guide strand is required for RISC recognition and loading.

Chemical modifications can be used to block the phosphorylation and loading of the passenger strand and promote guidestrand-only loading. In addition, chemical stabilisation of the phosphate can improve loading and the resulting activity of the siRNA in vivo.

Figure 2: Composition of siRNA and placement of chemical modifications. Top: Synthetic siRNA is comprised of an active (red) and a complementary passenger (blue) strand to make a duplex of approximately 20 base pairs. Phosphorylation on the 5’ end of active strand is required for RISC loading and function. The seed region (underlined in figure) is also involved in downregulation. Conjugation of a ligand such as cholesterol, cell penetrating peptide or GalNAc can facilitate delivery of siRNA into the cell. Bottom: Chemical modifications can be applied to any position on the RNA (common positions are indicated by colours). These modifications improve characteristics of siRNA including function, off-targeting, nuclease stability and tolerance by the innate immune system.

Improving Nuclease Stability When unmodified siRNAs are injected into the bloodstream, they are degraded within minutes, due to the 2’-hydroxyl on the sugar making RNA susceptible to degradation by RNAses. Modifications on the 2’ position of the sugar can improve stability against RNAses, and 2’- fluoro (2’-F) and 2’-O-methyl (2’-OMe) modifications are commonly applied to both 5’ and 3’ terminal nucleotides of the siRNA to protect against exonucleolytic degradation. Backbone modifications, such as phosphorothioates (PS), can also improve nuclease resistance against endonucleolytic attack.

Innate Immune System Unmodified siRNA can cause toxicity in cells as it may stimulate the innate immune system. The innate immune system is activated by longer double-stranded RNA structures and consequently minimising duplex lengths reduces immune systemassociated toxicity.

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Both sequence motifs and chemical modifications, or the combination of these, can cause cellular toxicity. For example, PS modifications on the backbone can cause toxicity when used in certain sequence contexts. Also, there are known toxic motifs associated with locked nucleic acid modifications. Avoiding combinations of these motifs and modifications is key to designing an effective and non-toxic siRNA. In addition to increasing cellular stability, modifications to the 2’-positions of the sugar such as 2’-F and 2’-OMe help the siRNA evade the innate immune system.

Unwinding and Strand Selection Unwinding of the duplex is an essential step of loading the guide strand (and not the passenger strand) for effective silencing and preventing off-targeting by the passenger strand.

Chemical modifications can make base pairing between guide and passenger

Delivery and Bioconjugation Since siRNA is negatively charged and hydrophilic, crossing the cell membrane is a major obstacle. A variety of delivery approaches have been, and are continuing to be, explored. siRNA can be encapsulated in polymeric and lipid nanoparticles for in vivo delivery. In addition, conjugation to delivery moieties have also been researched. Several ligands have shown promise, including conjugation to cholesterol, lipids, antibodies, aptamers, N-acetylgalactosamine (GalNAc), among others. The position of the conjugated ligand is important for maintaining siRNA function with the 3’ end of the passenger strand being a preferred location. Also, the length and composition of the linker between the siRNA and ligand can affect delivery and functionality.

Many of these bioconjugation strategies have shown promise, but finally after decades of research investment, two RNAi therapeutics have been approved.

One aspect of their siRNA design that contributed to success is the use of GalNAcconjugated siRNA for specific delivery to liver hepatocytes. GalNAc binds to the asialoglycoprotein receptors which are expressed at a high level in hepatocyte cells; once bound, the GalNAc and siRNA are brought into the cell by endocytosis.

GalNAc-siRNA conjugates provided an exciting advancement in delivery of siRNA Autumn 2020 Volume 12 Issue 3

Drug Discovery, Development & Delivery to hepatocyte cells and paved a path for RNAi therapeutics moving forward.7 Modification Strategy An effective synthetic siRNA must be recognised by the RNAi mechanism components for processing, unwinding, RISC loading and mRNA targeting. While some modifications can improve the molecular properties of the siRNA, others can compromise gene knockdown.

Chemical modifications affect many molecular properties including the sugar conformation, winding of the duplex, and helix conformation. The chemical modification pattern that is applied must leave the RNA looking like an A-form helix.

In general, 2’-F more closely mimics the 2’-hydroxyl in size and charge, so this modification is often applied to the guide RNA strand, which is more sensitive to modification. 2’-OMe modifications are often applied to the passenger strand that is not loaded into RISC. It has also been found that these types of modifications are tolerated well when applied in an alternating pattern to maintain the A-form helical structure.

Overall, the goal is to modify siRNA to improve nuclease stability, evade innate immune system response and improve delivery while maintaining ability of siRNA to interact with the RNAi machinery.

(Reviewed in8,9) Rational siRNA Design Many algorithms have been developed to design sequences that are both functional and specific. A workflow for efficient siRNA design and selection will include multiple steps to ensure functional knockdown of the intended target while avoiding offtargeting.10 First, target gene sequence space is defined and used to build a comprehensive siRNA candidate list. This is followed by removal of candidate sequences outside the open reading frame and 3’ UTR, not present in all of the transcript variants, or containing characterised SNPs. Additional filtering of sequences that are likely to decrease function is required.

Filtered candidates include sequences with degenerate base symbols, toxic motifs, repetitive bases, excessively high or low GC content, microRNA seed matches, and sequences that cause secondary structure in siRNA. The remaining siRNA candidates are scored according to a functionality algorithm to select highly functional siRNAs; criteria may include thermodynamic asymmetry, possible fold-over structures and positionspecific nucleotide preferences. Finally, www.ipimediaworld.com

5.

6.

7.

8.

9.

10.

candidate sequences are aligned to all targets in the transcriptome to eliminate sequences that have perfect or near-perfect complementarity to unintended targets.

Additional design parameters may be required depending on the specific therapeutic siRNA programmes. For example, it may be necessary to design siRNA sequences that are identical or similar enough to be functional in mouse, rat and human ortholog gene to facilitate animal studies, or the disease application may require targeting all the protein-coding transcripts while avoiding a non-coding transcript.

A large body of work has defined how sequences are selected and how chemical modification can affect silencing efficiency.

However, each unique application requires empirical testing. Success of an siRNA programme depends on testing multiple sequence candidates with the desired chemical modifications to find the most potent siRNA. REFERENCES 1.

2.

3.

4.

Lee, R.C., R.L. Feinbaum, and V. Ambros, The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell, 1993. 75(5): p. 843-54.

Wightman, B., I. Ha, and G. Ruvkun, Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell, 1993. 75(5): p. 855-62.

Fire, A., et al., Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature, 1998.

391(6669): p. 806-11.

Elbashir, S.M., et al., Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature, 2001. 411(6836): p.

494-8.

Mohr, S.E., et al., RNAi screening comes of age: improved techniques and complementary approaches. Nat Rev Mol Cell Biol, 2014. 15(9): p. 591-600.

Caruthers, M.H., A brief review of DNA and RNA chemical synthesis. Biochem Soc Trans, 2011.

39(2): p. 575-80.

Springer, A.D. and S.F. Dowdy, GalNAc-siRNA Conjugates: Leading the Way for Delivery of RNAi Therapeutics. Nucleic Acid Ther, 2018.

28(3): p. 109-118.

Khvorova, A. and J.K. Watts, The chemical evolution of oligonucleotide therapies of clinical utility. Nat Biotechnol, 2017. 35(3): p.

238-248.

Takahashi, M., et al., Current Progress and Future Prospects in Nucleic Acid Based Therapeutics. 2017.

Birmingham, A., et al., A protocol for designing siRNAs with high functionality and specificity.

Nat Protoc, 2007. 2(9): p. 2068-78.

Annaleen Vermeulen Annaleen Vermeulen is a Principal Scientist at Horizon Discovery. She studied nucleic acid structure by NMR at the University of Colorado at Boulder where she received her doctoral degree in chemistry. Annaleen joined the Research and Development Team at Dharmacon (now part of Horizon Discovery) in 2004 and contributed to development of several products in the gene editing and RNAi fields.

Email: annaleen.vermeulen@ horizondiscovery.com

Amanda Haas Amanda Haas is a Product Manager at Horizon Discovery. Amanda joined in 2005 and worked in multiple departments including Manufacturing, Chemistry R&D, Biology R&D and Product Management. She is responsible for custom synthetic manufacturing and also contributed to new product development in multiple areas across RNA interference and CRISPR-Cas9 genome engineering. She received her degree in chemistry at The University of Miami.

Email: amanda.haas@horizondiscovery.com

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Clinical and Medical Research

Diagnostic Techniques for COVID-19

SARS-CoV-2, or the pathogen which causes COVID-19, is a virus containing a positive-sense RNA as its genetic constituent. Morphologically, it contains spike-like projections on its surface and is hence named as ‘The Coronavirus.’1 On March 11, 2020, the disease was declared a ‘pandemic’ by the WHO2 and since then, the search for an effective diagnostic tool was the key to controlling the devastating repercussion of the viral outbreak.

In this regard, the present article intends to review the current array of techniques available for the detection of SARS-CoV-2.

What is the Role of Diagnostic Techniques in COVID-19?

As a rule of thumb, any initial strategy intended towards containing a disease outbreak should focus on the ways to reduce disease transmission either by reducing the total number of susceptible individuals in a population or by limiting the primary reproductive number (R0).3 This can be achieved by combining efforts aimed at early detecting and isolation of potentially infectious individuals.4 Diagnostic kits in such a scenario can prove to be a boon in containing a disease outbreak by reducing transmission of disease through early detection of cases in a community.

However, their definitive role is subject to change based on the available testing type, the resource required for testing, and the kit’s turnaround time.5–6 Countries that could effectively utilise diagnostic techniques to curb the pandemic include South Korea, Singapore, Taiwan, and Hong Kong.7–9 Defining Key Aspects for the Effective Use of Diagnosis Techniques Who to Test?

The COVID-19 pandemic is an emerging and rapidly evolving situation. Therefore, countries around the world have taken various testing strategies to curb the spread of the pandemic based on their public health policies, available resources, and degree of community transmission of 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the virus. In India, the United States, and countries around the world, initially, the diagnosis of viral disease was limited due to regulatory obstacles.10,11 Thus in such a scenario, health authorities (CDC and ICMR) have laid down several testing criteria to prioritise testing of the most susceptible individuals.

The CDC prioritises testing of the three groups: patients hospitalised with symptoms of COVID-19, symptomatic individuals who are at a high risk of poor outcome, and those who have had close contact either with a suspected or confirmed case of the disease (in ≤ 14 days of disease onset) or have a travel history to an area affected by the pandemic.12 Likewise, the Indian Council of Medical Research (ICMR) highlights the importance of testing of both symptomatic (criteria similar to CDC) and asymptomatic individuals. For asymptomatic individuals, the apex body considers testing of a person living in the same household as that of a confirmed case followed by the testing of healthcare professionals involved in the treatment of COVID-19.13 How to Test?

Tests to detect COVID-19 can broadly be divided into two main categories: the molecular diagnostic technique, the antigen detection technique, and the serological technique.

Molecular Diagnostic Technique The real-time polymerase chain reaction (RT-PCR) technique is the gold standard for identifying infection with SARS-CoV-2 as far as a molecular diagnostic technique is concerned. In this technique, a nasopharyngeal specimen is taken using a flocked swab and immediately transferred into a universal transport medium to preserve viral nucleic acid. After that, the sample undergoes RNA extraction and qualitative RT-PCR. A positive result after an RT-PCR indicates the presence of SARS-CoV-2.11,12 Nowadays, the isothermal amplification technique is also being used commercially for the detection of SARS-CoV-2. The technique allows rapid amplification of DNA at a constant temperature and is resistant to inhibitors in a complex sample. Furthermore,

the method has an amplification factor of up to 109 (comparable to 30 cycles of PCR).13 Antigen Detection Technique Direct detection of the COVID-19 antigen is a viable alternative to molecular technique, but its commercialisation is still in its developmental phase. Moreover, the currently available antigen detection kits (for influenza and respiratory syncytial virus) have suboptimal sensitivity. Therefore there is a likelihood that a similar problem would exist for SARS-CoV-2, and so, clear guidance should be laid down for the proper interpretation of results generated out of such a technique.11,12 Serological Technique Serological techniques are an essential diagnostic tool for the detection of individuals who had prior exposure to SARSCoV-2 as they can gauge the proportion of the population which has immunity against the pandemic. Furthermore, this information can help governments across the globe to effectively ease down on widespread lockdowns. However, their value towards the diagnosis of acute infection is probably limited as antibodies take days to weeks to be measurable.11,12 An up-to-date list of commercially available diagnostic tests for COVID-19 can be found at https://www.360dx.com/ coronavirus-test-tracker-launched-covid19-tests.

Are there Any Other Auxiliary Diagnostic Techniques Available?

While diagnostic techniques help in the detection of the disease, auxiliary tests can help clinicians in differential diagnoses and early recognition of various stages of the disease.14,15 Computed Tomography (CT) of the Lung In patients with COVID-19, a CT of the lungs shows multifocal bilateral patchy groundglass opacities (GGOs) or consolidation along with interlobular septal and vascular thickening (mostly in the periphery).

Additionally, these opacities can either be patchy and round or triangular and linear (spider-web) in shape.16,17 Furthermore, CT findings can also help in the interpretation of disease progression. (Table 1) Autumn 2020 Volume 12 Issue 3

(mostly in the periphery). Additionally, these opacities can either be patchy and round or triangular and linear (spider-web) in shape. (16,17) Furthermore, CT findings can also help in the interpretation of disease progression. (Table 1)

Clinical and Medical Research

Table 1: Characteristic findings from CT for the evaluation of stages of the disease (1623) Stages of disease Early

specificity, quick turnaround time, and would allow testing of the disease under the resource-limited setting.33,34

Characteristic findings in CT   

small lobular and subsegmental patchy GGOs thickening of vascular lumens and interstitial changes



gradual progression of lesions gradually to multiple GGOs along with the presence of dense consolidation thickening of the interlobular septum in GGOs (similar to “crazy paving” pattern) and diffuse lesions in both lungs (in severe cases) along with signs of air bronchogram and blood vessel penetration

Conclusion The COVID-19 pandemic has highlighted the role of diagnostic techniques in combating Progressive and  the spread of communicable diseases. peak Additionally, it has also pinpointed the  importance of research and development in the wellbeing of a country and its  resolving of the GGOs and consolidation and people as a whole. Therefore, countries Remission  absence of “crazy paving” pattern and subpleural parenchymal fibrosis lesions as seen in patients with severe COVID-19 around the world should pledge to invest Table 2: Summary of changes in biomarkers an appreciable amount of their total (15, 25-30) Table 1: Characteristic findings from CT for the evaluation of stages of the disease16–23 GDP towards the progress of science and In cases requiring a differential diagnosis (between COVID-19 and non-COVID-19 viral technology for successfully warding off such Biomarker a CT-scan hasChange withspecificity COVID-19 but Sensitivity pneumonia), shownintopatients have high moderate Specificity sensitivity. (24) pandemics in the near future.

C-reactive protein

Increases

83%

91%

Assessment of Biomarkers as a Diagnostic Lactase dehydrogenase IncreasesTechnique for COVID-19 100% 86.67%

Acknowledgement

Serum amyloid A Increases N/A N/A The author wishes to thank Dr Subrina AInterleukin-6 person affected with COVID-19 may suffer from a wide range Increases 73.3%of symptoms 89.3% ranging from Jesmin (MD, Ph.D., FRCP, MS, FACC, FAHA, mild to severe illness. This varied NLR presentation and increases often complicates 88% diagnosis, 63.6%prognosis, FICA), a medical scientist, analyst, writer, and White cell count LC decreases N/A in the prompt monitoring of the disease. Biomarkers, in this respect, can beN/A a helpful tool clinician for helping out with peer review of D-dimer of a patient’s condition (Table Increases 86.7% cases of 82.1% assessment 2) and thereby prevent fatality from the this article.

PLR Increases 100% 81.5% disease.

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However, most of these studies citing been designed used to combat What Other Diagnostic Techniques canhave we Expect in the and Future?

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Therefore further researchare is well theequipped presencetoofdetect SARS-CoV-2, there are transmission of COVID-19: lessons from Although each of these techniques the presence of SARS-CoV-2, warranted to establish the role of bio- certain limitations (cost, turnaround time, containment efforts in Singapore. J Travel Med. there are certain limitations (cost, turnaround time, portability, and temperature stability) that markers in the diagnosis of COVID-19. portability, and temperature stability) that 2020, 18;27(3). doi:10.1093/jtm/taaa039 can be used to design diagnostic techniques for the future. can be used to design diagnostic techniques 9. Wang CJ, Ng CY, Brook RH. Response to COVID-19 in Taiwan: big data analytics, new technology, What is the Role of Contact Tracing as a for the future. and proactive testing. JAMA. 2020, 323(14):1341Two of these latest technologies to drive the design of future diagnostic tools include Diagnostic Technique?

1342. doi:10.1001/jama.2020.3151 CRISPR and isothermal amplification.

These techniques are deemed to have high specificity, Contact tracing is defined as the process Two of these latest technologies to drive 10. Das A. Why Covid-19 testing has been slow to of identifying, assessing, and managing design of diagnosticunder tools include quick turnaround time, and would allowthetesting offuture the disease the resource-limited take off. Times of India (19.05.20). Retrieved people who have been previously exposed CRISPR and isothermal amplification. from https://timesofindia.indiatimes.com/ setting. (33, 34) to the virus but are either asymptomatic These techniques are deemed to have high india/why-covid-19-testing-has-been-slow-

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 61

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Diagnostic Testing for Severe Acute Respiratory Syndrome-Related Coronavirus-2: A Narrative Review [published online ahead of print, 2020 April 13th]. Ann Intern Med. 2020; M20-1301. doi:10.7326/M20-1301 Isothermal DNA Amplification. Jena Bioscience.

(25.05.20). Retrieved from: https://www. jenabioscience.com/molecular-biology/ isothermal-amplification Luo Z, Wang N, Liu P et al. Association between chest CT features and clinical course of Coronavirus Disease 2019 [published online ahead of print, 2020 April 22nd].

Respir Med. 2020;168:105989. doi:10.1016/j. rmed.2020.105989 Kermali M, Khalsa RK, Pillai K, Ismail Z, Harky A. The role of biomarkers in diagnosis of COVID-19 - A systematic review [published online ahead of print, 2020 May 13th]. Life Sci. 2020;117788. doi:10.1016/j.lfs.2020.117788 Bernheim A, Mei X, Huang M, Yang Y, Fayad ZA, Zhang N et al. Chest CT findings in coronavirus disease-19 (COVID-19): relationship to duration of infection. Radiology 2020:200463. doi:10.1148/radiol.2020200463 Wu J, Wu X, Zeng W et al. Chest CT Findings in Patients With Coronavirus Disease 2019 and Its Relationship With Clinical Features.

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Radiology. 2020;295(3):715-721. doi:10.1148/ radiol.2020200370 Duan YN, Qin J. Pre- and Posttreatment Chest CT Findings: 2019 Novel Coronavirus (2019nCoV) Pneumonia. Radiology. 2020;295(1):21. doi:10.1148/radiol.2020200323 Shi H, Han X, Zheng C. Evolution of CT Manifestations in a Patient Recovered from 2019 Novel Coronavirus (2019-nCoV) Pneumonia in Wuhan, China. Radiology.

2020;295(1):20. doi:10.1148/radiol.2020200269 Wei J, Xu H, Xiong J et al. 2019 Novel Coronavirus (COVID-19) Pneumonia: Serial Computed Tomography Findings. Korean J Radiol.

2020;21(4):501-504. doi:10.3348/kjr.2020.0112 Li K, Wu J, Wu F et al. The Clinical and Chest CT Features Associated With Severe and Critical COVID-19 Pneumonia. Invest Radiol.

2020;55(6):327-331. doi:10.1097/RLI.0000000000000672 Zhao W, Zhong Z, Xie X, Yu Q, Liu J. Relation Between Chest CT Findings and Clinical Conditions of Coronavirus Disease (COVID-19) Pneumonia: A Multicenter Study. AJR Am J Roentgenol. 2020;214(5):1072-1077. doi:10.2214/ AJR.20.22976 Bai HX, Hsieh B, Xiong Z et al. Performance of radiologists in differentiating COVID-19 from viral pneumonia on chest CT [published online ahead of print, 2020 March 10th]. Radiology.

2020;200823. doi:10.1148/radiol.2020200823 Han Yi, Zhang H, Mu S et al. Lactate dehydrogenase, a Risk Factor of Severe COVID-19 Patients. medRxiv 2020.03.24.20040162. https://www.medrxiv.org/content/10.1101/ 2020.03.24.20040162v1

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Int Immunopharmacol. 2020;84:106504. doi:10.1016/j.intimp.2020.106504 Qu R, Ling Y, Zhang YH et al. Platelet-tolymphocyte ratio is associated with prognosis in patients with coronavirus disease-19 [published online ahead of print, 2020 March 17th]. J Med Virol. 2020;10.1002/jmv.25767. doi:10.1002/jmv.25767 Chen N, Zhou M, Dong X et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395:507-513. doi:10.1016/S0140-6736(20)30211-7 Huang C, Wang Y, Li X et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497-506. doi:10.1016/S0140-6736(20)30183-5 World Health Organization. Contact tracing in the context of COVID-19: interim guidance, May 10th 2020. (23.05.20). Retrieved from: https:// apps.who.int/iris/handle/10665/332049 World Health Organization. Coronavirus disease 2019 (COVID-19) Situation Report –73, April 2nd 2020. (23.05.20). Retrieved from: https://www.who.int/docs/default-source/ coronaviruse/situation-reports/20200402sitrep-73-covid-19.pdf Subbaraman N. Coronavirus tests: researchers chase new diagnostics to fight the pandemic.

Nature: News Explainer, March 23rd 2020.

(24.05.20) Retrieved from: https://www.nature. com/articles/d41586-020-00827-6 Yu L, Wu S, Hao X et al. Rapid detection of COVID-19 coronavirus using a reverse transcriptional loop-mediated isothermal amplification (RTLAMP) diagnostic platform [published online ahead of print, 2020 April 21st]. Clin Chem.

2020;hvaa102. doi:10.1093/clinchem/hvaa 102

Subhajit Hazra Subhajit Hazra, M.Pharma (Pharmacology), is an experienced medical writer specializing in the creation of medical/scientific content for the medical communication industry in India. Along with being a medical communicator, Mr. Hazra also holds a special interest in astrobiology research and its content development.

Email: subhajithazra.freelancer@gmail.com

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Technology

Pharma’s Quantum Leap: Launching New Medicine in the Age of AI The importance of the pharmaceutical industry has been thrown into sharp relief by the COVID-19 pandemic, with governments, business, and everyday people pinning their hopes for the future on the industry’s development of a vaccine or treatment. The pandemic has also exposed pharma’s challenges to the public.

Commentators and leaders have expressed shock at how long the discovery and testing processes will take to find a vaccine or treatment.

The US President even met with top pharma executives early in the pandemic to push them to go faster – only to be rebuffed and told the discovery process and drug trials cannot be accelerated all that much.

The truth is the pharmaceutical industry has long been squeezed by tight regulation, cost controls on medicines, and the necessarily extensive drug discovery and research process. There is some hope, however, we are on the cusp of a change across the sector. In February 2020, a team at MIT discovered a new antibiotic in record time using a machine learning algorithm. Will AI technology usher in a quantum leap in pharmaceuticals? Will this new technology solve some of pharma’s longstanding structural problems?

Pharma: Between a Rock and a Hard Place The future may be rosy, however, the pharma sector faces significant challenges at the moment. The problem is the sheer cost of bringing a drug to market remains exceedingly high and many drugs fail before ever reaching the market. The average cost of drug development varies greatly across the pharma industry, which makes it difficult to pinpoint accurate data.

The Tufts Center for the Study of Drug Development puts the cost of bringing a drug from research to the market at $2.7 billion, while a study by JAMA Network pins the cost between $314 million and $2.8 billion. The point is clear no matter which study you believe: it is monumentally expensive to develop new drug treatments.

64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Drug costs soar because of the nature of research and the fact only about half of the chemical compounds identified in a study make it to the human drug trial or Phase III, with the others being discarded or at best set aside for future research. The costs are also driven up by the necessary regulatory research framework in which research operates and by the subsequent required reporting.

good use cases for AI technology and it can help the pharmaceutical industry in specific cases. We need to be careful, however, when we talk about AI. We need to stop thinking of it as magic and move to thinking of AI like any other technology: a tool with the potential to solve a problem.

Identifying the right problems to solve is critical to leveraging the right solutions with tremendous impact.

Even when a medicine reaches Phase III, it’s not guaranteed to make it to market.

Phase III is often the most expensive part of bringing a drug to market and can last up to several years, depending on the drug being evaluated. At the conclusion of the Phase III trial, medical writers must then manually go through the data and write the daunting CSR (clinical study report), a process which can take months or even a year.

Data: Why AI Makes Sense in Pharma AI is, at its core, computer software that analyses data, applies a reasoning process to the data, and then identifies patterns in the data to utilise — explaining and collating the data as output. Admittedly, this is a vague and highly technical definition so let’s look very briefly at an example.

Many pharma companies are using natural language generation (NLG) to automate the writing of portions of the CSR report. NLG technology connects to structured clinical data, analyses it, and explains the results of the analysis in written language.

Some industry analysts were surprised by lacklustre growth numbers in 2019 from some of the biggest pharma companies in the industry. It makes sense, however, when you look at the structural challenges in the industry. Soaring research costs coupled with crowding in the market (e.g. competitive companies that sell the same drugs and research the same topics), and controls on the costs of medicines all lead to squeezed industry profits.

Many in the pharmaceutical industry have hyped Artificial Intelligence (AI) as a panacea with the potential to cure pharma’s chronic problems. There are

Simply put, good quality structured data is the fuel on which AI technology runs.

Anecdotally, the longest pharma projects we’ve seen occurred due to the work that is required to structure and organise the data.

The better structured the data, the faster an AI project can be deployed and the lower the overall cost of the project.

Challenges exist, but the pharmaceutical industry is well positioned to leverage AI. Autumn 2020 Volume 12 Issue 3

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Technology reports up until that time. The value of NLG was immediately clear, but the cost of development and deployment three years ago was too high for many, and reaching a positive ROI was years out. But, the NLG sector has since changed.

New scalable NLG tools cut development time from months or years, to a matter of weeks. These newer tools also cost a fraction of their older counterparts and are built from the ground up to be secure, easy to use, and scalable.

Indeed, like pharma itself, AI is a data-driven industry. How does drug discovery work?

Scientists analyse data sets, either to test hypotheses or to identify potential chemical reactions that could imply a pharmaceutical usage. Drug discovery is a data-driven pursuit. Likewise, the evaluation of drugs is data-driven. A medicine is trialled by a large group of people. Researchers collect and analyse data and then explain the results of the data and analysis in written form in the CSR. The data which fuels Big Pharma companies today is the data that will fuel great AI-driven pharma companies tomorrow.

A major challenge remains, however. The more structured and organised the data, the shorter the time-to-value of AI applications can be reached. Some pharma companies don’t have a sufficient level of structured and well-organised data. Their datasets are scattered across the organisation, in different silos and spreadsheets. Thankfully, this issue is being solved across the pharmaceutical industry. Conventional database and data-wrangling tools are allowing companies to organise and value their data assets at a marginal cost.

and for better or worse, we are accustomed to seeing AI plastered across the media as either a panacea or a plague. How are pharma companies using AI and are there better use cases to start with? What about quick wins to prove that AI works and to create momentum within the organisation?

Automating the CSR can cut months off of the time to write the report. Generally, you are not going to automate the whole CSR document with AI; instead, you are going to automate the data-driven sections, leaving the more creative analysis and connections for the medical writers. Leave automation to robots and creativity to humans. A win-win proposition.

1. CSR Automation The CSR is based on clinical data collected during Phase III of the drug trial. The conventional approach is for medical writers to collate and analyse the data and then write their findings into the CSR document.

This manual approach is time-consuming and expensive, and keeps medial writers and researchers from moving on to the next project.

2. Drug Discovery and Development One of the biggest challenges facing the pharmaceutical sector is the development of new treatments. Simultaneously, companies have had hundreds of failed drugs that have never made it to market for a number of reasons, but still cost a significant amount of money to develop. AIpowered drug discovery addresses both of these challenges: to harness AI to repurpose existing compounds and to discover new treatments.

Beginning in 2017, pharma companies began looking at NLG software to see if it could write portions of the CSR. NLG is an AI-powered technology that was best known for writing news stories and financial

Technically, there are different AIpowered drug discovery approaches.

Sometimes, the approach is to look for treatments for a specific illness, for example COVID-19. In that case, you model

Top AI Use Cases in Pharma Today In early 2020, AI made headlines with drug discovery tools that helped pharma companies comb through existing clinical data to identify compounds that could help in treating COVID-19. These headlines followed press coverage in 2019 that showed pharma companies using AI technology to automatically write portions of the daunting CSR to help bring clinical trial drugs to market sooner.

AI headlines aren’t anything new. The technology has captured public opinion, 66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2020 Volume 12 Issue 3

Technology the disease and then mine existing data to identify correlations and outcomes at scale that might suggest a pharmacological treatment.

The technology uses the disease model to “test” the results of what will happen if the model is exposed to a range of compounds in various combinations. It throws combinations of compounds already present in the pharma’s inventory to see what might (virtually) work. This approach has shown a lot of promise because it is directed to look for specific outcomes within a specific model. It also requires well-structured data and an approach that protects patient data if that data is being used. However, this approach has made headlines for identifying new antibiotics and helping speed up vaccine development.

The second approach is much less structured. Here, the idea is to mine through clinical data to identify patterns and potentially identify compounds that could be repurposed to treat other ailments.

The potential value here is no less high, because the technology could find potential treatments to diseases that researchers didn’t imagine were possible, using drugs that are already developed. Again, the challenge here is one of data quality.

Drug discovery use cases in AI are almost always powered by machine learning technology. Machine learning performs with the highest level of accuracy when it has the largest amount of data. This means that the pharmaceutical company using it must have large amounts of data to use, and that data must be well structured in well-organised databases.

3. Sales Enablement While not specifically a pharma-specific use case, pharma sales executives face unique challenges in terms of regulations and the sheer complexity of the products they sell.

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Again, this is a use case about data. Pharma companies have data on the medicine they sell; regulations are essentially business rules and they have customer data. The challenge is that human beings aren’t data processors, so simply giving this data to salespeople and hoping they will use it isn’t enough.

Google Health found that AI could identify cancer in breast mammograms with fewer false positives and fewer false negatives than radiologists. In China, they even deployed this technology for tomographic screening of the lungs of COVID-19 patients, where the technology performed with 99% accuracy.

NLG technology analyses the product data and customer data, and identifies which regulations come into play, in order to generate a memo or script for each sales executive. Pharma companies get a quick win as they can test the software and how they work with it on a use case that also offers them boosts in sales productivity, creating a win-win.

The key with this technology is to understand it isn’t a replacement for radiologists; it’s a tool to help them and make them perform better. To use the China example, the tool was given to radiologists and it highlighted areas of concern for them to review. This collaboration between man and machine often presents itself in the best use cases of AI. Too often, in the public imagination, AI is a replacement for workers.

In this use case and many others, however, AI is used to better expand human capacity.

4. Image Recognition in Radiology This use case is actually broader in terms of medical and pharma technology, and is one of the most exciting AI-powered diagnosis use cases we’ve seen. Correctly identifying tumours in x-rays is incredibly difficult, even for the most highly trained professionals.

It’s also very time-consuming and there aren’t enough of these experts to expand capacity in many health systems.

AI-powered image recognition technology has improved immensely over the last five years. In the early 2010s, AI-powered image recognition software couldn’t even recognise the difference between a cat and a ball, or a cat and a car. It was hopelessly bad and many dismissed its potential. It was big news in early 2012 when Google trained its algorithm to correctly recognise a cat with 70% accuracy. Now, Google can correctly identify 5000 different species of plants and animals, and image recognition technology is going through a golden age.

In late 2019 and early 2020, a raft of new stories announced AI-powered algorithms could identify cancerous growths with higher accuracy than a doctor. A study overseen by

Conclusion NLG technology is incredibly powerful computer software with the potential to fundamentally change the pharmaceutical industry and address some of the structural challenges the industry currently faces.

More than 30% of a CSR can be automated using AI-powered NLG software, significantly reducing the time needed to create the report and thus, the amount of time it takes to bring a drug to market. The increase in speed created by AI-powered natural language generation technology changes the economic balance pharmaceutical companies base their R&D and M&A investment on, and also helps them to create a competitive edge.

Robert Weissgraeber Robert Weissgraeber is the Managing Director and CTO of AX Semantics, where he heads up product development and engineering. Robert is an in-demand speaker and an author on topics including agile software development and Natural Language Generation (NLG) technologies and a member of the Forbes Technology Council. Prior to AX Semantics, Roberts wasChief Product Officer at aexea. He studied Chemistry at Johannes Gutenberg University and did a research stint at Cornell University.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 67

Technology

Trapped Ion Mobility Mass Spectrometry (TIMS) Drives High-throughput Phosphoproteomics Research Unlike genomic and transcriptomic research, the measurement technologies for proteomics are still evolving, and the complete analysis of a proteome has not yet been achieved. The end goal of proteomics studies is not just to identify all the proteins that can be expressed, but also to uncover cellular protein events such as protein expression/ degradation, protein localisation, protein interaction, protein posttranslational modifications (PTM), and protein processing/splicing.

Protein phosphorylation is an abundant form of reversible PTM and plays a vital role in various cellular processes, such as protein synthesis, cell division, signal transduction, cell growth, development, and ageing1. As such, it regulates important metabolic, hormonal, developmental, and stress responses. Atypical phosphorylation can contribute to a range of disease states, including cancer and diabetes.

Phosphoproteomics – the characterisation of proteins with phosphorylated PTMs – is therefore an important tool for obtaining insights into health and disease.

In cellular signal transduction networks, reversible phosphorylation is one of the key events in transducing a signal into the nucleus to control gene expression.

Approximately 30% of human proteins were previously estimated to be phosphorylated, but researchers at the Laboratory of Molecular and Cellular BioAnalysis at Kyoto University developed a highly selective enrichment method for phosphopeptides and, when applied to proteome-wide acquisition of cellular phosphorylation status, revealed that at least 70% of human proteins are phosphorylated2,3.

Recent technological advances have enabled the use of mass spectrometry (MS) in phosphoproteomic approaches to address the scope of phosphorylation.

We have developed phosphoproteomics methods to carry out in vivo phosphoproteome profiling of kinase-targeting drugs, which would facilitate drug discovery 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and development for cancer therapy, as well as enable the exploration of the functional analysis of newly discovered phosphorylated molecules.

MS-based Phosphoproteomics Deep characterisation and quantitative analysis of proteins and PTMs are critical to understanding signalling pathways and abnormal disease states. Developments in high-resolution mass spectrometers and specific enrichment of phosphorylated peptides tailored for the global analysis of protein phosphorylation represent powerful tools for molecular and cellular biologists studying signal transduction pathways.

Despite these advances, identifying PTMs remains significantly more challenging compared with unmodified peptides, as they often occur at low abundances and the differences in protein phosphorylation span several orders of magnitude, driving the need for instruments with higher sensitivity and increased peak capacities.

Protein expression varies depending on the genetic background of an individual, but also on time, localisation, and as a physiological response to external stimuli (stress, disease, ageing, effort, etc.).

Moreover, because of the combined effects of alternative splicing, point mutation, PTM and endogenous proteolysis, a given protein (gene expression product) can be expressed as many different proteoforms, each having a dedicated biological activity. The sophistication of modern instrumentation enables the identification of tens of thousands of phosphopeptides in a singleshot liquid chromatography coupled with mass spectrometry (LC-MS) run, but the percentage occurring as positional isomers is unknown.

The combination of ion mobility spectrometry (IMS) with MS is a wellestablished technique that has shown considerable potential for improving peptide identification, providing structural information that is complementary to LC and MS. IMS-MS separates ions based on differences in their shape (IMS) and mass (MS), delivering information on the threedimensional (3D) structure of an ion. This added ability to separate ions by differences

in conformation makes it possible to separate isobaric and isomeric species, such as phosphopeptide positional isomers (i.e., peptides that differ only by the residue that is phosphorylated), which are not easily distinguished by MS techniques alone4.

The commercialisation of trapped ion mobility spectrometry (TIMS) in 2016 built on the advances in IMS technology made over previous years. TIMS enables the interrogation and manipulation of mobility separated ion populations in the gas-phase, with high efficiency, duty cycle and high resolving power in millisecond-second timescales, and with the possibility to measure collisional cross section (CCS) using first principles that can be further utilised for structural assignments5, in CCS-aware workflows. The addition of TIMS provides a fourth dimension that is complementary to the previously used mass, intensity and retention time dimensions, resulting in 4D-Protoemics methods (Figure 1). TIMS is most often coupled with a time-of-flight (TOF) mass analyser to capitalise on its highspeed capabilities.

A fractionation approach is often used to obtain deeper proteome coverage, but this method is time-consuming, and if many clinical samples are analysed, the timeframe is not realistic. Modern TIMS-QTOF MS systems utilising parallel accumulation – serial fragmentation (PASEF) can provide the necessary high speed and increased sensitivity. The novel design allows for ions to be accumulated in the front section, while ions in the rear section are sequentially released depending on their ion mobility. Modern TIMS-QTOF MS with PASEF can provide sequencing speed > 100 Hz without losing sensitivity or resolution by synchronising the quadrupole isolation mass window with the elution time of the specific peptide packages from the TIMS funnel.

Our research found that PASEF can effectively increase MS/MS acquisition rates to reach new depths in phosphoproteomics, improving both identification and confidence in results. The high speed and sensitivity of the PASEF acquisition mode also facilitates high throughput on a TIMS-QTOF MS system.

Autumn 2020 Volume 12 Issue 3

Technology 19,000 kinase inhibitors targeting ~260 protein kinases have been reported7, and ~30 small-molecular kinase inhibitors have been approved for clinical use by the United States Food and Drug Administration (US FDA)8. Our work aims to connect the kinases with their substrates to reveal the entire picture of the signalling network, using experimental and computational approaches.

For the past 20 years, identification of phosphorylated proteins based on MS has been used in many studies aimed at large-scale analysis of cellular signalling.

Building on our work on the kinome with LC-MS/MS9,10, researchers are now achieving throughput levels only possible with TIMSQTOF MS.

Figure 1: Dealing with proteomics samples complexity can be reduced by spreading it into a fourth dimension: 1 – Retention time, 2 – Mass to charge ratio, 3 – Intensity, 4 –Ion mobility.

That capability is particularly important for processing the high quantity of samples required for metaproteomics studies. They now plan to take advantage of the PASEF acquisition mode in current research to investigate the interaction between humans and bacteria at the proteome level in order to uncover potential biomarkers of disease6.

Protein Kinase Profiling TIMS-QTOF MS has implications in drug discovery, particularly for phosphorylations related to cancer. By implementing the

one-minute gradient with the timsTOF Pro, a laboratory can investigate the mode of action of kinase inhibitors (Figure 2).

Kinase networks are important for cellular signal transduction, by their catalysis of reversible protein phosphorylation, and kinase-mediated phosphorylation signals are known to cause or drive the progression of diseases such as cancer.

Many drugs that inhibit a specific kinase or kinases have been developed for kinasetargeting therapy and, to date, more than

Figure 2: Capillary LC with timsTOF Pro. 1 minute gradient, 100 sec/run, 864 runs/day. TIC = total ion current; XIC = extractedion chromatogram. www.ipimediaworld.com

Future Developments The increased versatility of computational proteomics, in combination with software and hardware developments, is a significant future direction for proteomics. An important advancement in MS-based phosphoproteomics is data-independent acquisition (DIA). DIA is a relatively recently developed MS acquisition technique where, unlike data-dependent acquisition (DDA), MS2 scans are acquired in a continuous and unbiased manner for all precursor ions falling within a specific mass range. The combination of next generation sequencing (NGS) with proteomics is becoming more widely used in multi-omics fields such as proteogenomics, which is finding application in clinical research, particularly precision oncology11.

The combination of DIA with PASEF (Figure 3) allows researchers to compensate for the traditional DIA pitfalls by using a pattern of m/z isolation windows within consecutive TIMS events. The percentage of ions used in the dia-PASEF can be greatly increased (reaching up to 100% for low complexity samples, and still 5X higher than with traditional DIA methods using comparable isolation windows size and m/z range for high complexity samples). The diaPASEF cycle time can be reduced to make it compatible with short gradient separation while preserving a high selectivity. It benefits from the TIMS space concentration effect that allows for increased sensitivity and takes DIA selectivity to the next level with full 4D-proteomics support.

Over the last two decades, significant advances seen in technology and new methodologies have made proteomics INTERNATIONAL PHARMACEUTICAL INDUSTRY 69

Technology

5.

6.

7.

8.

9.

10.

11.

Figure 3: Example of diaPASEF windows distribution. Display of the 64 25 width m/z used with the 1,7 sec cycle time diaPASEF method. This window scheme uses 6.25% of the ions; an equivalent 3D DIA scheme would use only 1.25%.

an extremely powerful tool for protein scientists, biologists and clinical researchers.

The current coverage of the proteome is far from 100%, and researchers are continually looking for improvements. It is clear that developments in MS-based proteomics, such as TIMS enabled 4D-Proteomics, have allowed researchers to gain deeper insights into the molecular and cellular functionality of the human body through the improvements in throughput and sensitivity.

In particular, the PASEF acquisition method can provide extreme high speed and sensitivity to reach new depths in shotgun proteomics and phosphoproteomics, using low sample amounts. These 4D-Proteomics approaches will allow scientists to routinely explore parts of the proteome not previously accessible.

70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Ion Structure by Ion Mobility SpectrometryMass Spectrometry, J Am Soc Mass Spectrom, 27(5): 786-794.

Fernandez-Lima F (2016). Trapped Ion Mobility Spectrometry: past, present and future trends, Int. J. Ion Mobil. Spec, 19:65–67.

Lin M-H, Sugiyama N, Ishihama Y. Systematic profiling of the bacterial phosphoproteome reveals bacterium-specific features of phosphorylation. Sci Signal, 8(394):rs10.

Hu Y, Furtmann N and Bajorath J (2015). Current compound coverage of the kinome, J Med Chem, 58(1):30-40.

Wu P, Nielsen TE and Clausen MH (2016).

Small-molecule kinase inhibitors: an analysis of FDA-approved drugs, Drug Discovery Today, 21(1):5-10.

Sugiyama N and Ishihama Y (2016). Largescale profiling of protein-kinases for cellular signaling studies by mass spectrometry and other techniques, Journal of Pharmaceutical and Biomedical Analysis, 130: 264-272.

Sugiyama N, Imamura H and Ishihama Y (2019).

Large-scale Discovery of Substrates of the Human Kinome, Scientific Reports, 9:10503.

Ang MY, Low TY, Lee PY, Nazarie WFWM, Guryev V and Jamal R (2019). Proteogenomics: From next-generation sequencing (NGS) and mass spectrometry-based proteomics to precision medicine, Clinica Chimica Acta, 498:38-46.

REFERENCES 1.

2.

3.

4.

Ardito F, Giuliani M, Perrone D, Troiano G and Lo Muzio L (2017). The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (Review). Int J Mol Med. 40(2):271-280.

Olsen JV, Vermeulen M, Santamaria A, Kumar C, Miller ML, Jensen LJ, Gnad F, Cox J, Jensen TS, Nigg EA, Brunak S and Mann M (2010). Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis, Sci Signal, 3(104):ra3.

Sharma K, D’Souza RCJ, Tyanova S, Schaab C, Wiśniewski JR, Cox J and Mann M (2014).

Ultradeep Human Phosphoproteome Reveals a Distinct Regulatory Nature of Tyr and Ser/ThrBased Signaling, Cell Reports, 8(5):1583-1594.

Glover MS, Dilger JM, Acton MD, Arnold RJ, Radivojac P and Clemmer DE (2016). Examining the Influence of Phosphorylation on Peptide

Yasushi Ishihama Yasushi Ishihama is a professor of the Graduate School of Pharma-ceutical Sciences, Kyoto University. He has been working in the field of proteomics for 20 years. He has made contributions to this field especially by developing the basic technologies as well as by applying these tools to biology. His group also established ‘one-shot’ proteomics by ultrahigh resolution monolithic silica columns to uncover proteome on a microarray scale. He is also interested in comprehensive analysis of cellular signalling networks using experimental and computational approaches. He has published over 180 papers, cited over 20,100 times. He received the Research Award from the Mass Spectrometry Society of Japan (2011), the Award of the Japanese Proteomics Society (2013) and the Award of the Society for Chromatographic Sciences (2018). He is currently a president of the Japanese Proteomics Society, a vice president of the Japan Society for Analytical Chemistry and an executive council member of AOHUPO. Autumn 2020 Volume 12 Issue 3

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gastric juices in the stomach. The accelerated dissolution in acidic environments results in a

Manufacturing

quicker release of calcium ions, which are then ready to be absorbed into the bloodstream via the small intestine.

Backed by Science To verify the enhanced intestinal absorption of the new functionalised calcium carbonate Calcium Bioavailability is Key compared to other commercially available calcium sources, researchers tested the bioavailability with a Caco-2 cell line model, which is a widely used in vitro method to determine nutrient absorption by the intestine. (Table 1)

Calcium source

For the first time in history, most people can expect to live into their 60s and beyond. According to the World Health Organization, one in five people will be 60 or over by 2050.1 Yet while there’s no doubt that a longer life brings great opportunities, the extent to which they can be enjoyed depends on an individual’s physical and mental state. Healthy ageing is the process of maintaining the functional ability that enables wellbeing in older age, beyond merely prolonging life – put simply: how you look and feel is more important than your actual age.

Prevention Starts Early From early on in life, people can do a lot to protect their future health. A balanced diet with sufficient nutrients, vitamins and minerals is the foundation of optimal ageing.

The mineral calcium, for instance, is vital for various bodily functions: it helps maintain strong bones, control blood pressure, ensure proper muscle contraction and nerve conduction, and support heart health. An adequate daily calcium intake throughout life is therefore essential. It also reduces the risk of fragility fractures, thus enhancing mobility and overall quality of life. However, for many, particularly athletes, the elderly and those who avoid dairy products, it can be difficult to achieve an adequate dietary intake. In addition, at certain times of life, such as during adolescence, the body requires more calcium to build strong bones.

Post-menopausal women also need more calcium because they absorb the mineral less efficiently, and additional intake helps to slow down loss of bone mass. For these groups, calcium supplements and fortified foods can be helpful.

Next-generation Calcium Mineral The amount of calcium in the diet is not the only thing that is important for strong bones. Also crucial is the bioavailability of this mineral – in other words, the amount that is absorbed by the body through intestinal cells. Recently, a highly bioavailable source of calcium has been launched which is suitable for powdered formulations targeting healthy 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Calcium citrate tetrahydrate New functionalised calcium carbonate (Omyaforte™) Calcium carbonate Tricalcium phosphate

Amount required to satisfy 30% RDA Milligram 1428 770

Elemental calcium

Bioavailable calcium

300 300

10.2 17.1

750 770

300 300

9.0 5.6

Table 1: Comparison of different calcium sources and the amount required to reach 30% RDA

Table 1: Comparison of different calcium sources and the amount required to reach 30% RDA

agers and others who may be calcium- Backed by Science deficient. This new mineral consists of To verify the enhanced intestinal absorption The results show that the new functionalised calcium carbonate is almost twice as calcium and tricalcium phosphate, and is of the new functionalised calcium carbonate biologically available as calcium citrate tetrahydrate and natural calcium carbonate (NCC). functionalised in a way that combines the compared to other commercially available best properties of both. calcium sources, researchers tested On average, calcium uptake efficiency for tricalcium phosphate was 1.85%, for NCC 3%,the for bioavailability with a Caco-2 cell line model, From a nutritional point of view, two which is a widely used in vitro method to factors are important: the amount of determine nutrient absorption by the elemental calcium in the salt and the intestine. (Table 1) bioavailability of the calcium. Compared to reference products, the new functionalised The results show that the new functiocalcium carbonate offers a higher elemental nalized calcium carbonate is almost twice calcium content and greater bioavailability. as biologically available as calcium citrate It contains 39% elemental calcium – tetrahydrate and natural calcium carbonate almost twice as much as calcium citrate, (NCC). On average, calcium uptake efficiency which has just 21%. Thanks to a patented for tricalcium phosphate was 1.85%, for NCC recrystallisation process, it offers a new 3%, for calcium citrate tetrahydrate 3.41%, mineral composition and structure with and for functionalized calcium carbonate high porosity, which allows for faster it was 5.68%. (Figure 1) access to gastric juices in the stomach.

The accelerated dissolution in acidic These results suggest that the type of environments results in a quicker release calcium salt may affect the bioavailability of of calcium ions, which are then ready to calcium, since the uptake efficiency values be absorbed into the bloodstream via the vary. small intestine.

Figure 1: Comparison of calcium absorption for different calcium salts Autumn 2020 Volume 12 Issue 3

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Manufacturing In addition, functionalised calcium carbonate shows the fastest calcium ion release compared with the other calcium sources. This means higher solubility of the salt in acidic environments – e.g. in gastric juices. (Figure 2) This research clearly demonstrates that the new functionalised calcium carbonate not only contains a high percentage of 39% elemental calcium, but is also extremely bioavailable, making it an excellent and proven source of calcium.

Huge Bone Health opportunities An increasingly ageing global population means that demand for calcium supplements and calcium-fortified foods will continue to grow. According to Mintel research, the leading markets for bone health products are India, China, Great Britain, Germany and the USA. More than 70% of new products with bone health claims are launched in Asia-Pacific and Europe.2 Consumers view health and wellness as a holistic, proactive and ongoing pursuit. Their needs can be readily addressed through fortified foods, drinks and nutritional supplements, whether these are for medical purposes or preventative measures. Beyond healthy agers, professional athletes and weekend warriors are also seeking targeted nutritional support. Functionalised calcium carbonate is suitable for them all – from sports nutrition products to vitamin and mineral mixes, bone health blends and rehydration powders.

Figure 2: Comparison of calcium ion release for different calcium salts

In addition, the ingredient is suitable for a variety of foodstuffs, without affecting sensory properties. Since it combines both high levels of elemental calcium and effective calcium uptake, only a small amount is needed to reach recommended daily intakes: as little as 770 mg is required to reach 30% of the daily recommended dose of 1000 mg calcium, compared to 1428 mg of calcium citrate tetrahydrate, for instance. The result is fortified foods with pleasant taste profiles that require very

little intervention while promising high bioavailability.

Thus, the new functionalised calcium carbonate opens up great opportunities for manufacturers who are looking for nutritious, effective and easy-to-process ingredients that address concerns about bone health.

REFERENCES 1.

2.

WHO, Global strategy and action plan on aging and health, 2017 Mintel Global New Products Database

Lalit Sharma Driven by a desire to improve people's health and quality of life, Lalit Sharma is an Innovation Manager at Omya. His focus is to enhance the accessibility of food and nutrients by making such nutrients cost-effective, more biologically available and sustainable.

With a Food Science and Technology (MSc) background, he has worked as a food process engineer for different consumer goods and multinational organisations, from concept phase through to product launch.

Email: info.pharma@omya.com

74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Manufacturing

Using Phase-appropriate Delivery to Accelerate Inhaled Product Development Different inhaled product development programmes can use different platform delivery technologies at various stages of development, and careful thought must be given as to what will work best at any given stage due to the broad choice of options.

To maximise the probability of success, delivery platform selection for each programme should be assessed individually so that the technical characteristics and the commercial drivers of each drug substance/ medicine are evaluated on their own merits. For a generic programme, there may be more constraints around the path to be followed, but outside of this area each new programme should be considered uniquely and it is important to bring as much experience as possible to selecting the appropriate delivery platform to progress the development, as well as to tackle the challenges that will inevitably arise along the way.

Device Choice For inhaled products, the main platform delivery system approaches are dry powder inhaler (DPI), pressurised metered dose inhaler (pMDI), nebuliser devices and liquid spray inhalers. There are some other types of devices and/or formulation technologies that have niche applications, but are less commonly used.

For each main platform approach, there are further layers of choice sitting underneath and the pros and cons for each need to be understood in detail so that the final choice can be made. For example, under the general banner of DPI devices there is a choice to make between a unit dose device and multi-dose device, and then furthermore between a spray-dried dry powder formulation, or a traditional lactose blend. Even within the option of a unit dose device, there is the choice between a non-proprietary capsule-based inhaler, or a unit dose blister device and even if the developer has got to this point there are multiple device designs with different user interfaces, to further complicate the 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

process of inhalation delivery technology platform selection.

Developers should try to adopt a device agnostic view, and then evaluate which platform (DPI, pMDI or nebuliser) is best for their particular candidate medicine, judging all the options impartially on their relative merits.

A basic commodity capsule-based inhaler can offer a flexible approach in the early stages of development, as different doses can be achieved via varying the formulation fill weight. This simple device type can deliver high doses of powder for a range of formulation types with good aerosolisation efficiency (formulationdependant). On the down side, such devices typically offer no additional intellectual property (IP) protection to the product and have a more complex user interface than the multi-unit dose DPI devices.

Multi-unit dose DPI-based medicines have been shown to be hugely successful in the treatment of mild/moderate asthma and COPD and are quick and easy to use, highly portable and have the potential to offer additional proprietary protection to products. pMDIs are also low-cost / high-volume devices with a generally universal userfriendly interface (simple “press and breathe”). Lung deposition is typically moderate, but the main limitation with this device type is the range of doses which can be delivered. With the increasing trend in the industry towards higher doses and high-cost biologic drugs, this is a delivery platform that can often rule itself out on both technical and commercial grounds.

Finally, nebuliser (especially smart nebuliser) devices are a higher-cost choice on account of their sophistication.

It takes longer to deliver the medicine to the patient using these device types, but the range of doses able to be delivered can be much higher (up to tens of milligrams). Smart nebulisers are also capable of delivering high and deep lung deposition, and may be superior even to high-performing DPIs. Consistent, high and

targeted delivery of a drug to the lung is obviously hugely advantageous and may increase probability of success in the early stages of development, and the process of formulation for nebulisation can be much simpler, especially if the molecule has good aqueous solubility.

Factors Affecting Device Development As stated previously, starting from a “device agnostic” position really helps to facilitate the process of impartially evaluating the factors contributing towards the decision on the most appropriate platform for a given application.

Developers should start with the API-specific technical considerations, for example whether the drug is a small molecule or biologic; what the dose range is likely to be; and the physical properties of the drug, such as its solubility. All these aspects will have significant implications for device and formulation selection. Obviously, the user profile of patients who will take the medicine is also hugely influential, e.g., the age range of expected users; do they typically have dexterity issues; and can they follow complex user instructions. This can be a significant issue for both young and old patients. Additionally, the lifestyle of patients and their expectations around device use (e.g., portability) should also influence the choice. A device that is difficult to use, or is inconvenient for the target patient population, is much less likely to be used, with likely negative consequences on adherence, clinical trial outcomes and the ultimate success of any inhaled drug therapy.

Economics and commercial considerations also need to be looked at early on. The cost of goods for a device, and likely volumes, could rule out certain options, possibly not in the early stages of development, but certainly in terms of the final product to be commercialised. These factors need to be weighed up alongside the cost of the API, and whether the developer’s ultimate strategy is self-commercialisation or to out-license to a larger partner postproof of concept (PoC) and/or whether the intent is to manufacture in-house or outsource to a contract manufacturing Autumn 2020 Volume 12 Issue 3

Manufacturing organisation (CMO). If the product candidate is a generic, the commercial considerations will also be significantly different than for an innovator (new chemical entity) product.

Finally, the disease and dosing regimen will impact the platform delivery technology selection decision: Is the medicine to be administered in a healthcare environment? (e.g., at hospital), or can it be taken by patients at home; how deep into the lungs must the drug reach for it to be efficacious?; and the number of doses the patient is required to take each day.

With all these factors to be taken into consideration, what may have worked for one product is unlikely to be transferrable directly to another. Often the drug molecule dictates what is possible, so some options can be excluded quickly based purely on technical considerations.

Very often, development programmes are purely focussed on the next milestone and value point inflection, so it is important to remember that the delivery platform does not necessarily have to be representative of the final commercial product – just “phase-

appropriate”, particularly in the early stages of development up to PoC. Maximising the Probability of Success The technology platform chosen must give the drug product the best possible chance of success. Although the factors previously discussed are numerous, in reality, a smaller number of considerations drive the majority of the decision-making.

The technical considerations are the most obvious: the drug molecule’s properties are at the heart of any device and formulation selection and some preclude certain possibilities, for example, any need for a high dose (>1mg) would preclude the choice of a pMDI; or an antibody fragment would be very unlikely to be stable following jet nebulisation.

Minimising costs whilst working as quickly as possible is also likely to be hugely influential in any programme, so can impact development choices. If a molecule is freely soluble and stable in solution, complex formulation studies can be avoided and the drug can be delivered as a solution for nebulisation. If many different

doses are required, varying volumes of a stock concentration can be nebulised, or a capsule DPI can be used and different formulation fill volumes of a standard dry powder formulation can be used to achieve the range of doses. The cost and availability of API material may also limit choices as wide development screening may not be feasible.

Finally, consideration must be given to maximising the probability of a successful clinical trial outcome. This may depend upon the efficiency of delivery to the correct area of the lungs, so more complex technologies such as smart nebulisation may be preferred over continuous nebulisation. Similarly, using a connected device that is able to gather information on patient usage will increase the confidence that patients have taken their medicine and have received the required dose effectively.

Making Informed Choices to Reduce Risk Despite the large number of factors influencing the choice of delivery platform, being mindful of using phase-appropriate platforms can be crucial in reducing

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Manufacturing risk, and saving time and money during development. There is the opportunity to change delivery platform between what has been used in the earlier stages of development in Phase I, or even up to proof of concept, and what ultimately might be commercialised.

way through to commercialisation with a capsule DPI or smart nebuliser.

only two solution strengths. The programme was ready for the clinic in just 18 months.

This is a strategy increasingly being adopted by all organisations (not just small biotechs), focussed on getting into the clinic quickly to demonstrate the value of a candidate medicine. The ultimate commercial platform is of less concern at this stage, where the emphasis is towards ensuring that the platform can maximise deposition, offer dosing flexibility and minimise drug usage – thereby ultimately saving costs.

Case Study: Accelerating a Small Molecule Developxment Programme to the Clinic In a small molecule development programme for a niche disease, key influencing factors for the choice of delivery platform led developers towards selecting a hand-held mesh nebuliser. The drug molecule was very water-soluble and a broad dose range was required, making it potentially somewhat less amenable to being formulated as a DPI (although a capsule format might also have been suitable). For the disease indication, very high and deep lung deposition was needed to maximise the probability of success and minimise material consumption.

Using smart nebulisation also offered the greatest potential to achieve high and deep lung deposition, and the mesh nebuliser in this case study also allowed consistent delivery, because the patient is guided by the device to take each inhalation the same.

Additionally, the device has a very low drug retention rate (less than 10%), meaning drug substance usage is very efficient and wastage is minimised.

Either smart nebulisation, or the use of a simple commodity capsule DPI, lend themselves very well to this approach.

These choices offer swift results and can demonstrate success so that milestones can be met in terms of funding or licensing.

Depending on the strategy, projects developed in this method may then be transitioned to a multi-unit dose DPI for commercialisation, or progress all the

Despite being high dose (10mg), only approximately 100g of API material was required to undertake all the pre-clinical pharmaceutical development: including formulation development work, analytical method development and phase-appropriate validation, stability testing and product performance characterisation studies. Using the smart nebuliser, six different clinical doses (1–80mg) were able to be delivered via

Conclusion There is a large choice of platform delivery device and formulation technologies that can be used in the development of an inhaled medicine, and there are a number of factors that may need to be considered in order to decide which technology to exploit and advance. By taking a rational and methodical approach to each programme, the options can be narrowed down based on the molecule’s properties to a smaller sub-set of factors in terms of technical needs, cost and time considerations, and maximising probability of success. It is important to remember that the platform decisions made to accelerate a programme to the clinic do not necessarily mean that the product is then defined throughout its lifetime. As shown in the case study, using a smart nebuliser or simple capsule device can allow for quick progression to clinical studies, but there are opportunities later on in development to change platform once milestones have been reached, as is appropriate for each particular product.

Sandy Munro Dr. Munro is responsible for Vectura’s new technology development and also for product development programmes utilising Vectura’s smart nebuliser devices. He joined Vectura in 2008 after a 20-year career at GSK, where he progressed to being Global Director of Inhaled Science and Technology. He holds a chemistry degree from the University of Edinburgh, and a PhD in synthetic organic chemistry from the University of East Anglia. He is also an honorary life member of the Aerosol Society.

78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 79

Packaging

Advanced Capsule Development for Today’s Needs: HPMC+ The use of compounds (of biologic or chemical origin), as therapeutics is as old as mankind. Traditionally, the administering of such therapeutic products to the body occurred through the mouth by swallowing.

As early as 1500 B.C. therapeutic products were being enrobed with a gelatin film, which can be considered as the first attempt at a gelatin capsule development.

Capsules Background Whilst the development of capsules has been relatively slow since then, more than 100 years ago the pre-manufactured empty two-piece capsule was introduced. These two-piece capsules consist of a body part that can be filled with the therapeutic agent or formulation, and a cap to close the open end to contain the product. The capsules were originally made of gelatin and quickly gained appraisal for medicinal products due to the ease of filling and administration.

They also assist with taste masking from unpleasantly flavoured medicinal formulations.

With the emergence of life sciences in the middle of the last century, our medical, pharmacological and pharmaceutical knowledge gradually increased. Since the 1960s, several new chemical entities now reach the market every year. Along with these new drugs, pharmacokinetics and drug delivery evolved as important sciences in their own rights. Gelatin capsules have served as enabling dosage forms to bring these new approaches to the market. For example, we can view these capsules as the forerunners of many of the new drug delivery technologies, like liquid and semi-solids, multiparticulates e.g. pellets and minitablets, as well as dry powder inhalation formulations.

Defining the Desired Product Characteristic Besides the versatility of the two-piece capsule dosage form, gelatin provides some favourable material attributes such as: high mechanical robustness, fast aqueous dissolution, taste and order masking, bi-chromatic differentiation,

and ease of swallowing. Based on these attributes, gelatin capsules represent a type of “golden standard” for the administration of a vast variety of drug delivery technology.

However, as pharmaceutical and medical science and technologies evolve, we are facing new challenges in the provision of effective drug products. These challenges span from access to medicines in developing countries, to highly sophisticated drug products for unmet medical needs. Whilst other drug delivery technologies are being developed, the capsules still play a crucial part in delivering affordable, accessible and even specialised medicines. In order to meet current and future challenges, it is essential Requirements

Scientific/ technical

Patient

Aspects

Science and technology continue, and will continue, to progress rapidly. The constant generation of new therapeutics and drug delivery technologies leads to the increasing demand for capsules with specific attributes in order to enable their development to the benefit of patients.

Such specific attributes are derived from the target product profile (TPP) that includes all the important aspects that the finished

Targets IR MR/SR Enteric

Capsule attributes 2–3 min 10–15 min 30–45 min pH dependent

-

Dissolution

-

-

Head space humidity

-

Stability

-

Fine particle fraction DPI Hygroscopicity Moisture sensitivity Degradation Impurities Market access

-

Mechanical resistance

-

Handling Packaging

-

Paediatric form Special populations

-

-

Weight/age/body surface dosing

Swallowability Palatability Acceptability Dose titration

-

Variable/flexible dosing

-

-

Differentiation

-

Polypharmacy Visual impairment Medication errors/safety

-

Adherence

-

Effectiveness Safety

-

-

Swallowability Appearance Taste Order Halal Kosher Vegetarian Vegan

-

Falsified medicine Substandard medicine

-

Standard manufacturing Equipment/component availability Technology transfer

-

Acceptability

-

Religious/ preference

-

Counterfeiting

-

Commercial

we work on the development of two-piece capsules with specific characteristics and/ or functionalities, while maintaining the key features of versatility and commercial viability of the gelatin capsule.

Technology accessibility

-

Low moisture Equilibrated moisture

-

25°C/60RH 40°C/75RH

-

Stress resistance Piercing/shearing performance (DPI)

-

Head space humidity (e.g. multiparticulates) Capsule size

-

-

Easy to open/ sprinkle (e.g. minitablets) Mono-chromatic Bi-chromatic Bi-chromatic/ imprint Fill volume (Fixed dose combination, multiple release) Easy to open/ sprinkle Surface properties Colour shade Size Shape

-

Polymer Capsule composition

-

Bi-chromatic/ complex printing Tagging

-

Machineability Yield Global supply chain

Regulatory compliance

-

Approval process Market access Commercialisation

-

-

-

Overall manufacturing cost

-

Market access Patient access

-

Ecological footprint

-

-

Energy, cleaning, waste, etc.

- per unit operation - per GMP space

Global monograph compliance Regional monograph references Formulation design Excipient selection Process design

-

Direct filling No of unit operations

-

Table 1: Target product profile (TPP) considerations relevant capsule and formulation selection

Table 1: Target product profile (TPP) considerations relevant capsule and formulation selection Autumn 2020 Volume 12 Issue 3

80 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Formulation and Process Design

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Packaging drug product needs to achieve [ICH Q8 R2 Guideline]. The major aspects that have to be addressed in the TPP depended on the specific molecule, therapeutic component or combinations thereof, the delivery form(s), the targeted patient populations, the specific markets/regions and, finally, the technology accessibility as well as overall manufacturing costs. Some of these considerations are listed in Table 1.

Formulation and Process Design By defining the TTP, the targets of the desired drug product attributes are clearly laid out, thus serving the development of detailed plans towards formulation and process development. The multifactorial nature of drug development requires a systematic approach that starts by a certain degree of prioritisation of the required and desired attributes, as well as the collection of existing or prior knowledge in the company.

Developing a product which is closest to all the required and desired final drug product attributes will benefit from a non-biased, evidence-based evaluation of the different potential formulation strategies.

In order to mitigate the risk, a formal risk assessment must be performed to identify known or predicted critical material attributes or process parameters that will, or might, impact the consistent product performance, attributes or manufacturability. During development, these critical material attributes and process parameters will be evaluated by experiments and/or simulation and predictive modelling to ensure that the product and process can be kept under control within the typical material and process variabilities [Stranzinger et al. Int J Pharm: X 1: 100004 (2019); Madlmeier et al.

Int J Pharm 567:118441 (2019)].

determine the manufacturing costs [Cogdill et al. J Pharm Innov (2007) 2:38–50]. Therefore, whilst it is critical that those in capsule development meet the ever more complicated needs of customers and the pharmaceutical market, they must carefully assess and balance the complexity of formulations and processes with efficiency in manufacturing.

Progressing Capsule Technology: HPMC Challenges in progressing capsule technology not only arise from the complexity of formulations and manufacturing costs.

New challenges are emerging as a result of other trends, such as shorter development timelines (fast track, breakthrough, priority review, and/or accelerated approval), paediatric formulations, personalisation of therapies, demographic changes, decentralisation of manufacturing, as well as cost containment and sustainability. All of these aspects require advanced excipients, formulations, processes and flexible dosage forms as they will play an essential role in supporting the emerging needs and meeting the challenges.

HPMC capsules and their advancement may provide a solution to many of the issues we are facing in developing appropriate capsules for complex formulations or specialised demands. Hydroxypropyl methycellulose, also referred to as hypromellose or HPMC, is a cellulose-based semisynthetic polymer established as a pharmaceutical excipient in the early 1970s. Four different types of HPMC, used for example as film forming agent in coatings or matrix former in modified release tablets, are described in pharmaceutical monographs [USP 41, Pharm Eur 10th edition]. HPMC is also considered a crystallisation inhibitor to increase solubility and bioavailability of poorly soluble low

ionised drugs containing a neutral amine group [Zarmpi et al. AAPS J 22:49 (2020)].

Additional beneficial functionalities of HPMC are the largely temperature- and humidityindependent viscoelastic properties, as well as its relative inertness against reactive chemicals [Handbook of pharmaceutical excipients. Eds: Rowe RC, Sheskey PJ, Quinn ME. pp. 326-329 (2009)].

To combine these unique HPMC material properties with the advantage of two-piece capsule technologies, intensive research and development of technology has been invested in, in order to manufacture different types of HPMC capsules. The latest addition to the portfolio of two-piece capsules is an HPMC capsule manufactured by an innovative thermogelation process.

This continues to broaden the range of functionalities and applications of capsules in drug development and manufacturing.

The thermogelation technology used in producing this capsule utilises the reversible sol–gel transformation of HPMC upon heating to 50°–90° C to form a pure HPMC capsule. Specific desired product characteristics defined in the TPP can now be integrated and delivered by these capsules.

The functionality provided by this pure HPMC capsule might avoid the need for intensive formulation and process development programmes caused by the addition of multiple excipients and processing steps. By avoiding these intensive processes, we can reduce complex manufacturing processes, and lower risks and costs.

Key Functionalities of Thermogelated HPMC Capsules Thermogelated HPMC capsules (e.g. ACGcaps H+) are characterised by a homogeneous, smooth surface structure with glass-like

120.00%

% acetaminophen dissolved

The strong focus on technology 100.00% and science in formulation, in addition to process design bias pH 1.2 - 0.1 N HCl 80.00% towards the use of multiple excipients and process steps pH 6.8 - phosphate buffer USP 60.00% often tends to over-engineer pH 6.8 - phosphate pharmaceutical products, with buffer 2nd JP 40.00% the consequence of product and pH 4.5 - acetate process complexity, tight controls, buffer 20.00% reduced yield and finally, higher purified water costs. Ensuring manufacturing effectiveness and efficiency 0.00% 0 5 10 15 30 45 enhancements is very challenging [Friedli et al. J Pharm Innov (2010) Time 5:181–192], and in an increasingly Figure 1: Dissolution profiles of thermogelated HPMC capsules (ACGcaps™ H+) filled with acetaminophen in different media (USP competitive market, formulation Apparatus 2 (Paddle) with sinker at 50 rpm; ACGcaps H+ capsule size 0 transparent filled with 464 mg acetaminophen (paracetamol) composed of 90 % acetaminophen; 1 % mag stearate; % PVP; 2 % (ACGcaps™ croscarmellose sodium and 4 with % lactose).

Dissolution profiles of thermogelated HPMC 3capsules H+) filled and process complexity willFigure 1:granules acetaminophen in different media (USP Apparatus 2 (Paddle) with sinker at 50 rpm; ACGcaps H+ Autumn 2020 Volume 12 Issueof 3 90 82 INTERNATIONAL PHARMACEUTICAL INDUSTRY capsule size 0 transparent filled with 464 mg acetaminophen (paracetamol) granules composed % acetaminophen; 1 % mag stearate; 3 % PVP; 2 % croscarmellose sodium and 4 % lactose).

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Packaging transparency. As for any two-piece capsules, colourants can be added to retrieve coloured transparent or opaque capsules, which can further be customised by mono- and/or bichromatic printing. Different dose strength, fixed dose combination products, products with multiple release profiles can all be effectively differentiated within the brand, but also across other drug products to reduce confusion and increase drug safety in the context of polypharmacy. In addition, the glass-like transparency of the capsules serves the patient preference in inhalation therapy, to be able to verify that the powder was present before and released after use.

Using standard dissolution tests (e.g.

USP type II apparatus with sinker) and acetaminophen as a model drug formulation, the capsule ruptures and releases the content within 5–10 minutes in all media (pH 1.2 – 0.1N HCl; pH 4.5 – acetate buffer; pH 6.8 – phosphate buffer).

The dissolution profiles are in accordance with the pharmacopeial requirements for immediate release oral formulations.

However, for weak acid or weak base drugs with poor aqueous solubility like dabrafenib, HPMC capsules might act as a crystallisation inhibitor and increase the bioavailability [Ouellet et al. J Pharm Sci 102(9): 3100–3109 (2013)]. For such BCS class two compounds, the thermogelated HPMC capsules provide superior dissolution and bioenhancement functionality, which might also contribute to a reduced inter- and intra-subject variability.

Specialised Patient Needs Multiparticulates like pellets, minitablets or granules are increasingly being considered as the formulation of choice for special patient populations to increase palatability and swallowability, to allow individual dosing according to body weight, body surface, age or kidney function [Klingmann et al. J Pediatr 163:1728-32 (2012); Klingmann et al. J Pediatr 167:893-6 (2015)]. Modified release, e.g. enteric formulations, are the preferred oral form due to their gradual and predictable release from the stomach [Digenis et al. J Clin Pharmacol 30, 621-631 (1990); Abrahamsson et al. Int J Pharm 140, 229-235 (1996)]. Many of these formulations are designed to protect acid and moisture sensitive drugs as well as quickly dissolve in the duodenum by using hydrophilic excipients. To achieve sufficient stability of such systems, the head space humidity in a two-piece capsule needs to be within a defined range. The capsule moisture (LOD) of HPMC capsules is directly correlated with 84 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the head space humidity and is adjustable without impacting the mechanical and elastic properties of the capsule or its dissolution HPMC capsule. For example, if manufacturing of products at conditions of 22°C and 20% RH, the HPMC capsule provides the respective design space for robust product performance. In the same way, interactive powder blends or engineered particles for dry powder inhalation require specific head space humidity that can easily be adjusted with HPMC capsules without negatively impacting the performance of the capsules in the diverse inhalation devices [Geller et al. J Aerosol Med Pulmo Drug Del 24(4):175-182 (2011)].

Advanced drug delivery technologies targeting specific areas in the GI tract, e.g. colonic delivery, and emerging sensitive therapeutics, e.g. live microbiota, require oral dosage forms that do not use compression and release the therapeutic agent within a specific gastric environment quickly. Coating of filled capsules have been demonstrated to be most suited for targeted delivery to the gastrointestinal tract. Aqueous coating composition has demonstrated favourable adhesion characteristics of HPMC, and as such on HPMC capsules. By using different types of coating polymers and varying the coating thickness, the in vivo release could be targeted to different areas within the gastrointestinal tract [Cole et al. Int J Pharm 231: 83-95 (2002)].

Conclusion Pharmaceutical drug products are an essential part in healthcare delivery in developed as well as developing countries.

Evolving science continues to fuel the therapeutic options for acute, chronic and life-threatening disease, as well as the relevant new drug delivery technologies to enable their therapeutic efficacy and site-specific delivery. There is a growing demand for affordable medicines from lowand middle-income countries and it is our global responsibility to produce high-quality medicines more efficiently and locally to meet these needs.

The two-piece capsule is an established dosage form with proven viability for a large variety of compounds, formulations, drug delivery technologies and applications.

Because a capsule product can be manufactured with just two-unit operation (blending and filling), encapsulation has been used from early medicine development, through to commercial manufacturing, with global availability

in pharmaceutical manufacturing sites.

However, advances in technology and the growing complexity of customer needs have resulted in rising manufacturing costs of capsules with more specialised properties or formulations.

To deliver on these emerging requirements, the advantages of capsules can be applied to a variety of other products by developing capsules with specific properties. The HPMC capsule manufactured by a thermogelation process provides a solution to many of the challenges faced by those developing and manufacturing drugs. It is a fast-dissolving capsule that provides the opportunity to be adjusted to specific moisture or head space humidity whilst maintaining the elastic properties even under stress (e.g. piercing or shearing in a device). As such, the capsule is highly resistant across environmental temperature and moisture conditions. For products sensitive to compression, liquid or semisolids or life microbiota requiring targeted delivery in the gastrointestinal tract, the capsule can be easily coated with different coatings and coating thickness. Using standard capsule-filling equipment, at known machineability performance, the new HPMC capsule also contributes to formulation and process simplification, which are the most important factors in increasing cost efficiency in pharmaceutical manufacturing.

Sven Stegemann Sven Stegemann, head of Global Scientific Business Development, ACG. Over the course of his 28-year career in the pharmaceutical industry, Prof. Dr. Sven Stegemann has worked as an adviser to major pharmaceutical companies on ways to improve the formulation design, development and manufacture of pharmaceutical products, including advanced drug delivery and manufacturing technologies and controls. In his academic role, he focuses his research on the rational development of patient-centric drug products and their associated manufacturing technologies, as well as education and training of students and young scientists.

Autumn 2020 Volume 12 Issue 3

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 85

Application Study

Best Practices for Glass Delamination Testing Studies Matthias Bicker, Daniel Haines, and Uwe Rothhaar

SCHOTT pharma services provides compatibility testing for drug products in glass vials1 including a delamination screening package aligned with USP <790>2, USP <1660>3, and EP 3.2.1.4 recommendations.

Over the last decade, the design of such studies was progressively improved to provide reliable data for risk assessment for drug container compatibility. The essential factor for the suitability of such investigations is the categorization of different observations with respect to their criticality and that features need to be found which are early indicators for the later occurrence of delamination (i.e. applied predictive screening test methods “should look for precursors that lead to delamination”3).

The containers to be tested and filled with drug product or placebo solution, can be drawn from real-time stability studies or stored under accelerated ageing conditions. The extent of glass corrosion and chemical attack is assessed by analyses of the inner glass surface morphology, the concentrations of extracted elements in solution, and by identification of particles and flakes. Some typical results derived with such studies have been previously published5,6 with additional information concerning glass leaching recently discussed7.

SCHOTT pharma services uses a combination of the recommended analytical techniques. Illustrative results are summarized in the following section.

Visual and Optical Inspection

Flake-like particles by visual inspection

•

Coloration ring by stereo-microscopy

Used to detect particles via visual inspection by eye and camera (filled vials) and to visualize coloration and scattering (for empty and for emptied vials)

•

Allows for the identification of containers with high particle load and with changed surface and surface near regions to determine the worst samples of a set by stereo-microscopy

SEM Cross-section Analysis

200nm

Roughening

• •

Reaction zone

Used to determine the extent of chemical attack of inner glass surface and of surface near regions Allows for classification between different levels of glass corrosion.

100.00 K X

Delaminated area (left) and reaction zone (right) (Note: scale bar valid for all three micrographs)

Typical features are roughening, formation of reaction zones and/ or delaminated areas at the interior surface in contact with the drug product

ICP Analysis

Concentration of selected leachables found after storage for 24 weeks at 40°C with different filling solutions

•

86 INTERNATIONAL INTERNATIONAL PHARMACEUTICAL PHARMACEUTICALINDUSTRY INDUSTRY

Used to quantify the amounts of leached glass elements

•

Allows for the confirmation of the chemical mechanism of drug container interaction Autumn Autumn2020 2020 Volume Volume 12 12 Issue Issue 3 3

Application Study SEM/EDS and Raman Microscopy

conditions and selected time points according to Tables 1 + 2 to quantitatively determine the amount of “glass” elements leached into solution for selected “glass” elements (e.g. Si, B, Ca, Al) to ascertain if the amounts and ratios found are normal or if there is a pronounced chemical attack.

Exemplary EDS spectrum of an inorganic flake-like particle

• •

Used to analyse the composition of particles after filtration Allows identification of morphology (SEM), elemental components (SEM/

•

Exemplary Study Protocol 1.

Visual inspection by eye and magnifying video camera with respect to the presence of particles or flakes (10 filled vials per time point according to Tables 1 + 2).

2.

Optical inspection of emptied containers per time point: Stereomicroscopy with extended depth of focus to qualitatively determine if there are any indications for reaction zones or scattering present on the interior surface (10 vials per time point according to Tables 1 + 2). Selection of two ”worst” samples on the basis

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6.

SIMS (secondary ion mass spectrometry) depth profiling of the interior surface to get information about the composition of the surface near region.

EDS), and molecular structure (Raman) of isolated particles to distinguish between glass flakes and other particles

Altered elemental composition of surface near layer with B and Na depletion

Used to characterize the elemental composition of the near surface region of container interior

Filtration of the solution of one selected vial according to Tables 1+2 through a silver membrane (pore size approx. 0.2 μm) using a vacuum filtration unit. Subsequent SEM/ EDS and Raman analyses of found particulate matter to determine the elemental composition and morphology of the particles by SEM/ EDS and the molecular structure by match of Raman signals to library.

Optional: (If the mechanism of glass corrosion is unclear or reaction zones are observed.)

Exemplary Raman spectrum of an organic flake-like particle

TOF-SIMS

•

5.

Allows a better understanding of the mechanism of drug container interaction and induced glass corrosion of stereo-microscopic inspection for subsequent SEM cross-section analyses.

3.

SEM (scanning electron microscopy) cross-section analyses on the interior surface of two “worst” vials for selected test conditions and selected time points as described in Tables 1 + 2; analyses of three areas: wall near bottom, middle of the vial body, and wall near shoulder. These investigations reveal the presence of a potential reaction zone.

4.

ICP (inductively coupled plasma) analyses of 10 mL drug solution pooled from the vials for selected test

The techniques described above are applied at different time points under accelerated storage conditions. These conditions are defined on the basis of the drug product application and customer requirements. Exemplary study designs for predictive delamination screenings for drug products with a shelf-life of three years at 5°C (Table 1) and 25°C (Table 2) are shown on the following page.

The tables illustrate the test methods applied for one set of vials filled with drug product and stored for different time points and include the number of characterized samples.

Rationale behind the Study Protocol Storage Conditions: The definition of the accelerated storage conditions requires an estimation of an acceleration factor. In the case of a delamination or a glass leachable study, the kinetics of solid-state reactions should be considered. In such cases the impact of increasing the temperature can be described by an Arrhenius equation k = A exp(-Ea/RT) (k: rate constant, R: universal gas constant, Ea: activation energy, T: temperature, A: frequency factor).

The calculation of the acceleration factor which is the ratio k(T2)/k(T1) requires an INTERNATIONAL INTERNATIONALPHARMACEUTICAL PHARMACEUTICALINDUSTRY INDUSTRY87 87

Application Study

Method

Empty vial

Storage conditions/time points After filling

Storage at 40°C

Control

0 weeks

4 weeks

8 weeks

12 weeks

Visual Inspection

–

10

10

10

10

Optical Inspection

5

10

10

10

10

Sem cross-section

2

2

2

2

2

ICP analyses*

–

Yes

Yes

Yes

Yes

Particle analyses by SEM/ EDS and Raman if flake-like particles are found

–

–

1

1

1

Sims (optional)

–

1

–

–

1

*: Drug solution pooled from multiple vials Table 1: Exemplary study design for a drug product with a shelf-life of three years at 5°C tested by using accelerated storage at 40°C

Method

Empty vial

Storage conditions/time points Storage at 60°C

After filling

Control

0 weeks

6 weeks

11 weeks

16 weeks

Visual Inspection

–

10

10

10

10

Optical Inspection

5

10

10

10

10

Sem cross-section

2

2

2

2

2

ICP analyses*

–

Yes

Yes

Yes

Yes

Particle analyses by SEM/ EDS and Raman if flake-like particles are found

–

–

1

1

1

Sims (optional)

–

1

–

–

1

*: Drug solution pooled from multiple vials Table 2: Exemplary study design for a drug product with a shelf-life of three years at 25°C tested by using accelerated storage at 60°C

estimation of the unknown activation energy Ea. The lower the Ea-value the smaller the acceleration. For the dissolution of a borosilicate glass (Pyrex, buffered at pH 7) an Ea-value of 54 kJ/mol8 was published and we use this value to calculate the storage

period at different temperatures. Using this approach, we obtain an acceleration factor of about 13.5 when storing a drug product at 40°C instead of 5°C For a drug product with a shelf-life of three years at 5°C the storage period at 40°C shortens to 12 weeks.

Please note that reactions with activation energies lower than 54 kJ/mol will have lower acceleration factors, while the acceleration will be higher for reactions with higher activation energy.

Table 3: Probability to find glass delamination and/or early indicators for number of samples investigated per time point 88 INTERNATIONAL PHARMACEUTICAL PHARMACEUTICALINDUSTRY INDUSTRY 88 INTERNATIONAL

Autumn 2020 Volume 12 Issue 3 Autumn 2020 Volume 12 Issue 3

Application Study Number of Samples: We recommend at least 10 vials per time point and per sample set and five additional empty vials per vial container type as reference samples.

It is quite unlikely to observe a delamination effect by only applying a standard USP <790> / EP 2.9.20.2,9 test method, because of the low frequency of randomly drawn vial samples showing visible flakes and because of the low sensitivity of the method. Therefore, we are using inhouse inspection methods in addition that allow the identification of containers with small flakes load and/or changed regions to determine the worst samples of a set by stereo-microscopy.

Early indicators for delamination like "reaction zones" will be found with a much higher probability for a population of vials (compared to the probability to find the final stage of delamination). Therefore, we adjusted the number of vials to find early indicators with a high probability. If the probability to find a feature (e.g. reaction zone) for a single vial out of one time point is Y, we can calculate the probability P to find this feature at least once in a group

Dr. Daniel Haines

of N vials with the equation P = 1-(1-Y)N, as shown in Table 3 below. It becomes clear that the reduction of the number of vials is significantly increasing the chance to miss a feature, which is why the aforementioned study design is recommended.

REFERENCES 1.

2.

3.

4.

5.

6.

FDA Guidance for Industry, “Container Closure Systems for Packaging Human Drugs and Biologics”, May 1999.

U.S. Pharmacopeial Convention (USP), USP <790>, “Visible Particulates in Injections”.

U.S. Pharmacopeial Convention (USP), USP <1660> Durability of Glass Containers, “Evaluation of the Inner Surface Durability of Glass Containers”.

European Union Pharmacopeia (EP), EP 3.2.1., “Glass Containers for Pharmaceutical Use”.

Rothhaar, U., Klause, M., Hladik, B. Comparative Delamination Study to Demonstrate the Impact of Container Quality and Nature of Buffer System, J. Pharm. Sci. Technol. 2016, 70, pgs 560 – 567.

Haines, D. Scheumann, V., Rothhaar, U. Glass Flakes: Pre-Testing Stops a Big

Dr. Uwe Rothhaar

Scientific Advisor for SCHOTT pharma services, earned his doctorate in Inorganic Chemistry at the University of Chicago. He joined SCHOTT in 2001 with a focus on developing glass coatings to control drug formulation interactions with glass surfaces. Since 2010 he is responsible for SCHOTT pharma services in North America providing analytical support of packaging material for pharmaceutical companies.

Director of SCHOTT pharma services earned his doctorate in Physics at the University of Kaiserslautern in Germany.

He joined SCHOTT in 2000 and focused his activities on analytical support around glass and glass surfaces and coatings. Over the last years he is responsible for SCHOTT pharma services providing compatibility and compendial testing for pharmaceutical containers for pharmaceutical companies.

Email: daniel.haines@us.schott.com

Email: uwe.rothhaar@schott.com

Laboratory address in Germany:

Laboratory address in USA:

SCHOTT AG SCHOTT pharma services Hattenbergstraße 10 55122 Mainz Germany Phone: +49 (0) 6131 66 7339 pharma.services@schott.com

SCHOTT North America, Inc. Attn. Dr. Dan Haines 201 South Blakely Street, #121 Dunmore, PA 18512 USA Phone: +1 570 457-7485 x 653 daniel.haines@us.schott.com

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Problem before it Even Starts, Contract Pharma 2013, June, pgs 92 – 98.

7. Hladik, B., Buscke, F., Frost, R., Rothhaar, U. Comparative Leachable Study for Glass Vials to Demonstrate the Impact of Low Fill Volume, J. Pharm. Sci. Technol. 2019, 73, pgs 345 – 355.

8. Perera, G., Doeremus, R.H., Landford, W. J. Am. Ceram. Soc., 1991, 74, pgs 1269 – 1274.

9. European Union Pharmacopeia (EP), EP 2.9.20., “Particulate Contamination Visible Particles”.

10. Laboratories of SCHOTT pharma services are DIN EN ISO/IEC 17025 accredited (DAkkS) and FDA registered.

SCHOTT pharma services can access more than 40 years experience in analytical testing of pharmaceutical packaging containers. All quality relevant documents are electronically available, ensuring a hassle-free audit process.

Dr. Matthias Bicker Scientific Advisor of SCHOTT pharma services earned his doctorate in Physics at the University of Goettingen in Germany. He joined SCHOTT in 2001 and was a key player in the development of new coating solutions for packaging containers, based on SCHOTT’s proprietary PICVD coating technology. Since 2005, he has continuously been working as a project manager on innovation projects for pharmaceutical packaging applications. Over the last 7 years, he has gained substantial experience in collaborating with the pharmaceutical industry in the area of characterization of primary packaging components aligned with most recent regulatory guideline recommendations and related analytical services supported by the contract laboratory SCHOTT pharma services.

Email: matthias.bicker@schott.com

INTERNATIONAL INTERNATIONALPHARMACEUTICAL PHARMACEUTICALINDUSTRY INDUSTRY89 89

Packaging

Automated Quality Control of Pharmaceutical Packaging Materials Inspection systems help print shops perform a 100% print inspection and save time at the implementation of new jobs, due to automated job setups and high-speed inspections. The customer proof is loaded and used automatically based on the entered job data. Even composite jobs, for instance front and back labels, can be checked against corresponding PDFs in one click. The information contained in the PDF is used to define priority regions and adjust inspection sensitivity automatically. The accuracy of web inspection systems enables the detection of defects at full machine speed.

Thanks to intelligent technology, modern inspection systems alert the operator only in case of significant deviations. Thereby the inspection system reduces potential eye strain and fatigue. The clear presentation of deviations and key statistical information – such as the defect heatmap – help the operator to understand the location and origin of printing defects easily. A comprehensive inspection report is automatically produced at the end of each job offering a tracking, analysis and communication support for printers and converters.

Checking contents and ensuring the print quality of pharmaceutical packaging is essential. The strict normative and legal requirements within the pharmaceutical

90 INTERNATIONAL PHARMACEUTICAL INDUSTRY

industry demand great expertise in the areas of data integrity and tamper-proofing of production and manufacturing processes.

Print inspection systems help pharmacists to avoid user-side process intervention and ensure high quality standards through automated checks and flexible system integration.

Minimisation of Liability Risks Potential sources of error can arise during the production and finishing of pharmaceutical print products, such as package inserts, packaging and labels, across various process steps. At the same time, illegible, incorrect or incomplete information can have lifethreatening consequences for patients. For this reason, pharmacists face high liability risks and expensive recall campaigns. The development of reliable technologies for the automation of quality controls makes manual inspection obsolete today. In order to ensure the required standards, more objective inspection solutions are needed to be used in the various production steps in accordance with the standards and prevent undesired process interference.

In the incoming goods department of the test laboratories, in production or already in the artwork or release phase of the suppliers, print inspection systems help to avoid expensive and image-damaging process errors, significantly shorten the inspection time and increase the quality of the packaging materials. Modern print image control systems enable even more detailed, language-independent checking of pharmaceutical labels and printed products such as package inserts by means of a pixelby-pixel comparison with a resolution of up to 600 dpi.

Data Integrity and Traceability By integrating automated print image controls into existing processes and workflows, manual and risky production steps are eliminated. Those systems provide the necessary interfaces to typical pharmaceutical information systems, such as a laboratory information and management system (LIMS), thus ensuring the integrity of the underlying test data.

Within the framework of valid quality controls, the release of the automated tests is also carried out according to the four-eyes principle that is customary in the industry.

Thanks to a secure database, all inspection orders awaiting approval can be checked independently of time and location. A second examiner then approves or rejects the results of the first examiner and adds his or her electronic signature along with a comment in the system. Final batch approvals or revisions can thus be handled within the existing workflow in accordance with standards and adapted to existing processes. For the documentation of each production and release step, as well as for reasons of traceability, comprehensive final reports are generated by the system and stored in a protected format in the network.

Simplification of the Audit Trail Review Inspections and audits are required in the pharmaceutical sector by the legislator and based on regulatory requirements (e.g. GMP, DIN-EN-ISO) – here too, print image control systems can actively support pharmacists. Thus, the documentation of all inspections and system configurations carried out within the workflow takes the form of an audit trail. The events and necessary interventions occurring during

Autumn 2020 Volume 12 Issue 3

Packaging

The EyeC Proofiler 600 DT is used for print sample testing in the incoming goods department of test laboratories and provides all the necessary functions for testing in accordance with the guidelines set out in U.S. FDA Title 21 CFR Part 11.

the inspections are stored in a protected, unchangeable format and assigned individual identification numbers to make the evaluation more comprehensible and traceable. For the identification of critical events, database-based tools such as an audit trail viewer make use of individually adaptable filters and a clear interface.

The recorded trailing data can be flexibly loaded and visualised in the system, and reveal staff training needs or manipulative

interventions. The saving and loading of search queries within the tool speeds up the review process and hence minimises the effort required by quality managers.

With the help of the finally generated PDF reports, the audit trail review can also be prepared more comprehensibly also for external auditors.

Testing of 1D/2D Codes and Braille With the increasing individualisation of

With the EyeC Review Station, inspections are now carried out according to the dual control principle, supported by a database and thus independent of time and location. www.ipimediaworld.com

printed products, the use of 1D or 2D codes (barcodes, data matrix and QR codes) on produced packaging and labels is also increasing. For this reason, print image control systems enable automated code grading in accordance with applicable guidelines such as ISO 15426, replacing a separate "barcode verifier" and visualising the barcode evaluation throughout the entire print job in a comprehensive test report. In addition to the verification of texts, graphics and codes, the systems also enable the testing of Braille in accordance with ISO 17351:2013 in a single pass. Besides visualising missing Braille dots or faulty Braille grids, the system also automatically checks the height of the Braille dots and provides a clear evaluation in the form of a comprehensive test report. Modern print image control systems thus increase the efficiency of necessary checks, make the purchase of additional devices for barcode evaluation or Braille measurement obsolete and ensure the production of compliant print products.

Comprehensive Support The inspection systems available on the market, consider the latest requirements for data integrity, data security and audit trail INTERNATIONAL PHARMACEUTICAL INDUSTRY 91

Packaging

The EyeC Audit Trail Viewer is used to review and track critical events in total confidence.

when inspecting pharmaceutical packaging materials. Pharmaceutical companies can therefore not only carry out fast and automated random checks on their print products, but also increase the security of their processes. All data can be easily and securely accessed and presented in the course of subsequent audits. Userfriendly systems also offer a comprehensive quality control solution at every stage of production: during design and approval, in the print shop or during incoming goods inspection in the testing laboratory. The underlying software must be developed in accordance with the applicable ISO

9001, GMP and GAMP 5 guidelines and must include all the necessary functions for inspection in accordance with the guidelines set out in U.S. FDA Title 21 CFR Part 11. Some companies also provide their pharmaceutical customers with all validation-relevant documents, such as URS, IQ and OQ in a corresponding validation support package.

Trends In particular, the label and packaging market is facing shorter time to market today. For this reason, manufacturing and processing operations are becoming

increasingly automated. In order to meet the increased quality requirements and strict customer specifications, for example in the pharmaceutical sector, automated inspection processes are more and more implemented as a standard in production to increase the accuracy and traceability of quality controls. Serialisation has brought a lot of challenges, especially for pharmaceutical companies and their suppliers. Modern inspection systems must therefore be able to support pharmaceutical companies and their suppliers with managing the data along the entire supply chain.

The increase in sustainable but highly refined print products also reinforced the necessity to use automated inspection systems. Modern solutions for quality controls help to carry out valid tests of printed products independent of material and format, delivering precise results to avoid waste and machine time during production and processing. In addition, print inspection providers offer single system solutions for cross-product inspections throughout the entire manufacturing process, including service and maintenance, for preventive measures and to reduce press downtime.

Nico Hagemann

The EyeC Validation Support Package provides the pharmaceutical customers with all validation-relevant documents, such as URS, IQ and OQ in a corresponding validation support package.

92 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Nico Hagemann is the director of the EyeC product management and product manager of the inline inspection systems. As an engineer in print and media technology, he has 15 years of experience in the printing industry. He started out in development at All4Labels (formerly Rako) and was responsible for inspection systems before joining EyeC as Application Engineer.

Autumn 2020 Volume 12 Issue 3

ECO-friendly plastic packaging From sustainable and renewable biomaterials and R-PET

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 93

Logistics & Supply Chain Management

Creating a Fit-for-purpose Supply Chain for the COVID-19 Vaccine The race is on amongst the international scientific research community to develop a vaccine that will prevent infection by SARS-CoV-2, the virus that causes COVID-19.

While many nations who were the early epicentres have successfully flattened the curve, both in terms of new confirmed cases and the number of people who are losing their lives to this novel Coronavirus, the virus is continuing to spread at an accelerated rate elsewhere, particularly in the Americas and Southeast Asia.

There is also the very real risk of a second wave of Coronavirus infection in countries that have already been badly hit earlier in 2020, as autumn looms.

By the end of 2021, the World Health Organisation (WHO) plans to deliver over 2 billion doses of a Coronavirus vaccine internationally to accelerate herd immunity and wipe out the highly infectious virus. But this ambitious timeline presents a huge challenge for pharmaceutical supply chains and healthcare systems.

Decades of underinvestment and growing pressure from numerous stress factors like new medicine types, increasing demand from emerging economies, the rise in counterfeiting and falsification, and stricter regulation has left the pharmaceutical supply chain in substandard condition.

For too long, the pharmaceutical industry has relied on supply chain networks that are neither flexible nor cost-effective.

Faced with the task of delivering a safe and effective COVID-19 vaccine to billions of people worldwide, the time for the pharma industry and its partners to act is now.

The benefits of a modern pharma supply chain that’s fit for today’s challenges and tomorrow’s will long outlive the COVID-19 pandemic. It will provide cost-saving and efficiency gains for years to come, while simultaneously helping the industry to fulfil its social responsibilities, including 94 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the need to both pioneer more sustainable manufacturing processes and produce more effective and safer medicines the entire world can afford.

Where are we with COVID-19 vaccine development?

Developing a new vaccine is a long and complex process, often taking between 10 and 15 years to complete. It also requires huge sums of public and private investment.

The record for the fastest new vaccine developed is currently held for the Zika virus (seven months) but the epidemic naturally came to a halt before the vaccine became available.

There’s also the uncomfortable fact that up to 94 per cent of new vaccines fail to pass the clinical trial stage because generally, vaccines are even more thoroughly tested than non-vaccine drugs due to the number of human subjects in vaccine clinical trials usually being greater.

In vaccine development, there are usually three different phases of clinical trials (Phase I involving a small batch of people, Phase II with a few hundred, then finally Phase III with thousands) and researchers usually leave months in between each

phase to review the findings and secure approval for subsequent phases.

According to WHO, as of 6th July, there are 21 candidate vaccines in clinical evaluation with the developers from the University of Oxford and Astra Zeneca, and Sinovac leading the way with their vaccines currently in Phase III clinical trials.

Many are expecting (and very much hoping) a vaccine is available within the next 12–18 months, and that it’s good enough to accelerate a population’s progression towards herd immunity before it’s reached naturally. And the international pharma supply chain needs to be ready to go in anticipation of this date.

What’s needed to deliver a safe and effective vaccine?

Delivering a new vaccine for COVID-19 to billions of people worldwide will be one of the greatest challenges faced by modern pharma and its supply chains. The difficulties are intensified by the shortcomings of the current pharma supply chain model, which has been short of investment and innovation for decades.

Linking the laboratory to the marketplace, the supply chain deserves the same Autumn 2020 Volume 12 Issue 3

Logistics & Supply Chain Management focus and investment given to the discovery, development and marketing of pharma products. Yet inefficiencies and bottlenecks remain, largely hidden behind the closed doors of warehouses.

dependent on the kind of vaccine which is found to work best, and that won’t be known until the Eureka! moment. Currently, there are clear frontrunners in the race, but this could all change at the final hurdle.

But faced with the responsibility of delivering the COVID-19 vaccine within such a short timescale, this could be the tipping point we’ve all been eagerly awaiting to kick start the next generation pharma supply chain.

For a vaccine to be made quickly and distributed to populations worldwide by 2021, we need to plan ahead. National governments need to start signalling the quantities of a vaccine they would be prepared to purchase and who they would prioritise immunising first. A further step could be committing to a pre-agreed purchase price ahead of the vaccine being approved to give greater certainty to manufacturers.

Upscaling Manufacturing Capacity As part of international initiatives to increase pandemic preparedness, upscaling manufacturing capacities for vaccines has been a priority for many years. There have also recently been additional emergency funding packages from governments worldwide in support of bolstering pharma manufacturing capacity even further, in anticipation of an approved COVID-19 vaccine.

However, where to channel this investment is a difficult decision to make before a vaccine has been approved. The manufacturing facilities needed will be

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The Cold Chain One of the major challenges in distributing a vaccine is always temperature.

Vaccines need to be kept at an optimum temperature, usually between 2 and 8 degrees Celsius, to be effective. This critical temperature must be maintained throughout the whole manufacturing and distribution process, up until the point when the vaccine is administered to a patient.

Cold chain logistics will, therefore, be a key focus in preparation for the point at which a COVID-19 vaccine is approved. A cold chain refers to a supply chain with cargo that undergoes end-to-end temperature control through transit and it’s a relatively new concept in pharma, as many traditional drugs do not need to be transported or stored in a temperature-controlled environment.

Thanks to the advent of a new class of pharmaceuticals – biologics - the cold chain has benefitted recently from greater investment, expansion and tracking innovations. But the challenges of cold chain logistics are ongoing, particularly in lower-income and remote locations, with tough terrain and warmer climates adding an extra element of risk.

Some companies are offering experimental drone deliveries of medicines to cut the time it takes for them to reach remote communities from several days to as little as a few hours. With the threat of COVID-19 being particularly high in remote communities with poor or no healthcare infrastructure, this may become a technique used more widely.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 95

Logistics & Supply Chain Management Primary and Secondary Packaging Manufacturing and assembling primary and secondary packaging for the vaccine is also going to be a test. Often, delivery devices and packaging will be manufactured separately before being filled and assembled, bringing together multiple stakeholders and increasing the margin for error.

In terms of primary packaging, pre-filled syringes would be the preferred option as a singular vehicle for, and direct administrator of, the vaccine, protecting its contents from contamination and misuse.

All compounds and primary packaging structures need to be extensively tested for materials, extractables and leachables, durability, shelf-life and more, and tested for suitability with secondary packaging.

Certain compounds may be considered non-toxic, but when tested for temperature, failure analysis and more, demonstrate a risk to patients.

A Hybrid Supply Chain Model Given the complexities and urgency in distributing a vaccine globally, a new approach is needed to assess, re-engineer and build upon available logistics assets and systems.

Historically, pharma companies have relied on a network of hundreds of suppliers placed around the world to manufacture, package and deliver different products to market. It’s still not uncommon for multiple teams to be managing multiple

96 INTERNATIONAL PHARMACEUTICAL INDUSTRY

international supplier sites. As a strategy, this is overly complex, largely inefficient and very expensive.

forms, with the key factor being they usually contain low quality or incorrect ingredients, or a wrong dose of them.

A pragmatic solution will be bringing it “under one roof” to deliver a vaccine at such a huge scale and within such a tight timeframe, merging the best of manufacturing, design and innovation, supply chain networking and infrastructure.

When doing so, there must be internationally dispersed sales offices, manufacturing cells and storage facilities in strategic locations.

Falsification can also be in the form of the information surrounding the product’s provenance trail, such as the manufacturer, country of manufacture and commercialisation owner. Similarly, the distribution channels logged in its records and documents can be falsified to cover up the original source.

Consolidating the supply chain brings a host of benefits including, but not limited to: reduced risks and overheads, greater innovation, increased speed to market, assurance of supply and compliance, tighter quality control and local availability via regional distribution sites on a global scale.

Limiting Counterfeit Activity As we’ve already seen with COVID-19 testing kits, fake products are flooding the market as criminals attempt to capitalise on the pandemic. As one of the world’s largest industries, the pharma sector is increasingly being targeted by criminals after a slice of this lucrative market. So much so, fake medicine is now the largest fraud market, worth over $200 billion per year.

Falsified medicine is the production of counterfeit pharmaceutical products that do not adhere to the strict regulatory standards imposed by government agencies to ensure the end user’s safety. This can take various

A crucial part of delivering a safe and effective COVID-19 vaccine will be ensuring falsified and counterfeit versions are not in distribution. The use of intelligent packaging and supply chain tracking software will be key.

Smart tracking systems, built into primary and secondary packaging, is also an exciting area of innovation within the pharmaceutical industry. Managing and recording all the typical activities that occur in the supply chain, or designed to cover special requirements, tracking chips can log events or raise queries that occur across a product's lifespan remotely and in real time.

This is invaluable information for antitampering strategies, allowing companies to locate and interrogate a product anywhere in the supply chain. For example, the geographical location of a product and the route it took to arrive there can all be captured and stored, thus revealing any unauthorised journey routes or interventions.

Autumn 2020 Volume 12 Issue 3

Logistics & Supply Chain Management Communication, Education and the “Anti-vaxxers” There are also further complications to address once a vaccine is approved and distributed, particularly for ongoing communication and education initiatives.

Vaccination isn’t compulsory and the spread of online conspiracy theories is helping to fuel the so-called “anti-vaxx” movement around the world, which could mean take-up will be lower than expected amongst the public when a vaccine against COVID-19 is available.

It’s currently estimated in Britain, up to a third of people are either unsure about or would refuse a vaccine, rising to up to half of people in America. This represents a serious and growing problem that could hamper the success of the COVID-19 vaccine.

Messages spreading across social media portraying the often false negative consequences to vaccinations may be in the minority, but they are exceptionally pervasive.

Clear communication and health education, at both a grassroots and topline level can help to bridge this gap and combat the acceptance of fake news stories surrounding the Coronavirus and its vaccine.

As an alternative to simply listing all the positive facts about a COVID-19 vaccine and saying it’s safe, public health officials and clinicians across all nations need to listen and understand the specific concerns individuals and groups have and respond in a targeted way to change their opinions and dispel misinformation.

A Challenging Path Ahead It’s quite remarkable the speed at which we’re progressing towards a COVID-19 vaccine. The international scientific community, investors and governments alike have come together at this time of crisis for the good of mankind.

The pressure on supply chain networks to deliver a safe and effective vaccine is immense and will continue to grow as we edge closer to an approved product.

And at the same time, the pharmaceutical industry has an obligation to maintain

and strengthen supply chains for existing treatments and services.

While there is certainly a challenging path ahead, if there is one positive to come from this pandemic, it’s bringing into clear view the vulnerabilities that exist and taking action to strengthen global medicine supply networks for our post-pandemic future.

Rich Quelch Rich Quelch is an experienced global marketer within the healthcare and pharmaceutical sector. He has led the development of the Origin brand, positioning it as a world-leading supplier of innovative and groundbreaking pharmaceutical packaging devices, as well as offering a unique supply chain model that is disrupting the pharma industry.

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Logistics & Supply Chain Management

End-to-end Visibility – The Foundation of Addressing Today’s Challenges in Pharmaceutical Distribution Over the last few years, challenges in the distribution of pharmaceuticals have grown with the need to have better visibility along the entire chain in order to act fast due to disruptions or prevent them from happening at all.

Thankfully, technology in recent years has provided more than just visions of how to address these challenges.

It provides solutions to connect and synchronise the flow of physical goods with the flow of information, therefore reducing the manual effort to handle information. Creating insights out of data and sharing these insights across the supply chain have gone beyond the pure proof-of-concept phase. Companies should start to digitalise this process in a targeted manner, looking for solutions that are adaptable and future-proof.

The principle of providing the patient with the best treatment at the right time, with high quality and low cost, has remained unchanged in the pharmaceutical industry.

Achieving this objective however has not become easier over the years. In particular for the distribution of finished goods, ensuring quality while reducing effort in today’s global supply chains with large product portfolios has become more and more difficult over time.

Challenges Supply Chains Face Today – Increasing Complexity, Regulatory Scrutiny and Customer-centricity A general increase in supply chain complexity and risk is one of three key challenges in goods distribution, driven mainly by continuously expanding global supply chains. This entails companies working with several logistic service providers (LSPs) for different product types or distribution channels (e.g. direct markets vs. wholesale), where the LSPs use their own, often unknown, subcontractors.

Shipments to remote regions or to regions with economic and social instability are harder and more costly to manage. Highvalue treatments with short shelf-lives further add to complexity in managing the distribution effectively.

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Secondly, in the last few years we have seen a rise in regulatory scrutiny in the pharmaceutical industry. Just in the area of finished goods distribution alone, there were key regulatory pieces which came into force either fully or in a phased approach: The EU Falsified Medicines Directive (FMD), which requires prescription medicine to be tracked and monitored on a sales unit level, the updated EU Good Distribution Practice (GDP), which included more stringency regarding condition monitoring of goods, and the US Drugs Supply Chain Security Act (DSCSA), which also requires unit-level traceability to be implemented by 2023 and sets out new rules with regard to resaleable returns. Such regulatory requirements are an additional burden on the organisation and come with an increase in costs and process complexity.

Thirdly, customer-centricity has also arrived in the pharma industry. On the one hand this is driven by the patients themselves with higher expectations regarding transparency, information accessibility and interaction options – one example is how patients today can self-diagnose using online resources to the extent that they already have certain treatment suggestions they would like to discuss with their doctor1. On the other hand, there is an increasing trend towards tailored treatments based on gene therapy or personalised drugs driven by the smaller pharmaceutical or bio-tech companies themselves to increase the ratio of efficacy to cost, as producing “blockbuster” drugs are becoming more and more expensive2.

The bottom line is that pharma needs to move closer to the patient and see them more as customers, with success driven by a greater focus on the customer experience, rather than on the actual product and related specifications3. However, in order to be a part of the customer journey, pharma companies need to know more about their customers, which means relying on advancements in technology to collect information in an efficient and unobtrusive manner.

On top of all of this, the last few months have shown that global supply chains have been put to the test by COVID-19. The pandemic has exposed weaknesses, which manifested through delays or shortages of goods. Companies will not only need to look into fixing weak links in supply chain processes and revalidate them but rethink their global supply chain strategy to avoid the impact of such catastrophic events as best possible. A broader portfolio of sourcing and distribution options will need to be taken into account, increasing redundancy to some extent but at the same time increasing flexibility to adapt to imminent supply chain disruptions.

End-to-end Visibility is the Door to the Digital Kingdom and Technology is the Key To address these challenges, the importance of end-to-end visibility and the ability to continuously collect data points with regard to the whereabouts and conditions of the goods shipped cannot be stressed enough.

This is the basis for improving control as well as implementing automation to

Figure 1: The vision: an interoperable & holistic distribution management platform based on end-to-end visibility Autumn 2020 Volume 12 Issue 3

Manufacturing & Recycling of thermal packaging Europe - USA

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Logistics & Supply Chain Management reduce manual effort, for example through parametric quality releases. In order to achieve this, we see three key steps which need to be implemented: 1.

Establishing a clear link between the physical world and flow of goods with the digital world and flow of information,

2.

Generating actionable insights from collected data along the entire distribution chain irrespective of custodian and location, and

3.

Establishing a secure mechanism for sharing events with multiple supply chain actors.

Advancements in technology over the last five years have made it easier to implement the above-mentioned steps.

Today better and more affordable solutions are available on the market for collecting, processing, sharing and presenting.

Using smart IoT sensors in combination with cloud computing, it is now possible to connect to the physical world and clearly link the measured data to digital representation of the respective goods (a “digital twin”) with little to no manual effort. In combination with machine learning methods, the collected real-world data can be analysed autonomously to identify patterns and generate insights to support decision-making. And finally, DLT-based networks enable a trusted and secure way of not only representing the flow of goods in the digital world and sharing related events with supply chain partners, but also as a platform for implementing data-driven process automation based on agreed business rules while ensuring data integrity without a centralised governing structure.

A project we completed with a partner around adaptive packaging selection for last-mile pharmaceutical deliveries illustrates the potential of new technologies as mentioned above. Instead of using just one passive cooling solution for all types of temperature conditions, a more flexible offering with a variety of options best suited for the respective conditions on the day of shipment was envisioned. The overarching goal was to reduce manual handling effort and costs by choosing lighter and cheaper packaging solutions if temperature conditions were favorable. Based on the on-average lower costs, a more attractive pricing for the service could be offered to 100 INTERNATIONAL PHARMACEUTICAL INDUSTRY

customers and the competitiveness with temperature-controlled alternatives, such as active cooling. A system would suggest the optimal packaging and day to the logistics team from an available selection based on the predicted temperature, a chosen shipment time window within one to two weeks and a variety of parameters driving the predication risk, such as temperature bounds, value of the shipped goods or model accuracy. The underlying model would use a combination of IoT sensor data and machine learning to predict the temperature within the package based on historic sensor data, start and end point of the route (detailed route information was not required) and the external temperature forecast. To understand how many shipments would not require full thermal insulation, but only a reduced level or even none (standard packaging) we sampled 800 shipments in Switzerland during the winter period between January and February. The results showed that for cold chain shipments with a temperature band of 2 to 8 degrees Celsius, around 40% had the potential for optimisation.

The model showed an average accuracy level of 91% when validating the predicted temperature with the actual temperature measurement in the package. Particularly promising was that accuracy of the model increased over time through self-learning, with levels reaching 99% to the end of the period. This example of digitalisation nicely illustrates how measuring, optimisation and automation go hand in hand to improve day-to-day logistics processes by leveraging digital data.

Key Technology Driving Supply Chain Digitalisation Cloud Computing In a nutshell, cloud computing is the delivery of pay-per-use computing services over the internet (“the cloud”) to move away from on-premise IT hardware and to offer faster innovation, flexible resources, and economies of scale. Cloud computing started picking up between 2005 and 2010, when the likes of Amazon and Google launched their cloud services, allowing the rental of online space to either edit and store documents or to run applications remotely. Today it has become the backbone of most companies that rely on cloud services for anything from storage and applications to infrastructure and backup solutions.

Internet of Things (IoT) The IoT is a system of interrelated computing devices embedded in or attached to a variety of objects. These devices are provided with unique identifiers and the ability to transfer data over a network without requiring human interaction. IoT essentially enables smart and saleable data collection in the physical world. Having emerged around 2013, IoT adoption grew in the last three years, with more companies being able to reap firsthand benefits from applying the technology in their operations4.

Figure 2: An application example of AI and IoT – dynamic packaging selection: The optimal packaging is suggested by a system using information on the route, the external temperature forecast, historic shipment temperatures along that route and product quality information, such as the allowed temperature bands.

Autumn 2020 Volume 12 Issue 3

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Logistics & Supply Chain Management

Artificial Intelligence (AI) AI can be described as machine-based intelligence capable of taking actions to achieve specific goals based on the perception of the environment.

Machine learning (ML), a subset of AI, is the use of algorithms for classification and prediction, relying on patterns and inference instead. In the business world AI is almost synonymously used for ML. According to a McKinsey study, AI adoption continues, with the largest cost savings seen in the area of supply chain management and manufacturing5.

Distributed Ledger Technology (DLT) DLT, commonly referred to as block-chain, enables independent computers (“nodes”) to synchronise transactions in the form of a distributed ledger, where each node holds its own copy. Transactions are stored in blocks which are linked via unique references. DLT comes in two flavours: public, where participation in the network is open, or private, which is an invitation-only network run by a group of entities (nodes).

The decentralised network design and data immutability combined with the ability to execute tasks based on codified business rules (“smart contracts”) make it an interesting platform for sharing information and implementing process automation between entities. One example in the pharma supply chain is PharmaLedger, an EU Innovative Medicines Initiative, where a DLT governance model is being developed to ensure crossstakeholder collaboration in tracking, verification and authentication of physical goods downstream6.

Considerations for Implementing End-toend Monitoring Systems Understanding the key challenges supply chains face in the distribution of finished goods, end-to-end visibility is the foundation to address these challenges. With technology being at a point to facilitate with innovative solutions, the question remains how such an end-to-end monitoring and tracking system should look and what steps one should take to get started.

When looking into introducing such a system, we suggest assessing the following management and analytical functionality along the following dimensions: 102 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 3: Conceptual considerations for implementing end-to-end monitoring systems

• • • • •

The system users The IoT sensor devices The shipments The individual articles on sales unit level The deviations occurring during shipments

A distinction is required between shipment and articles primarily, as condition deviations during shipments can impact the respective articles differently based on their individual product stability data over the course of several shipment stages.

A key point is that the system can assign collected sensor data on an article level, irrespective of what IoT sensing device is being used per stage in the distribution.

More expensive real-time data loggers used in the primary distribution from manufacturer to a regional distribution hub (shipment duration typically between three to five days) for example, are too costly and are overkill in the last-mile distribution from wholesaler to pharmacy (shipment duration typically within 24h).

An often forgotten aspect is the ability to handle the large amounts of data being collected. This is not just a question of having sufficient and flexible storage space which is easily accessible, but the effort to process the data to generate insights.

Five years ago, advanced analytics might have been more of a nice-to-have, however due to the increase expected through IoT sensing devices, functionality that can reduce manual effort of pre-processing and analysing data has grown in relevance.

Finally, strong interfacing capabilities are a must in order to connect to other relevant supply chain or quality management

systems within the company. Such interfaces are ideally already available for the most commonly used applications, or if not, require little customisation. In particular, connections to warehouse management systems help to avoid breaks in condition monitoring between individual distribution segments, as sensor devices used during shipment are removed or exchanged at these points and facilitate an on-the-fly configuration of the sensing devices during the commissioning of a shipment, pulling the respective configuration data from the central cloud-based management platform.

One big challenge with regard to sharing data remains a missing industry-wide adopted model for (a) generally sharing data on a DLT network and (b) sharing events related to the condition of goods.

With regard to DLT interoperability, one option currently in discussion is to adapt the current GS1 EPCIS standard, which is widely used across industries to share supply chain events and information with other parties7.

How to Get Started on the Supply Chain Digitalisation Journey Taking first steps in any digitalisation endeavour can be daunting. At Modum, based on our experience, we advise our customers to start following six simple steppingstones: 1.

2.

Start small but commit - understand what you want to achieve overall, get your organisation and sponsors mobilised and define clear benefit objectives and pilot key performance indicators Choose the right product – focus on high-value products or products requiring a new type of supply chain (e.g. personalised treatments), and Autumn 2020 Volume 12 Issue 3

Logistics & Supply Chain Management

3.

4.

5.

6.

choose a product where control of the distribution lies predominantly with you (e.g. direct markets) Choose the right lanes – choose distribution lanes where you have a strong relationship with your supply chain partners and where the distribution is completed in maximum three hops Involve your distribution partners – inform them of the benefits and rationale of what you are trying to achieve, understand any potential risks from their end and engage with them as full members of the pilot Onboard a vendor that is also a change partner – choose a sparring partner with a keen understanding of operational processes as well as technology, that can adapt quickly to changes, and introduce the vendor as an integral part of the project team with direct access to relevant parts of your organisation Keep the bigger picture in mind – outline the next phase and its

objectives already in the planning phase of the pilot, understand internal organisational hurdles and showcase the pilot concept, planned benefits and interim results continuously to key stakeholders throughout the pilot The first step is by far the most important one – in our experience projects often start out with great enthusiasm, however interest wanes if key stakeholders and their needs are not taken into account. Therefore, it is crucial to get a commitment from all relevant stakeholders right from the start and “keep the fire alive” as time goes by.

Overall, however, our discussions with different parties along the pharmaceutical supply chain show that the need to increase supply chain visibility is undisputed. The effective use of the real-world data to gain insight into supply chain events and disruptions, identify trends or even predict and consequently facilitate and automate the decision processes, will be a key success factor for companies in the future. The

information transparency has the potential to increase trust between supply chain actors, improve efficiency and control, and reduce the operational compliance burden companies are faced with today.

REFERENCES 1.

2.

3.

4.

5.

6.

7.

Macphail, T., WebMD Knows Best? How the digital era is changing the way we make medical decisions (2015), https://slate. com/technology/2015/03/webmd-and-selfdiagnosis-how-the-internet-is-changingmedical-decisions.html, visited February 2020 Jørgensen, J.T., From Blockbuster Medicine to Personalized Medicine (2007), https://www. medscape.com/viewarticle/573750_5, visited June 2020 McKinsey & Company, From product to customer experience: The new way to launch in pharma (2018), https://www.mckinsey.com/ industries/pharmaceuticals-and-medicalproducts/our-insights/from-product-tocustomer-experience-the-new-way-to-launchin-pharma, visited July 2020 The Economist, The IoT Business Index 2020: a step change in adoption (2020), https:// eiuperspectives.economist.com/technologyinnovation/iot-business-index-2020-stepchange-adoption, visited June 2020 McKinsey & Company, Global AI Survey: AI proves its worth, but few scale impact (2019), https://www.mckinsey.com/~/media/ McKinsey/Featured%20Insights/Artificial%20 Intelligence/Global%20AI%20Survey%20AI%20 proves%20its%20worth%20but%20few%20 scale%20impact/Global-AI-Survey-AI-provesits-worth-but-few-scale-impact.pdf, visited June 2020 PharmaLedger, https://pharmaledger.eu/ about-us/activities/, visited July 2020 GS1, https://www.gs1.org/standards/ blockchain, visited July 2020

Carl Spörri As Chief Marketing Officer at Modum, Carl Spörri is responsible for the product portfolio as well as marketing and communications. He holds an MSc in electrical engineering from ETH Zürich and has over ten years of experience consulting clients in various industries in digitalisation and change management. Carl is particularly passionate about applying technology to make daily life easier for businesses and helping them implement innovative business models.

Email: carl.spoerri@modum.io

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

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