IPI Spring 2021

Volume 13 Issue 1

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Pharmacokinetic and Statistical Considerations in First-in-Human Clinical Trials EU MDR Changes are Only the Beginning – Ensure IFU Compliance Now and be Prepared for More to Come Key Considerations When Repositioning a Known Drug For Inhalation Therapy Adopting Connected Drug Delivery Devices: Top Tips for Pharmaceutical Companies Sponsor Company:

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Delivering solutions, shaping the future.

Contents 06 Editor’s Letter TALKING POINT

DIRECTORS: Martin Wright Mark A. Barker INTERNATIONAL MEDIA DIRECTOR: Keith Martinez-Hoareaux keith@pharmapubs.com BUSINESS DEVELOPMENT: Chloe Roberts Brown chloe@pharmapubs.com EDITORIAL: Virginia Toteva virginia@pharmapubs.com DESIGN DIRECTOR: Jana Sukenikova www.fanahshapeless.com FINANCE DEPARTMENT: Martin Wright martin@pharmapubs.com RESEARCH & CIRCULATION: Orla Brennan orla@pharmapubs.com COVER IMAGE: iStockphoto © PUBLISHED BY: Pharma Publications J101 Tower Bridge Business Complex London, SE16 4DG, United Kingdom Tel: +44 (0)20 7237 2036 Fax: +44 (0)01 480 247 5316 Email: info@pharmapubs.com www.ipimediaworld.com All rights reserved. No part of this publication may be reproduced, duplicated, stored in any retrieval system or transmitted in any form by any means without prior written permission of the Publishers.

The next issue of IPI will be published in Summer 2021.

ISSN No.International Pharmaceutical Industry ISSN 1755-4578.

The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred.

This publication is protected by copyright.

2021 PHARMA PUBLICATIONS / Volume 13 Issue 1 – Spring – 2021

08 Nemera: The Holistic Partner for Your Combination Product Development In this interview, Mark Tunkel, Nemera’s Global Category Director for Services, illustrate how Nemera can partner its customers in their device strategy, from early stage to GMP manufacturing, involving patients in every step of the process.

12 Respiratory Drug Development – Perspective from Spray and Aerosol Characterisation Expert IPI speaks with Dino Farina, Founder and CEO of Proveris, on how they have helped customers to develop optimally performing orally inhaled and nasal drug products (OINDPs) for patients around the world.

REGULATORY & MARKETPLACE 16 Marketing Medical Cannabis in Europe Major global cannabis exporters cannot tap into a common regulatory pathway to European markets. Cannabis is a massive opportunity, but marketing cannabis products in the diverse European market is a complex challenge. Peter Kohut at Arriello explains that although the European medical cannabis market is complex, this is not a barrier to entry to a market that is becoming increasingly attractive to major pharma players.

18 EU MDR Changes are Only the Beginning – Ensure IFU Compliance Now and be Prepared for More to Come Despite the delay of EU MDR into May 2021, some organisations are still burning valuable time in terms of updating the labelling and instructions for use of their medical devices. Bob Tilling at Kallik shares his experience from recent customer projects and explains how medical device manufacturers can recover lost time in preparing for EU MDR labelling and IFU compliance.

20 Can the UK Solve its ‘Money Laundering’ Problem with the Proceeds of Medicinal Cannabis?

The manufacture, marketing and supply of medicinal cannabis products raise complex regulatory issues in the jurisdiction where those activities take place. These go beyond the issues applicable to medicines in general, even some whose potential harms are far greater. John Binns and David Hardstaff at BCL Solicitors LLP explain how new opportunities for investment will help further drive developments and growth in a sector that promises significant potential gains for patients in need.

24 Managing Competition, Price and Access The changing paradigm for the pharmaceutical sector High medicine prices impose a burden on national healthcare systems, for which pharmaceuticals account for a significant share of spending, especially for countries in the early stages of maturity in the pharma sector. Craig Wylie, Vikas Kharbanda, Dhiraj Joshi, Dr. Regien Sumo, Mario Elhoyek and Dobromira Boyadjieva at Arthur D. Little discuss competition in the pharma sector and present an integrated framework for authorities to strengthen pharma competition.

28 Comparison of Regulatory Process of COVID-19 Vaccines; Between Emerging Markets, EU Coronavirus disease, COVID-19, has affected all of our lives greatly since the end of 2019. We have faced experiences that we have never come across before. We need to take precautions, because

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Contents this infectious disease spreads through droplets of saliva or discharge from the nose when an infected person coughs or sneezes. Pelin Boran at Pelin Boran Regulatory Affairs Solutions & Consultancy discusses that all the data on quality, safety, immunogenicity and efficacy should comply with the standards and criteria, both country-specific and from a global perspective.

DRUG DISCOVERY, DEVELOPMENT & DELIVERY 32 The COVID-19 Catalyst – Accelerating the Move to Patientpowered Medicine COVID-19 is changing the world. The new reality it creates, however, will in many ways be the same as it was always going to be. Rather than changing the course of events, the current pandemic is simply speeding them up. Claus Møldrup at DrugStars explains how technology not only changes healthcare’s ability to understand and treat patients, but also heralds a fundamental shift in the patientprovider dynamic.

36 Innovate UK-funded Project Results in Next-generation AI Drug Discovery Technology A promise of artificial intelligence is that it will gain more value from the complex and expensive data generated in drug discovery, by identifying hidden patterns and valuable conclusions that will guide better decisions when designing and selecting high-quality clinical candidates. Professor John Overington at Medicines Discovery Catapult, Tom Whit ehead at Intellegens and Matt Segall at Optibrium describe how to achieve this by aligning different factors.

42 The Danish Approaches for Personalised Medicine – for the Benefit of Patients The term tailor-made or personalised medicine covers a form of drug treatment in which the use of drugs is adapted to the individual patient's special disease situation and biological characteristics.

The desire is to achieve a unique treatment result that best meets the individual patient's genetic profile. Rasmus Beedholm-Ebsen at Invest in Denmark analyses the Danish healthcare system, which offers unique possibilities for realising the potential of personalised medicine.

46 Key Considerations when Repositioning a Known Drug for Inhalation Therapy In recent years, the pharma industry has seen significant growth in finding new uses for old drugs. The repurposing and repositioning of existing drugs have become an increasingly common way to find new treatments in recent years. Regulators are expecting some form of therapeutic rationale. Geraldine Venthoye, Executive Vice President Product Development, Vectura, looks at the opportunities for inhaled drugs.

50 A Greener Future for the Inhalation Industry: A Critical Year for Our Climate This article explores the legislative and economic drivers of why the industry needs to adapt, and crucially why now is the time to act. It is also important to ground ourselves and remember why we develop medicines; to better the health of the public and save lives. Adam Kay at Pharmaserve North West discusses the challenge to produce sustainable products cannot compromise the safety, efficacy and patient adherence to inhaled medicines.

MEDICAL DEVICES 54 Connectivity, Cybersecurity and Medical Devices: What are the Threats?

Developers of medical devices are taking inspiration from consumer products use of connected technology; realising that smarter devices offer huge benefits to patients, POC workers, and manufacturers. Whilst these technologies can be used to increase the functionality of devices, they can also open them up to cyber-threats. Thomas Watts at Team Consulting looks at ways to identify common risks and vulnerabilities in medical devices and how to defend against them, to help put you on the right development path.

CLINICAL & MEDICAL RESEARCH 58 Digital Medication Adherence in Clinical Trials Drug developers work tirelessly, progressing their compounds from the laboratory to the clinical phases, and rigorously assessing the medication use in Phase II and Phase III clinical trials is crucial to the future success of the treatment. Significant investment of time, resources and capital is employed in these developments, yet they are still, to a great degree, vulnerable to the risks associated with medication non-adherence. Bernard Vrijens at AARDEX Group discusses the reasons.

60 Pharmacokinetic and Statistical Considerations in First-in-human Clinical Trials The purpose of first-in-human (FIH) studies is to evaluate the pharmacology, tolerability, and safety of the drug or investigational medicinal product in humans for the first time. They are designed to reveal the best dose and dose regimen to be used in later Phase II studies. Given the exploratory nature of FIH studies, the question of what statistical analysis is required for pharmacokinetics (PK) data has long been a contentious topic. Joanna Magielse at SGS seeks to explore the topic in more depth.

64 How Approaches to Clinical Research Are Set to Change in the ‘New Normal’ 2020 was an extraordinary year for the whole of humanity. But for the clinical research sector, it has proved to be particularly defining.

Rising financial and time pressures on the life sciences industry will continue to drive changes in how clinical trials are conducted for many years to come. Rich Quelch at Origin discusses the positives

2 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Spring 2021 Volume 13 Issue 1

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Contents which have come out of an extremely challenging year, professionally and personally.

68 Beta Glucans and Endotoxin Testing The presence of bacterial endotoxins in different media, solutions and laboratory materials can be determined by utilising the limulus amebocyte lysate test. Lisa Komski at Fujifilm explains that, for routine testing in the quality control laboratory, it remains of vital importance to establish a reliable and reproducible method of testing so that any reaction can be examined to determine if the cause is indeed due to endotoxin or to the presence of (1,3)-β-D-glucan.

TECHNOLOGY 70 Whitepaper: Together Beyond COVID-19 – A Look at the Future To understand the challenges that the pharmaceutical industry faces during COVID-19, open-ended interviews were conducted with top pharmaceutical companies around Europe. The methodology followed during the interviews was semi-restrictive, using a general outline of questions that led to other topics based on the spontaneous response of the interviewees, but always about the general topic: COVID-19 and digital transformation. As a result of the interviews, meaningful qualitative data was collected. This paper by Marta Vila Ramos at Pharmalex et al., summarise the main highlights, together with the future vision.

74 Redefining Healthcare: Digital Trends in 2021 2020 has redefined healthcare for good. As with many industries, the impact of COVID-19 cannot be understated, as healthcare was placed at the centre of the global agenda. Richard Yeatman at IgniteData shows how digital transformation is enabling growth in the delivery of faster, better quality options, revolutionising how patients engage in and access their healthcare. And with increased personalisation and greater efficiencies, this supports the collective goal of ensuring that patient experience always comes first.

76 Next-generation Aseptic Tech Needed to Cut Contamination Risk The need for sterile manufacturing conditions in the pharma space continues to rise, increasing industry demand for solutions to help achieve aseptic processing goals without compromising on manufacturing efficiency. In this article by Christian Dunne, Head of Sterile Solutions, ChargePoint Technology, we will find out more about the next generation of equipment designed to help balance the aseptic-efficiency equation.

80 Adopting Connected Drug Delivery Devices: Top Tips for Pharmaceutical Companies It has long been recognised that there are serious shortages in the healthcare workforce across all settings and disciplines. In this context of staff shortages and increased demand for healthcare, pharmaceutical companies are going beyond simply manufacturing drugs. They are increasingly providing holistic service packages that include training and education around their medicines. George I’ons at Owen Mumford Pharmaceutical Services explains how connected drug delivery could significantly enhance such services, by producing valuable data insights on medication compliance, which can then be used to improve therapy management.

MANUFACTURING 84 The Effects of Heat from Electro-mechanical Components in Critical Instrumentation Heat in electronic and fluidic control systems such as those seen 4 INTERNATIONAL PHARMACEUTICAL INDUSTRY

in analytical, scientific and medical instruments will in many cases be an unwanted by-product of the excessive power required to initially operate electro-magnetic devices such as solenoid valves and electro-mechanical devices. Although the initial power is unavoidable, the need to maintain full power when the device has been energised becomes excess to requirement in many instances.

Gary Stevens at NResearch explains that in the majority of cases, it is possible to reduce the power to a level that maintains the required function but reduces the excessive currents being drawn.

88 Are Plant-based Softgels the New Gold Standard for Pharma?

Softgel capsules are gaining popularity throughout the nutraceutical and pharmaceutical industries. As well as safely facilitating the delivery of poorly soluble active pharmaceutical ingredients, softgel technology offers several benefits over other oral dosage forms, including versatility and rapid absorption. Thanks to ease of swallowing, convenience, and quick onset of action, Steve AmoussouGuenou at Roquette Pharma Solutions explains why softgels are the preferred dosage form for manufacturers, consumers, and patients alike.

92 Granulation in Pharmaceutical Technology Granulation plays a key role in the production of solid dosage forms in the pharmaceutical industry. Besides wet granulation and can be accomplished using different types of equipment, dry granulation is becoming more and more famous. Tobias Borgers at L.B. Bohle explains that due to the flexibility, simple implementation of the process, and potential, the TSG developed by L.B. Bohle is the perfect, versatile machine for continuous manufacturing processes in research and development and in production.

LOGISTICS & SUPPLY CHAIN MANAGEMENT 96 Deploying AI in the War on Counterfeit Drugs To provide patients with timely access to novel and effective therapeutics, pharmaceutical organisations must maintain robust, trustworthy supply chains. The supply chains are growing increasingly global and complex, opening them up to dangerous quality control and safety issues like theft, fraud, and counterfeiting. Jaleel Shujath at Absorption Systems explains how advanced technologies, such as blockchain and artificial intelligence (AI), can help to overcome the challenges of supply chain fraud and theft, and ensure that global supply chains remain safe, agile, visible, and reliable.

100 Cold Chain in 2021: COVID-19’s Continued Influence The pharmaceutical and cold chain industries were pushed this previous year to innovate through vaccine development, temperaturecontrolled packages that met the needs of new deep-frozen vaccine storage and increased demand for existing products. Dave Williams at Peli BioThermal predicts how COVID-19’s influence persists, and in some instances, may have a long-term ripple effect.

102 The Life-Saving Technology that will Securely Deliver Vaccines Around the Globe The COVID-19 pandemic is retightening its grip in many parts of the world as case numbers rise again and the long-dreaded second wave takes shape. That has in turn thrust global pharmaceutical distribution into the spotlight, and it seems clear that the typical in-transit spoilage rate of pharmaceuticals – as much as 12 per cent – can no longer be accepted when the stakes are as high as they are now. Nico Ros at SkyCell and Prith Banerjee at Ansys explain why use of innovative technologies holds the key to minimising spoilage rates and saving lives.

Spring 2021 Volume 13 Issue 1

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 5

Editor's Letter I hope that everyone is enjoying the arrival of spring, working from home or wherever you may be reading this spring edition.

February saw World Cancer Day and there are some interesting developments into the diagnosis of bowel cancer.

As Prof Johnson observes, "Every year in England, we diagnose around 42,000 people with bowel cancer; that's more than 100 people a day".

There is an exciting piece of technology called PillCams, created by Medtronic, which are cameras encased in a capsule to make them easier to ingest, and it is hoped they can replace more invasive methods of screening.

One of the positives to come out of COVID-19 is that this is accelerating the move to patientpowered medicine. Claus Moldrup at DrugStars explains that during the past 12 months, technology has changed healthcare’s ability to understand and treat patients. However, to really see this being sustainable and available to everyone in society, I do wonder if patients are going to be willing to pay more for their healthcare?

This also leads well into the futuristic world of AI drug delivery technology. Professor John Overington at Medicines Discovery Catapult, Tom Whitehead at Intellegens and Matt Segall at Optibrium tell us about how Innovate UK have funded projects in this area.

The Danes celebrate two things openly; their ranking as the happiest people on the planet, along with their acceptance of paying the highest income tax in the world. Rasmus BeedholmEbsen at Invest in Denmark analyses the Danish healthcare system, which offers unique possibilities for realising the potential of personalised medicine.

But is this because they can afford it, and what can the rest of the world learn from this?

Our connected world also has its challenges, in terms of threats such as connectivity, cybersecurity

and data security. Thomas Watts at Team Consulting explains how to ensure you are able to defend yourself and to ensure you are on the right path.

With the global world we live in, one of the challenges is to ensure that the medicines we are taking or given are the real thing. This is very much seen in the painkiller market. The global counterfeit drug detection devices market is set to surpass around US$1.5Bn by 2029. Jaleel Shujath at Absorption Systems tells us how the role of advanced technologies such as blockchain and artificial intelligence can help to overcome the challenges of supply chain fraud and theft.

2020 certainly brought the whole world to a stop, and this certainly has been felt in the clinical research sector as there was a 38% drop in new clinical trials started in 2020. Rich Quelch at Origin tells us how the life science sector will continue to drive changes in how clinical trials are conducted, and digitalisation will help this. I hope that we see a lot more being done in the area of reducing stress and anxiety for people needing to visit a hospital.

Richard Yeatman at IgniteData gives us his view about the expected digital trends in 2021, and how they are going to enable growth in the delivery of faster, better quality options, revolutionising how patients engage in and access their healthcare.

George I’ons at Owen Mumford Pharmaceutical Services highlights there is a serious shortage of healthcare staff, which is why they have created a holistic service package that includes training and education around their medication. His focus is on the importance of how connected drug delivery could very much help with medication compliance and can improve therapy management.

One exciting enhancement of how patients can take their drugs is soft gel capsules technology. It has been around for over 80 years and has very much been used in the paediatric delivery of drugs. It looks like now they are going to get even more sustainable due to being plant-based. Steve Amoussou-Guenou at Roquette Pharma Solutions explains why this is going to be the preferred dosage form for manufacturers, consumers, and patients alike.

I hope you enjoy this addition of the magazine and that we are maybe able to start to look forward to being able to move around to see family and friends in the summer. I am wondering how people felt at the end of the Spanish flu, how did people get back to normal, and what can we learn from that time in history?

Lucy Robertshaw, CEO LucyJRobertshaw

Welcome to the Spring issue of IPI. It has been a year since the first lockdown. A year of an enormous challenge to the pharmaceutical industry.

Now, as vaccination campaigns gain speed and millions of people worldwide have received at least one dose of the COVID-19 vaccine, cases and hospitalizations appear to be dropping.

even mild cases can lead to the “long COVID” phenomenon of lingering symptoms. Hospitals, though, will not become overwhelmed with emergency cases, and deaths will become increasingly rare.

Large swaths of the population might still become infected and develop minor disease or asymptomatic infections. That prospect worries some scientists and clinicians, who note that

Please stay safe and well and I hope you enjoy the first issue of the journal for 2021.

Yet, there is growing recognition that even if widespread vaccination can’t halt the spread of the virus, it promises a major step back toward normal.

Virginia Toteva, Editorial Manager – IPI

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

Georg Mathis Founder and Managing Director, Appletree AG

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

Catherine Lund, Vice Chairman, OnQ Consulting

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

Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

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

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

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

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

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

Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group

Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

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

Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

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

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

Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting Stefan Astrom, Founder and CEO of Astrom Research International HB T S Jaishankar, Managing Director, QUEST Life Sciences Spring 2021 Volume 13 Issue 1

wel-screen

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Talking Point

Nemera: The Holistic Partner for Your Combination Product Development Q1: Nemera is a world leader in the design, development, and manufacturing of drug-delivery devices for the pharmaceutical, biotechnology and generic industries. Can you give our readers a brief history of Nemera, and where do you see Nemera positioned in the next five years?

As a world-leading drug delivery device solutions provider, our purpose of putting patients first enables us to design and manufacture devices that maximize treatment efficacy.

We are a holistic partner and help our customers succeed in the sprint to market of their combination products. From early device strategy to state-of-the-art manufacturing, we’re committed to the highest quality standards.

Agile and open-minded, we work with our customers as colleagues. Together, we go the extra mile to fulfill our mission.

Q2: What therapeutic applications are the primary main focuses at Nemera today and why?

By focusing on solutions that make patients’ lives easier and safer, we have built a strong portfolio of innovative products and technologies for five routes of administration: parenteral, ophthalmic, ENT (ear, nose, and throat), dermal and inhalation.

We partner with our customers to provide a wide range of device platforms, services, and commercial manufacturing capability to support their needs across their pipelines and associated delivery modalities. We strive to drive innovation across all routes of administration to serve the future needs of our customers.

Our parenteral offering includes reusable and disposable pen injectors, customisable platforms of passive safety device for prefilled syringes (Safe’n’Sound®), as well as customised solutions based on parenteral 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

technologies such as auto-injectors, implanters, and wearables.

In ophthalmics, we strive to improve patient experience by developing Novelia®, a safe and effective multi-dose eye-dropper platform to deliver preservative-free formulations. Novelia® is used all over the world, both for Rx and OTC treatments.

The number of drugs delivered through the ear, nose and throat is expanding. We develop and manufacture a comprehensive range of pumps and valves, compatible with a wide choice of actuators for each ear, nose and throat delivery, suitable for regulated and low regulated markets.

The dermal application is a convenient non-invasive way to administer lotions, gels or creams to the skin. Our devices deliver precise and consistent dosing with our metered-dose atmospheric or airless delivery systems for Rx and OTC formulations.

With long-standing know-how in inhalation delivery, we are today the leader in the dry powder inhalers (DPIs) manufacturing business. Our expertise covers dry powder inhalers (reservoir, blister pre-metered multi-dose, capsule) but also dose indicators and actuators for pressurised metered-dose inhalers (pMDIs).

Q3: With proven know-how of the combination products ecosystem, Nemera provides an end-to-end offering, to support its customers’ device strategy. Could you please tell us more about that?

Successful combination product development revolves around critical patient insights, robust device strategy and targeted selection plan. We urge our customers to look at the larger ecosystem that must be considered to ensure optimal success. On the one hand, healthcare professionals, health systems, payers for value-based care and on the other hand, regulators for market access and the intended filing approach.

The latter can significantly impact device

selection and development strategies. These factors then need to be considered within the available or emerging technology landscape. This broader understanding is critical in meeting the needs of patients and can impact how technology may be selected, as well as early considerations around the impact of the other aspects of the ecosystem in development initiatives.

We believe that success will come from addressing these factors both strategically and tactically. Once we have gained visibility into what the patient and stakeholder needs are, developers should consider how to best satisfy those needs as holistically as possible while continuing to work with patients and clinical stakeholders prior to new product development processes. This requires synthesising the patient and stakeholder information with other ecosystem inputs into a device strategy roadmap, which can be utilised in several ways to make device selection decisions. We believe a partner like Nemera with strong IP platforms, development services, and manufacturing capability allows customers to achieve the outcome of a successful regulatory submission and commercial launch of safe, effective, and differentiated combination products with a single partner who can manage all the aspects critical for success.

Q4: An effective drug-delivery device can be life-changing for patients needing continuous medication, but it is important to verify devices’ usability and effectiveness. What experience have you had in the design and verification and what can you highlight for our readers about the challenges and learnings along the way?

At Nemera, whilst supporting our customers' combination product journey, we ensure that requirements are established properly, and device function is verified at the appropriate levels throughout each step of the development, clinical supply, industrialisation and commercial manufacturing processes.

Patients with chronic conditions have to become independent with their treatment Spring 2021 Volume 13 Issue 1

Talking Point administration. This is why, at Nemera, we must ensure that every device we develop is user-friendly and highly performant.

Combining design research and human factors, our goal is to deliver highly patient-centric solutions that encourage adherence and provide better clinical outcomes, improving devices’ practicality, functionality, and efficiency. This focus during development makes a real difference in supporting users along every stage of the patient journey.

Q5: Could you explain the importance of the human factors in the development process of an effective device?

Human factors are critical, and we think that it is also closely linked to user experience differentiation. It is critical that human factors and patient experience activities are integrated for a successful drug-device combination product development process.

It’s incumbent on us to ensure that the selected device, in combination with drug, is appropriate, safe and effective for the target population. This also extends to optimising

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the patient experience to create competitive differentiation and to ensure adherence and engagement with patients and clinical stakeholders.

only satisfy regulatory requirements but lead to the development of safe, effective, and differentiated combination products.

A good example of this approach might consider our pen injectors or large volume wearable concept under development.

These devices are going to be of interest to customers in the biologic, biosimilar or generic markets, where in many cases competitors are targeting the same reference drug or devices, and differentiation wherever possible is critical.

Q6: The drive to enhance biologic therapies through more convenient delivery methods is creating dealmaking opportunities for companies with innovative delivery technologies.

How does Nemera support organisations in this quest? Further to that point, self-administration is also a growing trend. What do you think are the key challenges in successful drug delivery and patient self-administration, considering that poor patient adherence is one of the main reasons for the ineffectiveness of a treatment?

What contributions have you made to drug-delivery technologies which will help to reduce patient burden?

We need to be sure that we are addressing the defined user groups/populations and early use-related risk analysis activities to define the human factors and usability programme necessary for the intended regulatory/filing strategy. We also need to identify clinical risks through conducting formative and summative usability testing globally for all aspects of the device, and supporting assets in alignment with the human factors programme definition through human factors engineering report documentation for use in regulatory submissions. Human factors processes not

We believe at the earliest stages of establishing the functional requirements and user needs for a new device application, it is critical to fully understand the patient journey as well any related clinical

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Talking Point assessing the technology landscape to identify existing IP or platforms that may be fit for the intended purposes related to function and drug product attributes.

This includes decisions around modality such as auto-injector versus wearable injector, as well as variations within, if considering existing IP platforms. This includes ‘surrounding the device’ with custom support materials such as training programmes, instructions for use, and other means of engagement. At Nemera, we can offer customers both a variety of patientcentric IP platforms as well as custom development services to meet these needs.

processes to ensure every decision we make is considering their needs first. This is very focused on adherence and to integrate new technologies into therapeutic areas. This foundation gained through understanding both this journey and interactions with the healthcare system and healthcare provider experience enables us to capture the complete process patients go through in managing their disease – both from a self-administration standpoint and from a longitudinal perspective – as they progress with their condition and treatment through the healthcare system and life stages​.

Our team of design research experts does this by primarily utilising a technique called applied ethnography. This method relies on a combination of interviews and incontext observations of practices, processes and experiences within the patient’s home or actual use environment. At this stage, potential use cases are looked at broadly, that is beyond the administration event or solely complying with instructions for use as you might see in a human factors study. This can potentially start from when a patient is first diagnosed, to receiving their device, through the entire process of preparing, administering, and disposal and the times in between treatment so we can understand how that process changes over time, and how frequency of administration may impact the patient experience. This www.ipimediaworld.com

gives the most natural view of the patient experience as related to their environment, social/emotional contexts and all the other factors that influence use. It is equally important to gain an understanding of the experience of healthcare professionals as well as to consider this in relevant settings in clinical environments. This is of particular importance in applications where care is being provided in both in-home and clinical environments as well as a migration of care, such as an oncology ward, which has built in support systems to an environment of selfadministration, where clinical personnel are not present and the burden of support falls to a family member or caregiver. These cases are oftentimes driven by a migration in drug-delivery modality such as from IV to self-administered SC injection, and driven by the proliferation of biologics.

The outputs from this work include patient journey maps, clinical process maps, a robust understanding of prioritised user needs and values, and identification of pain points that can be leveraged into possibilities for improving the patient and provider experience across all aspects of the journey to make a significant impact on their lives beyond medication delivery.

This allows us to consider how to best satisfy those needs as holistically as possible while making decisions around

Q7: Nasal delivery is the logical choice for topical treatment of local diseases in the nose and paranasal sinuses such as allergic and non-allergic rhinitis and sinusitis. New and emerging delivery technologies and devices with emphasis on bi-directional delivery, a novel concept for nasal delivery that can be adapted to a variety of dispersion technologies, are being developed. How does Nemera support these technologies?

As explained by Pascale Farjas, Nemera’s Global Category Manager for Ear, Nose, Throat delivery, nasal drug delivery is a non-invasive method that allows for a rapid, high and local therapeutic effect. It offers significant opportunities for new drug development looking to deliver systemic drugs, vaccines and treatments for the central nervous system. The number of applications using the nasal route for local and systemic treatments is on the rise.

The clinical efficacy of a nasal treatment depends on how it is deposited in the nose. Since the pharmaceutical target (local, systemic, brain) is directly related to a specific nasal anatomical site, it is becoming increasingly important for device manufacturing experts to support new drug development in this area, while fostering patient adherence (i.e. easy-to-use and intuitive devices). We understand how vital it is to continue exploring customised solutions for nasal delivery treatments to address unmet medical needs. This is why we worked on a new concept, called RetroNose, to target nasal disorders through the oral cavity.

Four years ago, we initiated a collaboration with the Research Center for INTERNATIONAL PHARMACEUTICAL INDUSTRY 10

Talking Point Respiratory Diseases (CEPR) of Inserm and the University of Tours (France) to develop a different and portable delivery technology called RetroNose. CEPR’s know-how in respiratory preclinical and clinical research joined forces with Nemera’s expertise in the development of drug-delivery devices for a powerful partnership. The resulting technology, RetroNose, enables better drug deposition in the distal region of the nose without lung deposition.

RetroNose is a completely new drugdelivery device concept to dispense drug formulation to the nasal cavity. The principle of this concept is to deliver a spray through the oral cavity to deposit the drug in the nasal cavity from rear to front. The RetroNose pMDI concept involves device operation steps similar to breath-actuated pMDIs. It triggers positive pressure in the mouth from nasal expiration, possibly through mechanics or electronics. The first outcomes of our collaboration with CEPR were presented in 2018, demonstrating the advantages of RetroNose. The results show improved particle deposition in an upper airways model, which could be suitable for local, vaccine and systemic drugs delivery.

Spray triggering upon positive pressure in the mouth appears to be a promising path to ensure drug delivery in the nasal expiratory phase. In the future, a potential next step would be to test the clinical efficacy of RetroNose and its acceptance by patients through the human factors perspective.

Q8: You have a product called Novelia, your multi-dose closing tip system.

Could you explain this innovative product, and the popularity behind it?

As explained by Zoe Davidson, Nemera’s Global Category Manager for Ophthalmic delivery, eye drops are primarily used for glaucoma, dry eye disease (DED), conjunctivitis and allergy. For chronic diseases, when daily treatments are needed, preservative-free formulations are key to protecting the patient’s ocular surface, as preservatives can cause allergic reactions and irritations, and can even damage patients’ eyes. Thus, preservative-free formulations are needed for glaucoma and DED. At present, two options are available for dispensing preservative-free ophthalmic www.ipimediaworld.com

formulations: unit-dose systems or preservative-free, multi-dose systems. Unit-doses are generally considered to be not patientfriendly, and are often costly and bulky, making them unsuitable for home use for chronic conditions.

Therefore, in order to improve patient compliance and limit waste, the preferable solution is to use preservative-free formulations with the convenience of a multi-dose bottle.

This is why we developed Novelia®, a multi-dose eye-dropper delivering consistent drops for better patient adherence, designed and developed with patients in mind.

To prevent the entry of bacteria into the bottle and/or to filter air, more than half of bottles designed for multidose preservative-free eye drops on the market rely on a filtering system. As significant research has been carried out that challenges their effectiveness, we developed an alternative to filters: a nonreturn valve system used in conjunction with a silicone membrane to filter the returning air. The non-return valve ensures that no contaminated liquid can be re-introduced to the container after the drop has been dispensed – completely removing the need to filter the liquid. The intake of air into the Novelia dispenser takes place via a separate venting system with a silicone membrane called PureFlow® Technology.

Novelia’s PureFlow® has a double function: venting system for air diffusion into the bottle and flow control. Nemera has adapted the flow-control technology within Novelia that avoids multiple drop delivery into the eye and ensures that only one calibrated drop is dispensed at a time.

Nemera offers three different PureFlow® versions, each tailored to formulations of differing viscosities, from highly liquid to highly viscous.

Four user studies have been conducted between 2009 and 2018 with a total of 230 people interviewed (120 in Europe / 110 in the US) including senior users with chronic eye disease. These tests concluded that 76% of patients interviewed preferred Novelia over other similar devices on the market.

Contributing factors to Novelia preference included the intuitiveness of the screw-on cap and the associated reassurance, and the squeeze force required towards the end of the product’s life. Novelia required only 6%

more pressure to squeeze the bottle from the beginning to the end of the treatment, compared with 35% for the other device.

Also, 43% of patients think that Novelia® would enhance compliance over their current treatment.

One example of the importance of our user tests during the development phase is the choice of the blue tip of Novelia®.

Originally intended to be transparent, Novelia’s patented blue tip was the result of a previous user study, during the development phase. One test revealed that some patients had difficulties seeing where the drop was coming from as it emerged from the dropper. This was because the dropper valve was transparent and thus hindered patients when targeting the eye.

Consequently, the valve was changed from transparent to blue, providing an obvious contrast between the dropper tip and the rest of the top. Novelia’s patented blue tip continues to be a key driver of patient preference for the dropper, allowing for enhanced eye targeting and patient control.

Today, the Novelia® platform includes a broad range of configurations to handle different ophthalmic formulations and is used by patients all over the world for packaging of medical devices, and both overthe-counter and prescription products. For instance, Novelia® was the first multi-dose eye-dropper approved for Rx preservativefree formulations in Europe.

Mark Tunkel Mark Tunkel is Global Category Director, Services at Nemera. He was previously a partner at Insight Product Development, which was acquired by Nemera in 2019 and became the Insight Innovation Center. With more than 20 years of global business development experience and a deep understanding of the marketplace challenges and trends impacting the pharma industry, Mr. Tunkel has advised many of the world’s leading companies on their product development and innovation strategies, with an emphasis on driving realization and the most favorable business outcomes.

Email: mark.tunkel@nemera.net

INTERNATIONAL PHARMACEUTICAL INDUSTRY 11

Talking Point

Respiratory Drug Development – Perspective from Spray and Aerosol Characterisation Expert Dino Farina, Founder and CEO of Proveris Scientific Q1: Who is Proveris Scientific and how do you fit into the landscape of respiratory drug development?

Since our founding more than 25 years ago, Proveris Scientific® has striven to help our customers develop optimallyperforming orally inhaled and nasal drug products (OINDPs) for patients around the world. We do this by delivering innovative testing platforms, laboratory services, and deep product knowledge to customers who develop, manufacture, or test OINDPs. As experts in spray and aerosol characterisation, we are perhaps best known for our flagship SprayVIEW® measurement system. The SprayVIEW system is designed to be an allin-one testing platform that has become the industry standard for measuring and analysing the spray pattern and plume geometry produced by spray- and aerosolgenerating devices. Both measurements are critical quality attributes (CQAs), indicative of the performance of combination drug products and sensitive to minute changes in device design and drug formulation, and patient usage as well.

These systems have been validated and are critical tools in both development

and production environments at leading pharmaceutical companies, CDO/CMO/ CROs, device manufacturers, and regulatory agencies around the world. At the core of the SprayVIEW system are our line of Vereo® automated actuators, which allow for repeatable and controlled actuation of drug delivery devices including multi- and unit-dose nasal sprays, pressurised metered dose inhalers, and soft mist inhaler designs commonly incorporated in respiratory drug delivery devices. Human-realistic automated actuation has been suggested by regulatory agencies around the world as a key factor to decrease variability in drug delivery due to operator factors, thereby increasing the sensitivity for detecting potential differences between products in common in vitro tests.

Q2: In terms of contract services, what types of projects has Proveris Laboratories historically served?

OINDP development is driven by the needs of specific disease management such as: respiratory/lung diseases (e.g., allergies, asthma, and chronic obstructive pulmonary disease); central nervous system and neurodegenerative diseases (e.g., epilepsy, Alzheimer’s); pain management (e.g., cancer,

migraine); rescue treatments (e.g., seizures, drug overdose reversal); and more recently vaccine delivery. In general, inhalation and intranasal drug delivery offers a more targeted and accessible delivery route, thereby eliminating systemic exposure to the drug in question. This can be one of the reasons for choosing these delivery methods, as opposed to more common ones, such as oral tablets or injectables.

Traditionally, Proveris Laboratories, the CRO division of Provers Scientific, has been involved in helping customers develop and release combination drug products from the aspect of device characterisation and in vitro testing method optimisation. Our Proveris by Design™ approach helps our customers to unlock the complex relationships between formulation, device, and human usage. Very often we will start a customer project with an ergonomic hand study. This evaluates a customer’s device candidates (in some cases also an existing reference product if the project in question is a generic drug development project). With the utilisation of our patented Ergo™ technology, the corresponding velocity and acceleration profiles are measured. These parameters determine the optimum characteristics to properly actuate the devices according to the targeted patient populations.

Full characterisation services on the products in question can be provided using this information in conjunction with our Vereo automated actuator technology.

Common in vitro tests involved in these characterisation studies include those listed in Table 1.

Q3: What major events have occurred within your industry and what effects have they had overall?

Proveris SprayVIEW measurement system is the industry standard for measuring and analysing the spray pattern and plume geometry produced by spray and aerosol devices. In addition, it offers users the ability to do bioequivalence studies and perform new measurements, such as plume front velocity and evaporation fraction.

12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

A3: During the 25 years of working with a wide variety of companies, we have seen developments in all major categories of inhaler and intranasal drug products. In the early 1990s, much of the innovation was driven by the ban on ozone-depleting chlorofluorocarbon (CFC) propellants and the switch to hydrofluoroalkanes (HFA). This Spring 2021 Volume 13 Issue 1

Talking Point the coronavirus pandemic is driving R&D for SARS-CoV-2 preventatives, therapeutics, and vaccines delivered via inhalers and intranasal delivery methods.

Table 1

event injected a spark of innovation into the field of OINDPs, leading to the development of a new generation of pressurised metered dose inhalers (pMDIs) using HFA formulations, as well as technological advancements across all other major device types. These advancements include: new dry powder inhalers (DPIs) that required no propellant but instead rely on a quick, deep inhalation to draw the drug into the lungs or nasal passage; soft mist inhalers (SMIs) that require no propellant but instead use the mechanical force of a spring to turn a solution of medication into an aerosol; nasal

atomisers for nose-to-brain (N2B) delivery; and the development of vibrating mesh systems in nebuliser technology.

Another event that has had a major impact and caused our healthcare system to adapt is the opioid crisis. An urgent need for drug overdose rescue drugs led to the development and US FDA approval of singledose nasal spray NARCAN® in 2015, and the first generic naloxone nasal spray four years later in 2019. New device types were developed for this type of drug which are now referred to as unit-dose devices. Today,

Different configurations of Vereo Automated Actuators: (from left to right) SFMDx for pMDIs; NSx for nasal/oral sprays; DSx for dual-sided sprays and SSx for side-actuated nasal sprays. Vereo actuators are designed to model human-usage of orally inhaled and nasal drug products, ensuring precise control of important actuation parameters, including force limit, position, velocity, acceleration, and timing. Together with Viota software, the systems generate data to help evaluate device performance, and let drug developers investigate position and force profiles for each actuation. www.ipimediaworld.com

Finally, regulatory agencies are working to reduce barriers to generic development and to lower the cost of generic entry into the marketplace, spurring an increase in options for patients. The US FDA, for example, has been pushing for increased generic competition as one means of lowering prescription drug prices. As novel products are introduced and technological advancements occur, new and updated regulatory guidance documents are published to accommodate this effort. In the United States there are 40-plus new or updated guidance documents. In Europe, the European Medicines Agency works with the European Directorate for the Quality of Medicines on matters aimed at ensuring the quality of medicines and protection of public health. The European Pharmacopoeia 10th Edition (2019) Monographs provides guidance for nasal and inhalation products to the Council of Europe’s 38 Member States, of which six are European countries and 22 are non-European countries.

Q4: What role do Proveris Scientific instruments and services play in assisting your clients on their journey to commercial success?

We engage with companies from early product development through to commercial release with our wide array of products and services. Following the drug development process outlined by the US FDA, step 1 is described as the discovery and development phase. Late in this stage, companies are assessing delivery options for their drugs.

If evaluating orally inhaled and nasal drug products as an effective route, Proveris can provide a wide array of instrumentation and test services depending on the device type. Common test services include device characterisation, formulation screening, and hand studies. At step 2, safety and toxicity assessment, we help our clients establish a baseline performance for their products in our cGMP-compliant laboratory which is equipped for in vitro testing to support pilot-scale batch testing. Customers will use our advanced characterisation tools and capability for a wide range of in vitro testing to make key adjustments and decisions on things like formulation and device design before entering the clinical phase INTERNATIONAL PHARMACEUTICAL INDUSTRY 13

Talking Point (if necessary). Our tools allow customers to assess their products accurately in vitro and bridge the gap between in vitro and in vivo – a significant goal, especially in the development of a generic drug. Moving into step 3, clinical research phase, we have technologies to help with clinical end-point studies that are needed for product approval.

After step 4, FDA review, customers will move into step 5, post-market safety monitoring. It is in this phase when customers will utilise our core instruments, such as our SprayVIEW measurement system, Vereo automated actuators, Kinaero™ high-throughput firedown system, Indizo® automated collection system, and Viota® software to enable them to scale up their manufacturing with stability testing and QC batch release testing that is required from a post-market approval perspective.

Q5: Pharma, higher education, and focused industry groups are fully engaged in the pursuit for solutions to combat COVID. Can you briefly describe the projects you are seeing related to this effort?

In early April 2020, we began a collaboration with Mass General Brigham (MGB) Center for COVID Innovation in Boston, Massachusetts USA on a respirator mask project. The MGB

Proveris Scientific’s INVIDA platform is an example of an offering that helps clients bridge the gap between in vivo and in vitro by providing a human-realistic model of the human respiratory tract. Proveris can tailor custom studies to offer clients a visualisation of the drug as it moves through the throat, as well as quantified deposition of the dose in order to study where the drug is reaching.

COVID Innovation Group (covidinnovation. partners.org) is a partnership of Massachusetts General Hospital and Brigham and Women’s Hospital, two of the world’s most prestigious hospitals and research institutes, known for their teaching and training association with Harvard University’s School of Medicine.

MGB is working with Proveris to provide testing and feedback on our respirator mask designs. In addition, we have projects with research and development groups for nasal spray prophylactic therapy to prevent people from getting coronavirus, again leveraging our core competence in nasal spray, particle capture, and so forth, just now using them in the reverse. We

have also had several companies come to us for contract test services through our cGMP-compliant laboratory for device characterisation work on intranasal vaccine candidates for COVID-19. After the release of the major vaccines currently available (Pfizer, Moderna, AstraZeneca, etc.), we believe you will see a next wave of approvals for different delivery methods, including ones in the inhaled and nasal delivery spaces. These types of innovations will help lessen the burden on distribution and administration of the vaccine which will be key in certain populations and rural areas. So, while the coronavirus pandemic has been a horrible thing to have to deal with, the staff at Proveris are fortunate to be among the frontline effort to help in the fight. We are proud to take on a mission as large as this one and include it in our core values for the organisation.

Dino Farina

The Kinaero high-throughput fire-down system ensures reproducible actuation throughout pMDI product life testing. It offers programmable shaking angle, frequency, duration, and inter-actuation delay along with multiple modes of actuation (force, position, or time-based) for flexibility during automated fire down. Universal cassettes allow for variability in different device dimensions and unique design features offering maximum versatility to accommodate future devices 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Dino Farina is a business owner and inventor. His expertise is in optical measurements of fluid flow, experiment design, analysis, and pharmaceutical regulatory science. He is the named inventor on over 40 US and international patents. He holds two master of mechanical engineering degrees from Stanford University, and is the recipient of the prestigious NASA Student Fellowship grant to study advanced fluid dynamics at the NASAAmes Research Center in Mountain View, California.

Spring 2021 Volume 13 Issue 1

YOUR PARTNER…

FROM DEVELOPMENT TO COMMERCIALIZATION

Scientific expertise and testing strategies for innovator and generic OINDPs • Human Usage Studies

• In Vitro Testing

• Batch Release Testing

• Device Selection

• Drug Product Characterization Studies

• Long-term Stability Testing

• Formulation Screening

• Priming/Repriming

• Root Cause Analysis

• Temperature Cycling

• OOS/OOT Investigation

Alternative BE Studies • Regional Drug Deposition • Plume Velocity

• Device Robustness • Stability Studies

• Evaporation Fraction

G TURIN TORY A E F A NOW LABOR T N A I COMPL

cGMP www.ipimediaworld.com

LEARN MORE: www.proveris.com contactus@proveris.com INTERNATIONAL PHARMACEUTICAL INDUSTRY 15 +1 508 460-8822

Regulatory & Marketplace

Marketing Medical Cannabis in Europe

Major global cannabis exporters cannot tap into a common regulatory pathway to European markets. Cannabis is a massive opportunity, but marketing cannabis products in the diverse European market is a complex challenge, writes Arriello Director of Drug Safety Peter Kohut.

Medical cannabis has shown efficacy in trials and is being deployed legally in medical settings as a therapeutic for conditions ranging from palliative care for cancer to appetite stimulant in patients with AIDS-related wasting syndrome. Yet, there is considerable variation in regulatory approach between European countries.

Across Europe, some countries allow the use of medicinal products containing cannabinoids, while others allow the medical use of unauthorised products or preparations. Some have standalone medical cannabis programmes. Some countries allow cannabis product manufacture. Others do not allow manufacture but do permit cannabis import, while in other countries you can do both.

Even the definition of ‘medical cannabis’ is not fully agreed and terminology has grey areas. CBD is a chemical substance found in cannabis that has medical benefits. It is the key ingredient of approved medical cannabis drugs for children and adults with a rare form of epilepsy. CBD oils and supplements are also offered to consumers over the counter, but the efficacy of weaker consumer preparations is unproven.

Cannabidiol (CBD) is one of 113 identified cannabinoids in cannabis plants and accounts for up to 40% of the plant’s extract.

Clinical research on CBD includes studies related to anxiety, cognition, movement disorders, and pain. CBD does not have the same psychoactivity as THC, the primary ingredient in cannabis that “gets you high”.

Tackling the Challenge There is a pressing need to have clear policies and regulations and harmonisation across territories. Until that happens, 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

European markets present a challenge.

The first step in tackling that challenge is recognising that European countries fall into three broad groups when it comes to their legal framework for medical cannabis. Some countries, including the UK, the Netherlands, Poland and Portugal, have well-established medical cannabis legislation.

In many of these countries, the relevant legislation is quite recent. The government of Greece approved the legalisation of cannabis for medical use as recently as 2018, the same year as the UK, while Germany made it legal for doctors to prescribe medical cannabis in 2017.

Cyprus is governed by the Medical Cannabis Law 2019, which states: “Patients will be supplied with medicinal cannabis by pharmacies upon presentation of a prescription from a specialist physician. This process ensures that patients will receive quality cannabis, under the supervision of a specialist, avoiding the need to obtain cannabis of dubious quality from the illegal market.”

In these countries, the use of medical cannabis is clearly provided for under law and pharmacovigilance regulations relating to medical cannabis are the same as for medicinal products. That means patient safety is the same as for any other drug and the same measures can be taken to identify and deal with counterfeit drugs.

In other countries, including Sweden, Latvia, Belgium and Albania, medical cannabis is strictly prohibited. It is illegal to use, buy or sell cannabis. At the present time, there are no routes to market medical cannabis into those countries.

Somewhere in the middle are countries that permit the supply of specific cannabis products under specific conditions. These include countries with trial period or pilots underway examining the possibilities for the use of medical cannabis. In these countries there are opportunities to market medical cannabis, with care.

Some countries allow importation and/ or use of medical cannabis at the discretion

of physicians, usually relating to specific treatment for a named patient. In Croatia, for example, there is just one cannabis medicinal product registered containing cannabidiol (Epidyolex). The only way to register cannabis there is through an imported licence.

France, Ireland and Denmark are running trial periods for medical cannabis, while in Finland only Sativex (an oromucosal spray) is available on prescription, for patients with MS. CBD may be prescribed for other conditions, decided on a case-by-case basis by the Finnish Medicines Agency (FIMEA). A prescription can only be issued by a neurological expert (or doctors in a neurological clinic) and is viewed as a ‘last resort’ if the patient hasn’t responded to other medication.

Narcotics Licences While some countries have specific regulations relating to medical cannabis, in others, products that contain cannabinoids that do not have any formal authorisation as medicinal products, may have a narcotics licence, as they do in Germany, for example. Similar narcotics legislations in other countries may provide life sciences companies with a route into these markets.

Clearing the Hurdles In European countries that do allow medical cannabis, whether in established law or in pilot projects, there is a further issue relating to the form of preparation allowed. Medical cannabis may be supplied in oils, capsules, as dried plants or a liquid solution. On top of that, there is a lack of standardisation in the manufacturing of medical cannabis products, their ingredients and labelling.

There are further questions about how to get medical cannabis into the hands of patients. In target countries, is access to medical cannabis products prescriptionbased or is OTC provision likely for some formulations.? Will prescriptions be limited or not? Will prescriptions be reimbursed by the government or insurance companies?

The answers to these questions are all key to building a business case for marketing medical cannabis into individual territories.

Spring 2021 Volume 13 Issue 1

Regulatory & Marketplace

There is little consistency across Europe relating to when medical cannabis may be used as medicinal products – and for which patient conditions. Clinical trials are showing good results for many conditions but there is only Europe-wide approval

for one medicinal cannabis product. The European Medicines Agency granted Orphan designation to UK-based GW Pharma for Epidiolex (cannabidiol) for the treatment of Dravet syndrome, and Lennox-Gastaut syndrome, rare and severe forms of epilepsy.

The European medical cannabis market is complex. But this complexity is not a barrier to entry to a market that is becoming increasingly attractive to major pharma players. Now is the time to grasp the nettle and get ahead of the competition.

Peter Kohut Peter Kohut is Director of Drug Safety at Arriello and an experienced EU QPPV. He began his career in biochemical research, before entering the pharmaceutical industry where he has worked in clinical trials and post-marketing safety roles. Arriello is a global provider of innovative, highimpact market access, regulatory affairs & pharmacovigilance solutions and services for pharma and biotech firms primarily in Europe and North America.

Email: peter.kohut@arriello.com

www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 17

Regulatory & Marketplace

EU MDR Changes are Only the Beginning – Ensure IFU Compliance Now and Be Prepared for More to Come Despite the delay of EU MDR into May 2021, some organisations are still burning valuable time in terms of updating the labelling and instructions for use (IFUs) of their medical devices.

Here, Bob Tilling, VP Global Sales at Kallik, shares his experience from recent customer projects and explains how medical device manufacturers can recover lost time in preparing for EU MDR labelling and IFU compliance – and make sure they are better positioned for other regulations which are bound to follow.

Certain industry commentators have suggested that the one-year delay in new EU MDR rules has helped buy medical device manufacturers enough time to ‘fix’ issues with their enterprise labelling. But despite buying them more time, the delay has not changed the scale of the task at hand.

The new MDR regulations are four times longer and contain five more annexes than the EU Medical Devices Directive (MDD) and will require most medical device manufacturers to update their clinical data, technical documentation and labelling. Many device manufacturers have miscalculated the scale of the task. Initial estimates of Class III device labels and IFUs have typically been out by a factor of three or more – 100 IFUs and 2000 labels have become 300 and 6000 respectively. Ensuring compliance across labels, cartons and IFUs for every single device adds another dimension. Once extrapolated out across Class II and Class I devices, then both the second and third waves of EU MDR start to look alarming.

Even those organisations that have emerged from the maze of Class III device labelling realise they require a better map next time. Others who are yet to start their EU MDR change project face many blind alleys. Once the labelling is done, IFUs are up next and also for some, patient implant cards. Some manufacturers have started to recover lost ground on labels and are now getting to grips with the challenge of addressing IFUs. But worryingly, others are still burying their heads in the sand.

18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The IFU Problem Defined A mid-sized device manufacturer may have anything from 100 to over 1000 IFUs across their product line. Rewriting these contentheavy documents in a style appropriate for the user, adding new symbology and statements, plus translating into languages for 20+ EU countries makes the task of updating these to comply with EU MDR larger than first anticipated.

But there’s also a disconnect to bridge between labels and IFUs – where little, if any, upstream alignment exists. Often, the first time labels and IFUs come together is at the point of packaging and shipping, not the ideal time or place to be checking for consistency. IFUs also tend to be owned by artwork teams rather than labelling teams and don’t change as regularly, limiting capacity for wholesale changes. Where IFU artworks are outsourced, there is the added risk that agencies lack resources to manage the changes in required timescales – if they actually comprehend exactly what is required.

There are important IFU distinctions for those manufacturers that also sell products outside the EU. Content from translation agencies will also need to be included, followed by several internal review and approval cycles before going to print.

PLM Will Not Bail Out Medical Device Manufacturers – and there are Lengthy Labelling Lessons to be Learned Product lifecycle management (PLM) does not provide the silver bullet to EU MDR compliance. There may be multiple production variants of a single label stored in PLM software resulting from the need for localised content, different pack sizes and varying production data. Geographically dispersed factories operating a variety of labelling software solutions make it impossible to gain a single view of these variants. Additionally, IFUs arriving via a different route into goods inwards may bypass PLM systems entirely. Despite regulatory departments being responsible for what goes on the labels, they may not have sight of the finished goods, being left to rely on the efficacy of less qualified colleagues.

Some organisations are making headway transitioning from MDD to MDR from a labelling perspective. Some device manufacturers are approaching MDR as an opportunity for business transformation, while others have tried to force feed change into already broken processes. Already reaching breaking-point for Class III, these processes won’t scale for Class II and Class I devices. Many are quickly learning it takes much longer than forecasted – taking three months to locate all the impacted labels, six months to complete the change cycle followed by three months of print and publishing lead-times – equivalent to one year of elapsed time plus another three months to achieve certification.

The timescale could be even longer for extensive IFU documents. The worst-case scenario is that some devices might not ship, disrupting global healthcare supply chains, revenues and shareholder confidence.

Cloud-based Labelling and Artwork Management Software brings Medical Device Manufacturers into the Future This is where cloud-based artwork and labelling management software helps quicken the EU MDR migration. In a fraction of the time taken by labelling teams to extract content from legacy systems, a cloud-based solution can be operational and ready to recoup lost time. Bringing all labelling and IFU content together in a single solution that fully integrates with localised print facilities and third-party agencies enables globally dispersed teams to operate from a single source of truth.

By removing siloes of information and automated manual processes, they also guarantee safety and security with full traceability and accountability.

Advanced software tools and techniques reduce the number of label and IFU template variants, minimising risk of errors and noncompliances from misinterpretation – and shortening creation and review cycles. In the context of MDR, finding impacted labels, updating content, designing new label and IFU layouts, managing translations and demonstrating 21 CFR Part 11 compliance starts and finishes with cloud-based artwork and labelling management software.

Spring 2021 Volume 13 Issue 1

Regulatory & Marketplace Case in Point – Artwork Management and Labelling Software Delivers Quantifiable Benefits Mid-sized Class III device manufacturers producing approximately 350 IFUs typically forecast over 3500 hours to achieve readiness for EU MDR certification, based on current systems and processes.

This is where introducing centralised management solutions with a degree of automation can begin generating time and cost efficiencies. For example, creation of multiple language EU MDR compliant 30page IFUs can be cut from 3–5 hours to under 40 minutes, and individual label generation can be reduced from one hour to around 10 minutes. With 350 IFUs and 10,000 labels, that recovers five person years of time just for Class III devices alone, freeing up resources to start preparing for Class II compliance.

out in the UK, will need to carry a new UKNI marking. Every impacted label will need to be identified, updated and approved. Other countries including China and Australia are also implementing requirements similar to EU MDR. Volumes of Class II and Class I device labelling and IFU changes will have an

overwhelming impact on organisations that fail to embrace change and a move towards technology-based solutions. Lost time can still be recovered, but only if organisations act now. Delaying action and investment until the second wave of EU MDR hits is certain to result in major disruption, lost revenue and potentially serious consumer harm.

When external agencies are engaged, economies increase further. Translated text and phrases can be stored and reused.

Streaming label and IFU layouts and content directly into InDesign also minimises the number of design studio iterations. Applying business rules logic to pre-populated label templates for locale-specific variants reduces error-prone repetitive tasks and minimises dependence on tribal knowledge.

Avoid Side-effects of Non-compliance – Now and Into the Future More labelling changes are on the horizon beyond EU MDR. Brexit requires all devices shipped to the UK after June 2023 to carry a UKCA marking. Moreover, products shipped to Northern Ireland from 1 January 2021 where conformity assessments are carried

Bob Tilling Bob Tilling is the Head of Global Sales at Kallik, an enterprise labelling and artwork management company. He has a wealth of knowledge when it comes to the life sciences industry, particularly regarding medical devices.

Bob helps businesses in highly regulated industries begin their journey of transforming their labelling and artwork management.

Email: bob.tilling@kallik.com

www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 19

Regulatory & Marketplace

Can the UK Solve its ‘Money Laundering’ Problem with the Proceeds of Medicinal Cannabis?

The manufacture, marketing and supply of medicinal cannabis products raise complex regulatory issues in the jurisdiction where those activities take place. These go beyond the issues applicable to medicines in general, even some whose potential harms are far greater, due to the cultural and moral judgements that have been applied to cannabis for many years. Inevitably, there is a large and growing variation in the level and nature of regulation that applies in various jurisdictions, with some countries having gone as far as to legalise cannabis in general (including for recreational use), and others being slow even to allow medicinal products in which cannabis is an ingredient.

A Restrictive Environment The UK is, broadly speaking, at the more conservative end of that spectrum for the moment, allowing some bespoke and restrictive exceptions for medicinal cannabis products, while keeping its general prohibition in place. Just as important, however, given its importance as a global financial centre, is its regulatory approach to those who invest and trade in the shares of overseas businesses that sell cannabis products. There, thanks to a quirk in its notoriously restrictive money laundering laws, the UK has cast a dark and discouraging shadow over the prospects for major investment in the medicinal cannabis industry. Now, however, an announcement from its Financial Conduct Authority (FCA) has hinted at a potential way forward, and at the time of writing, the first listing of a cannabis company on the London Stock Exchange has taken place, with several other following closely behind.

The starting point for the UK, as for many countries, is that cannabis, and certain derivatives of cannabis such as THC, are controlled drugs, so that various actions in relation to them (including possession, supply, import, export, and cultivation of the cannabis plant) are criminal offences, punishable with imprisonment, unless done in accordance with licences. The primary legislation, which creates the offences, is 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the Misuse of Drugs Act 1971 (MDA), while the detail of licensing arrangements is contained in secondary legislation, including the Misuse of Drugs Regulations 2001 (MDRs), and in guidance issued by a division of the Home Office, the Drugs and Firearms Licensing Unit (DFLU). It is by way of changes to the MDRs and the guidance that the approach to medicinal cannabis has changed over recent years, as attitudes towards the therapeutic value of cannabis have become more favourable.

The POCA Problem The problem with the UK’s money laundering laws, and how they apply to the proceeds of overseas cannabis business, comes from the provisions of the Proceeds of Crime Act 2002 (POCA), which prohibit as ‘money laundering’ virtually any dealings with the proceeds of ‘criminal conduct’, and go on to define that term to include conduct overseas that would breach UK law, if it occurred here. There are exceptions where that conduct was lawful where it occurred, but these have been disapplied for most offences that carry a maximum penalty of over 12 months’ imprisonment, which include the principal offences under the MDA. So, taking the MDA and POCA together, it would seem that to deal with the proceeds of (even lawful) cannabis products overseas would constitute money laundering under UK law.

This has all sorts of impacts beyond the merely theoretical (the prospect of a

UK investor in Canadian cannabis being arrested, let alone prosecuted or convicted, for that conduct being very remote), principally because of the way the financial sector has been co-opted into the UK’s antimoney laundering (AML) systems. For a UK bank, the regulatory risks of operating an account that might contain the proceeds of ‘criminal conduct’ are severe, which in turn means that it can be strongly in their interests to rule out such risks by turning away customers, submitting covert reports on them to the NCA, or even freezing accounts.

Some banks have precautionary policies that prohibit the receipt of funds from (even purely medicinal) cannabis business.

A Pragmatic Approach In the few years since this issue first arose, some interesting grey areas have emerged.

First, because of the criminal liabilities that underpin the regulation of medicines in the UK, and the role of its Medicines and Healthcare products Regulatory Agency (MHRA), a pragmatic approach to the interaction of POCA and overseas medical products is needed. Applying a strict interpretation to the question of whether overseas manufacture, sale, brokering etc. of medicines breaches the Human Medicines Regulations 2012 (the HMRs) quickly runs into problems: because other jurisdictions’ regulatory schemes and authorities are different, there are myriad UK entities that handle the proceeds of selling medicinal products that do not strictly comply with the HMRs, and in which the MHRA has had Spring 2021 Volume 13 Issue 1

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Regulatory & Marketplace no involvement. Are they to be considered money launderers too?

A pragmatic approach to interpreting the relevant provisions of POCA, therefore, assists those dealing with the proceeds of selling products that, if not actually authorised here by the MHRA, would be so but for the difference in their location, and have been rendered lawful by means of an equivalent regulatory process somewhere else. That could include, for instance, a UK shareholder in a US business that manufactured and sold branded overthe-counter painkillers, where there was an equivalent product in the UK that was regulated in the same way.

The need for pragmatism becomes more acute the further the overseas regulatory system differs from our own: if, for example, a product that in the UK was available only on prescription was sold over the counter in the US, it might be arguable that the proceeds of that sale would breach the provisions of POCA. (Unhelpfully, most of the offences in the HMRs carry maximum sentences above the 12-month threshold, so the exceptions for less serious conduct do not apply.)

The Change in Regulations Until recently, that pragmatism would have to be further stretched for virtually any medicinal cannabis product, there being virtually none that were in fact licensed and sold in the UK. That changed in 2018, with an amendment to the MDRs that introduced the concept of cannabis-based

22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

products for medicinal use (CBPMs), which are now available on prescription from an authorised consultant in certain very limited circumstances.

Conceivably, then, the argument under POCA for the proceeds of medicinal cannabis products is the same as for other medicines under the HMRs: assuming they are licensed in the jurisdiction where they are made and sold, the fact that they could in theory be prescribed as CBPMs in this jurisdiction would mean that their sale would not be ‘criminal conduct’. While this has yet to be tested in the courts, anecdotally, it would seem that many advisers and banks are relying on this argument to proceed with medicinal cannabis investments without making reports to the NCA. What About Cannabidiol (CBD)?

Another grey area in the treatment of cannabis products under UK law, including but not limited to POCA, is its approach to cannabidiol (CBD). As CBD is not itself listed in the MDA as a controlled drug, and provided (as is often claimed, but less often tested) it contains no measurable THC content, then no problems arise, under either the MDA or POCA. The problem, however, is that many jurisdictions have a de minimis percentage threshold for THC content, often set at 0.2%, below which the product is not treated as controlled. In the UK, though the 0.2% threshold is relevant to hemp cultivation licences, it does not (contrary to widespread misconceptions) make the difference between legal and illegal CBD products.

The fact that the market for CBD oils and other CBD ‘wellness’ products in the UK is thriving nevertheless is largely thanks to some creative use of a provision in the MDRs about ‘exempted products’, which require various criteria to be met, including a maximum amount of the ‘controlled drug element’ of a product to be below 0.1 mg.

While that arguably assists wholesalers and retailers, it is of no practical use to manufacturers handling the product in larger quantities.

The effect of these complex laws is that the boundaries between medicinal and ‘wellness’ products, and between zeroand low-THC, are particularly important in a POCA context. An overseas business that, due to less restrictive laws in this area, sold products with claims of medical effectiveness and some small measurable THC content would be committing ‘criminal conduct’ for the purposes of POCA, and an investor here who received the proceeds of such sales could be committing an offence.

The FCA’s Announcement What, then, has the FCA’s announcement contributed to this debate? On one view, it has done no more than confirm the consensus that has built up over the last few years, which, broadly speaking, divides the issue up according to the categories of products involved. At the simplest end of the spectrum, the sale of purely recreational cannabis products, though lawful in many jurisdictions now, would be considered ‘criminal conduct’ for the purposes of POCA, and the FCA would have a negative approach

Spring 2021 Volume 13 Issue 1

Regulatory & Marketplace questions of detail, and to lobby for a more workable approach than we have now. Investors will welcome the prospect of not having to take advice or make reports to the NCA on a regular basis, while banks may welcome the opportunity to profit from the business of customers they have previously turned away. Most importantly, new opportunities for investment will help further drive developments and growth in a sector that promises significant potential gains for patients in need.

John Binns to the prospect of a business that sold such products being listed on the London Stock Exchange. This much at least has always been clear, at least to the banks and lawyers who have had to wrestle with the issue.

The more interesting issue is what the FCA refers to as ‘overseas-licensed medicinal cannabis companies and cannabis oil companies’, which it says may be listed if it is satisfied ‘that their activities would be legal if carried out in the UK’ – in effect, the same test as in POCA. Intriguingly, it says that it cannot ‘assume a person who has been licensed in an overseas country would receive a licence here in the UK, as licensing regimes differ globally’, and that when considering whether to list a company, it ‘will also need to understand the legal basis of [its] overseas activities, for example the nature of the local licensing, and the licences the company holds’. As a sign of what is to come, the first company to be listed, MGC Pharmaceuticals, is a European-based biopharma company with a ‘nature to medicine’ strategy. Several other companies expect to list soon, including Kanabo, an Israeli company that has developed a medicinal CBD vaporiser.

Some Further Questions The FCA’s announcement implies an application of the pragmatic approach to interpreting POCA in this area, looking not only at the strict question of whether the products and their sales comply with the provisions of UK law (specifically the MDA, the MDRs, and the HMRs), but also at how their passage through the regulatory hoops applicable in their own jurisdiction might help to determine whether they would be www.ipimediaworld.com

lawful here. Given the restrictive nature of access to CBPMs here, that translation exercise must necessarily be approximate, though the exact process remains far from clear. Would it extend, for instance, to a company that sold a licensed medicinal product, prescribed by family doctors in Canada, that would in the UK be an unlicensed ‘special’, requiring a prescription from an authorised consultant?

The FCA’s reference to ‘cannabis oil companies’ also begs questions. As yet, there is no coherent system in the UK for licensing such products: the MHRA stands ready to deal with those that make medicinal claims (which most, inevitably, do not), while the Home Office has no policy to license them, and a parallel issue about whether and when CBD is a ‘novel food’ under EU law remains unresolved. So, what the FCA must mean is that the listing of companies selling such products depends on whether they either contain no measurable THC at all (in which case they would not be controlled drugs, and there would be no POCA issue), or fit the criteria for ‘exempted products’ in the MDRs (which would, because of the 0.1 mg maximum THC content, be of no practical use to manufacturers).

A Way Forward In fairness, the FCA’s statement is explicitly intended not to put an end to the debate about cannabis and POCA, but to bring it into a more formal and authoritative setting.

A more detailed guidance consultation is promised, which will provide those with an interest in the regulation of medicinal cannabis investments with a welcome opportunity to thrash out some of the

John Binns is a partner at BCL specialising in all aspects of business crime, with a particular interest in confiscation, civil recovery and money laundering under the Proceeds of Crime Act 2002 (“POCA”). His business crime experience includes representing suspects, defendants and witnesses in cases invoking allegations of bribery and corruption, fraud (including carbon credits, carousel/MTIC, land-banking, Ponzi and pyramid scheme frauds), insider trading, market abuse, pricefixing, sanctions-busting, and tax evasion. He has coordinated and undertaken corporate investigations and defended in cases brought by BEIS, the FCA, HMRC, NCA, OFT, SFO and others.

David Hardstaff David Hardstaff is an associate solicitor at BCL specialising in criminal and regulatory law. He advises individuals and companies in relation to controlled drug licensing and AML/Proceeds of Crime considerations in the context of the domestic and international cannabis market. He has particular experience in advising and representing individuals accused of sexual offences, drugs offences and offences involving violence. He is an experienced police station representative and advocate and represents clients in a broad range of proceedings at the Magistrates’ Court, Crown Court and Court of Appeal.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 23

Regulatory & Marketplace

Managing Competition, Price and Access The Changing Paradigm for the Pharmaceutical Sector High medicine prices impose a burden on national healthcare systems, for which pharmaceuticals account for a significant share of spending, especially for countries in the early stages of maturity in the pharma sector. Competition authorities have expressed concerns that access to affordable, innovative drugs may be at risk due to high prices, market withdrawals or other business strategies, along with national governments’ limited bargaining power against pharma companies. This Viewpoint discusses competition in the pharma sector and presents an integrated framework for authorities to strengthen pharma competition.

Access to Affordable and Innovative Drugs Average government spend on pharmaceuticals is about 57 per cent across OECD countries. Most private spending comes directly from households’ pockets, which reflects both high cost-sharing requirements and the extent of OTC selfconsumption. Moreover, drug prices vary greatly across countries. Recent data from Medbelle shows that, for generic drugs, the UAE pays over 10 times more than the median, while Egypt pays about 95 per cent less. For branded drugs, the US pays five times more than the median, while Indonesia pays about 90 per cent less. These differences result from multiple factors, such as production and other operating costs and price regulation.

Effective competition from generics/ biosimilars represents a vital source of price competition and significantly decreases price. In fact, when pharmaceuticals register patents to branded drugs, the registration is only valid for a certain period, after which other companies can produce generic versions. This not only makes older treatments more accessible, but also allows savings to be redirected to newer medicines. However, to mitigate the impact of generic entry, which greatly reduces revenues, originator pharma manufacturers often use strategies to extend the commercial life of patented 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

drugs. Some even resort to anti-competitive behaviours to prevent entry of generics that may threaten revenues and market share.

Consequently, competition authorities have investigated and sanctioned practices that lead to higher prices and involve anticompetitive behaviours. These authorities have expressed concerns that access to affordable, innovative drugs may be at risk.

There are limits to competition law; thus, continuous efforts by stakeholders must meet the challenge of sustainable access to affordable, innovative drugs, especially in countries where the pharma sector is in early stages of development.

Competition Overview in the Pharma Sector Market concentration and competition differ across the pharma value chain activities and product category groups, and are dependent on regulation within countries: •

•

Pharma manufacturers: For many stakeholders, the Herfindahl-Hirschman Index (HHI) for pharma manufacturing indicates a low-concentration industry.

However, concentration at the level of industry might not be the best indicator, as patents protect certain categories.

Thus, the branded-drugs market is more concentrated than that of generics.

This high market power is also due to competitive R&D and the merging of smaller firms with larger branded firms. The result has been no significant change in ranking of leading brandeddrugs manufacturers since 2011, which indicates serious competition concerns and continuing price increases.

Wholesalers: The wholesale market is characterised by low- and highconcentration markets, depending on regulations and distributing power.

Most countries have mixtures of national and regional wholesalers, with national wholesalers providing the full range of medicines and regional providing full and partial ranges. Some countries have many wholesalers with less than half of market share (low concentration), while others have fewer than four wholesalers with more than 85 per cent market share (high concentration).

•

Retailers: Market concentration in retail is low to medium, due to legacy government monopoly pharmacies and regulation. This corresponds to low concentration in markets with strict regulations and medium concentration in markets that have been recently liberalised, or where market positions of previously government-owned pharmacies are still strong or big chains prevail.

Competition Concerns in the Pharma Sector •

Anti-competitive mergers, which can appear as price increases or lack of merger control.

•

Abuse of dominance, which usually appears in five forms:

1.

Excessive pricing: Prices set significantly above competitive levels due to monopoly or market power.

2.

Denigration: Competitors criticised in a derogatory manner to minimise competitive potential.

3.

Kickbacks: Stakeholders offer negotiated bribery tactics in exchange for anti-competitive disadvantage to the briber.

4.

Patent misuse: Stakeholders extend patents over products set to expire to limit generic competition (“evergreening”) or introduce modified versions to switch patients from older versions without facing imminent risk of generic substitution (“product hopping”).

•

Restrictive horizontal agreements often appear in three forms: 1.

Price fixing: Rival companies come to illicit agreements not to sell goods or services below certain prices.

2.

Generic-delay agreements: Brand manufacturers negotiate with generic manufacturers to delay entry of substitutes and avoid threat to Spring 2021 Volume 13 Issue 1

Regulatory & Marketplace sales of more expensive branded products.

3.

•

Collusion: Rival companies cooperate for mutual benefit, but the decision to collude impacts the market as a whole.

Vertical agreements mainly take the form of contracts, which constrain competition.

In mergers, market definition of existing products typically considers overlaps and market shares of the merging firms’ products within a set of therapeutic substitutes; hence, large firms may have hundreds of separate markets to be assessed. Typically, mergers are approved subject only to divestment of products for which there is significant overlap between merging firms.

There is less clarity about how to treat R&D in mergers. Pharma firms often have clear pipelines of future products due to clinical trial needs, which makes it predictable which products will be available in a few

www.ipimediaworld.com

years. There is, however, debate about whether earlier “research capability” should be considered a potentially lost competition area in an “innovation market”.

In both abuse-of-dominance and horizontal collusion cases, competition authorities have recognised the importance of regulation, and generally respond with competition law only when regulation has failed. Arguably, litigation or regulation within the patent system should be enough to prevent abuses, but evergreening and product hopping, plus misrepresentation of rival products, have all been considered abuse of dominance. Competition authorities can only take action when the criteria for a competition case have been met. In such a regulated sector, if a competition authority finds itself repeatedly taking action against infringements, it is likely a sign something is wrong with the regulatory system and reform might provide a better solution. The highly regulated nature of the sector makes other forms of breachof-competition law less prevalent.

Strengthening Competition in the Pharma Sector Competition authorities aiming to strengthen competition should look toward collaboration with country-wide stakeholders. We have developed a frame-work with four key recommendations.

1. Strengthen competition enforcement: Problems often stem from combinations of evolving regulations and lack of enforcement. Competition law must remain comprehensive in its coverage, follow best practices and be strongly enforced.

Substantive provisions regarding abuse of dominance, collusion and merger control should be held to high standards. The law should embody excessive reliance on formal, rigid rules. Competition authorities must also be vigilant about stakeholders that abuse their dominant positions, especially in cases protected by patents and non-regulated OTC drugs.

2. Foster policy advocacy: Competition authorities should ensure there

INTERNATIONAL PHARMACEUTICAL INDUSTRY 25

Regulatory & Marketplace 4. Optimise governance: Sometimes, the sector is missing specialised bodies that assume essential responsibilities in regulating the pharma sector, or certain regulations are not strongly enforced. To ensure a fair market, competition authorities should advocate for ensuring the right bodies are in place and regulations within the sector are strongly enforced. The key is diversity of responsible authorities and bodies, each specialising in specific areas of monitoring and regulation.

is no lack of regulations essential to the healthy functioning of the pharma sector, and that regulations have direct/indirect impact on safeguarding competition. Policy advocacy can relate to various policies, dependent on the development of a country’s pharma sector. For those markets in early phases, policy advocacy can relate to the following: •

•

Strengthening public procurement processes: Provide an adequate degree of transparency in the procurement cycle to promote fair, equitable treatment of potential pharma suppliers. To avoid any tendering decision-making challenges between a country’s central public procurement entity of drugs and bidders, define a clear procedure for opening tenders and advocate for close cooperation. Moreover, advocate for the procurement entity to buy multiple medicines for different therapeutic categories from more than one manufacturer and/or increase frequency of tendering. To improve competition, the entity should consider allowing diversification of public formularies, as well as procurement of two to three alternatives under each treatment category. This allows accommodation of multiple therapeutic cases and treatment requirements for different patients, as well as more competition in the tendering process. Another option is to have more frequent tenders instead of the current practice, which is once every two years. Alternatively, follow a reimbursement negotiation model rather than a traditional procurement approach. Finally, secure mechanisms to prevent risks to integrity. (Protect procurement officials from undue influence, which is more prevalent in early-stage sectors.) Develop risk maps that identify the most vulnerable officials, as well as risk activities.

Also look towards separation of duties within the public procurement entity via multiple-level review and approval. In this set-up, different specialised resources would handle various parts of the procurement cycle.

Improving local innovation capabilities: Many countries in the early stages of the framework depend on import or international manufacturers. This

26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

reliance stems mostly from limited innovation capabilities in local pharma manufacturing. It presents a setback by discouraging dependence on local talent and innovation capabilities.

Best-practice countries, on the other hand, have reached advanced stages of manufacturing potential by undertaking and incentivising a range of initiatives. Competition authorities should advocate to various stakeholders within the country to improve local innovation capabilities.

•

Ensuring deregulation of retail activities: Deregulation of retail offers various consumer welfare benefits and positively affects competition.

3. Optimise existing systems and processes: Competition authorities should identify systems/processes to be optimised and then advocate for ensuring such optimisation to safeguard competition. Moreover, though many countries have initiatives to promote generic drugs, there are many others to consider (e.g., to strengthen guidelines so physicians dispense medicine based on molecule rather than brand). In addition, the early-stage pharma sector may face drug-shortage issues despite having several initiatives. Competition authorities should advocate for optimisation of initiatives (e.g., enforcing regulation to notify food and drug authorities of drug shortages, stimulating and improving digitalisation in the supply chain, and ensuring the tendering process considers the availability of drugs).

Conclusion The pharma sector will undergo increased pressure to ensure competition. To create a fair and competitive market in which patients have access to affordable and innovative drugs, an integrated framework is required. This allows competition authorities to ensure a level playing field.

This framework endorses proper actions for competition authorities to undertake in collaboration with various stakeholders.

Craig Wylie Craig Wylie is a Managing Partner at Arthur D. Little, based in New York, and a member of the global Healthcare & Life Sciences Practice. He has a background in Quality Operations, IT and Clinical Development, and focuses on pharmaceutical companies and the effective implementation of quality and regulatory compliance within this highly regulated environment.

Vikas Kharbanda Vikas Kharbanda is a Partner with Arthur D. Little, based in Dubai, and leads the Healthcare & Life Sciences practice in the Middle East. Over the past few years, Vikas has been working with several leading Healthcare service providers in the Middle East and Asia on their growth and expansion strategies.

Vikas also works extensively with clients, advising them in their digitalization strategies and leveraging technology to improve both patient experiences and operational effectiveness.

Spring 2021 Volume 13 Issue 1

LIFE SCIENCES

BIOPHARMACEUTICAL SOLUTIONS LIFE INSPIRED, QUALITY DRIVEN

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 27

Regulatory & Marketplace

Comparison of Regulatory Process of COVID-19 Vaccines; Between Emerging Markets, EU Coronavirus disease, COVID-19, has affected all of our lives primarily since the end of 2019. We have faced experiences and a period that we had never come across before. In particular, we have to wear masks, and we should have social distance and sterility in order to avoid it, because this infectious disease spreads through droplets of saliva or discharge from the nose when an infected person coughs or sneezes, according to the definition of WHO. Some of us still may not know about the virus itself. So, what are coronaviruses? Well, they are a large family of viruses that cause illness ranging from the common cold to more serious diseases such as Severe Acute Respiratory Syndrome (SARS-CoV). The 2019 version of coronavirus, COVID-19, was not seen in humans before and it has caused viral pneumonia, which was first seen in China and came out from Wuhan’s South China Seafood City market in December 2019, and has spread all over the world since then.2

Please see the table below for the vaccines that have been approved3: Name

Vaccine Type

Developers

Country of Origin

Approval

BNT162b2

mRNA-based vaccine

Pfizer, BioNTech; Fosun Pharma

Multinational

UK, Bahrain, Canada, Mexico, US, Singapore, Oman, Saudi Arabia, Kuwait, EU

mRNA-1273

mRNA-based vaccine

Moderna, BARDA, NIAID

US

US, Canada

Oxford accine

Viral vector

The Oxford University, AstraZeneca

UK

UK, EU

Sputnik V

Non-replicating viral vector

Gamaleya Research Institute, Acellena Contract Drug Research and Development

Russia

Russia

EpiVacCorona

Peptide vaccine

Federal Budgetary Research Institution State Research Center of Virology and Biotechnology

Russia

Russia

CoronaVac

Inactivated vaccine

Sinovac

China

China

Unknown (not announced)

Inactivated vaccine

Wuhan Institute of Biological Products; China National Pharmaceutical Group (Sinopharm)

China

China

BBIBP-CorV

Inactivated vaccine

Beijing Institute of Biological Products; China National Pharmaceutical Group (Sinopharm)

China

China, United Arab Emirates, Bahrain

The European Medicines Agency (EMA) plays a great role in regulatory guidance, as well as on the scientific evaluation, approval and monitoring of COVID-19 vaccines in the EU, as shown below for the flow of the stages:

Many pharmaceutical companies and scientists have been working on the solution. A lot of work and research have been done on vaccines, as well as on the pharmaceutical products for the treatment that could be the solution for the disease.

Figure 2. Flow of COVID-19 vaccine evaluation in EU

Globally, vaccine development for COVID-19 is being fast-tracked. Getting scientific advice from regulators helps to speed up the development process. EMA offers informal consultancy with its team “COVID19 Task Force (ETF)”, and they give fast scientific advice during this period.1

Figure 1. COVID-19 vaccine 28 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Even though safe methods are used for development of the vaccine, new methods have also been tried and used for the vaccines for COVID-19 for increasing the stability, quality, process period, and production efficiency. However, existing methods for vaccine production have also been used for increasing capacity and to have production at a large scale. EMA, and most of the health authorities in EU as well Spring 2021 Volume 13 Issue 1

Regulatory & Marketplace 150 working days with a “rolling review” procedure. So , the data can be evaluated when they become available during the development stage by EMA, to accelerate the MA application process.

As the evaluation is completed, EMA may recommend a “conditional marketing authorisation”, which is a kind of approval for medicines in emergency situations, and this is recognised by the WHO and EU Health Authorities.1

Figure 3. COVID-19 vaccines timeline in EMA

as in emerging markets are doing their best to speed up the evaluation period for COVID-19 vaccines to have the MA approval.

So, as the principle is protecting the people and avoiding the risks, the legislation in EMA and guidelines of national health authorities in EU provide guidance accordingly. In order to get approval, all the test results are submitted to the health authorities in the EU.

As biotechnology products are registered via a centralised procedure in EU, COVID-19 vaccines will also be evaluated with the same procedure. Although the standard timeline for the evaluation of a pharmaceutical product is up to 210 active days, EMA treats MA applications for COVID-19 products in an accelerated way, which allows the timeline for evaluation to be less than

The first COVID-19 vaccine (two-dose vaccine), Sputnik V, registered in Russia with 92% efficacy, which has a patent protection in Russia on its method as well as its substance and which came out earlier than most of the other vaccines in 2020, got the attention of many countries around the world including UAE, Saudi Arabia, Indonesia, Philippines, Brazil, Mexico, Serbia and India. Now it has been applied in 40 countries for MA approval.5,7 The results of Phase I–II clinical trials of the vaccine were published in one of the world's most respected medical journals, The Lancet, in September 2020, and Phase III data was published afterwards. Sputnik V can be administered to the population of a particular country after approval from a national regulator.

Sputnik V post-registration clinical trials included over 44,000 people in Russia, the United Arab Emirates (UAE), India, Venezuela and Belarus. More countries expressed interest in carrying out clinical trials of Sputnik V. Before the clinical trials, all of the preclinical trial stages with experiments on different types of animals were performed.

Clinical trials of the vaccine started accordingly, and Phase I and II were completed by August 2020. No unexpected or unwanted side-effects were seen. The vaccine generated cellular immune response.

After getting the Sputnik V vaccine, the members of the clinical trials did not get COVID-19 and its efficacy was confirmed with the test results shared with the health authorities.

Figure 4. Covid-19 Vaccine Approval Steps in EMA www.ipimediaworld.com

AstraZeneca, which is a British company and Gamaleya Research Institute, which is a Russian medical-research institute that developed the Sputnik V vaccine in Russia, signed an agreement in December 2020.

And AstraZeneca will start clinical trials to test a combination of its experimental COVID-19 vaccine with the Sputnik V shot INTERNATIONAL PHARMACEUTICAL INDUSTRY 29

Regulatory & Marketplace were found for different types of accelerated vaccine approval in a group of 24 countries.

Greater harmonisation would bring many advantages. It would be beneficial for pharmaceutical companies for common and accepted definitions, as well as guidelines for different types of approval, in order to see the status of their vaccine. This would really be time-saving for regulators and for the companies.4

Figure 5. Rolling review cycle of COVID-19 vaccines

to see if this can increase the efficacy of the British company’s vaccine. The Sputnik V coronovirus vaccine was applied in EMA in February 2021. 8 BioNTech’s vaccine, developed in Germany and having a partnership with Pfizer, which is BNT162b2, is an mRNA based vaccine, and they claim that it is an alternative to conventional vaccines because of their advantageous characteristics, which are subject to translation with clinical data, including: • Immunogenicity • Flexible manufacturing process • Safety They say “mRNA vaccines represent an alternative to more conventional vaccines because of their potential to produce a robust and targeted antigenic immune response, combined with their tolerable administration profile and rapid, scalable manufacturing”.6 And how do the mRNA vaccines work? mRNA vaccines teach the cells to make a protein that will trigger an immune response without using the live virus that causes COVID-19. The human body then makes the antibodies which support in fighting the infection. When a person is given the vaccine, their cells produce the spike protein. The cell breaks down the instructions and gets off them following the making of the protein piece. The cell then displays the protein piece on its surface. The immune system recognises that the protein is not present there any more and begins building an immune response and making antibodies.6,12 In the EU and Switzerland, BNT162b2 got conditional marketing authorisation 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to increase immunisation for people 16 years of age and older. In the USA it has been authorised under emergency use authorisation, as Pfizer-BioNTech COVID-19 vaccine. In the UK, it has been authorised under “Temporary Authorisation for Emergency Supply”. They have applied for MA approval in Japan and Australia as well, and have received approvals in many other countries. Also, additional submissions are in progress.

So, there are many vaccines being developed and the ideas and comments of the authorities may change from one to another. When we evaluate the aspect of EMA and FDA, we see that they differ in many ways. For example, the FDA asks for all the raw data from the laboratory, for non-clinical and clinical trials, whereas the EMA accepts the analyses data of the pharmaceutical. But in emerging markets, for instance in Africa, countries are looking for common regulatory aspect by sharing their experiences. In fact, even for the dosing there are different opinions, like the FDA’s, regarding the period of protection after a single dose of vaccine. They think the periods are not sufficient between the doses and the present clinical data is not sufficient.

And they say the target is to minimise the risks for the public health. Regulatory experts in MHRA also claim that more than 21 days are given between the two doses to see the results more properly. For PfizerBioNTech vaccine they are doing it, and they are evaluating Moderna in the UK.12 As the vaccines were administered before the conclusion of all three phases of clinical trials in China, Russia and the United Arab Emirates, it brought the acceleration of approvals harmonisation in vaccine regulation. At least 51 pathways

The regulatory experts want to share their experiences along with the data they have, discussing together in order to decide on the right and best solution.

So, a harmonised file complying with international regulatory standards and requirements would be suitable for a fast and precise way.

The ICMRA (International Coalition of Medicines Regulatory Authorities), which has members from China, Europe and the United States, have reached an agreement on the testing of COVID-19 vaccines, for the animal model part as well as the ideal clinical trial end points. The coalition’s COVID-19 team is now trying to harmonise the vaccine monitoring as they are prepared.

Previously, the WHO requested that both FDA and EMA should evaluate the suitability of COVID-19 vaccines for countries in need in emerging markets, for issuing emergency authorisations.

They are expecting an agreement and, if either of them agrees, then the WHO can issue its own EUL (emergency use listing), which would be a collaboration.

The WHO is really acting supportively on collaborations, exchanging experiences and fast-track approvals of clinical trials, as well as emergency MA approvals and clarifying the roadmap for each vaccine.

This means collaboration with the country regulatory experts will be required to apply local authorisation for emergency use.

The WHO’s emergency use listing (EUL) opens the door for countries in emerging markets to accelerate their own regulatory approval processes to import and administer the vaccine. It also makes it possible for UNICEF and organisations like the PanAmerican Health Organization to supply the vaccine for distribution to countries that need it.10 The WHO is really encouraging companies to develop more vaccines complying with Spring 2021 Volume 13 Issue 1

Regulatory & Marketplace

safety and efficacy standards in order to reach all countries.

The aim of the emergency use listing (EUL) procedure is to make the vaccines and pharmaceutical products, medical devices which comply with certain requirements and criteria of efficacy, safety, quality standards as reachable and available as possible. It is not an easy way to apply, since the process needs accuracy and speed at the same time.

Late Phase II and Phase III clinical data and safety, efficacy, quality data and a risk management plan are evaluated in EUL for the COVID-19 vaccine. The data is reviewed by the WHO experts and teams of regulators from national health authorities and further steps are taken accordingly.10,11 All the countries may follow a different flow and local policy along with the global regulation and procedure. But even though the application type is emergency or conditional, all the data on quality, safety, immunogenicity and efficacy should comply with the standards and criteria, both country-specific and from a global perspective. The developers and manufacturers should be committed to fulfilling the requirements in advance, as well. The regulators in the EMA, national health authorities in the EU, the FDA, the WHO, and other national health authorities should gather and the regulatory experts from different regions should have detailed www.ipimediaworld.com

discussions on the evaluation and decisionmaking in order to reach the best solution and the most accurate results.

drugs-vaccines-treatments/vaccines/pfizerbiontech.html

REFERENCES 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

www.ema.europa.eu/en/human-regulatory/ overview/public-health-threats/coronavirusdisease-covid-19/treatments-vaccines/ covid-19-vaccines-development-evaluationapproval-monitoring www.europeanlung.org/en/covid-19/what-iscovid-19/ www.raps.org/news-and-articles/newsarticles/2020/3/covid-19-vaccine-tracker www.nature.com/articles/d41586-020-03458-z Sputnik: Ref: FAQ | Official website vaccine against COVID-19 Sputnik V. (sputnikvaccine.com) Overview COVID-19 | BioNTech (biontech.de/ covid-19) RDIF applies for Sputnik V vaccine approval in 40 countries (news.ru) (news.ru/en/world/ rdif-applies-for-sputnik-v-vaccine-approvalin-40-countries/) Russia to submit Sputnik V vaccine for EU approval | Deccan Herald (www.deccanherald. com/international/russia-to-submit-sputnikv-vaccine-for-eu-approval-939000.html) www.biospace.com/article/fda-don-t-messwith-the-covid-19-vaccine-doses/?s=130 www.paho.org/en/news/31-8-2020 nationalregulatory-authorities-participatediscussion-covid-19-vaccines-who www.who.int/news/item/31-12-2020-whoissues-its-first-emergency-use-validationfor-a-covid-19-vaccine-and-emphasizesneed-for-equitable-global-access www.canada.ca/en/health-canada/services/ drugs-health-products/covid19-industry/

Pelin Boran Pelin Boran has a Bachelor’s degree in Chemical Engineering and an MSc. in Pharmaceutical Chemistry. 16 years of experience in the pharmaceutical industry in the areas of QC, R&D, Regulatory Affairs for Global Projects and Business Development. Have my own company, “Pelin Boran Regulatory Affairs Solutions & Consultancy” for 6 years. We share our global expertise to support our clients around the world and find the best solutions for them; on Regulatory Affairs, Pharmacovigilance, GMP inspections and Business Development Activities in EU, UK, USA, Canada, Latin America,Israel, CIS Region, Balkan Region, Turkey, Asia Pacific Region, MENA Region, GCC Region with my team mates. Our head office is in Istanbul, Turkey and we give our services end to end in all these regions and countries with my local team mates and partners.

Web: www.pelinboran.com Email: solutions@pelinboran.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 31

Drug Discovery, Development & Delivery

The COVID-19 Catalyst – Accelerating the Move to Patient-powered Medicine COVID-19 is changing the world. The new reality it creates, however, will in many ways be the same as it was always going to be. Rather than changing the course of events, the current pandemic is simply speeding them up. It is a rapid and fundamental transformation that is likely to have lasting impacts for healthcare providers, the life sciences, pharmaceutical industries and – most notably – patients.

Technology is a two-way street, where data – newly democratised – not only changes healthcare’s ability to understand and treat patients, but also heralds a fundamental shift in the patient-provider dynamic.

Accelerating Change COVID-19’s acceleration of existing change is most obviously seen with remote working technologies. These platforms have been available for more than a decade, but necessity has taken the trend, which may have needed another decade to fully mature, and made it instantly ubiquitous.

In the United States, for example, fewer than 5% of the workforce worked remotely in 20101. In 2020 this is now estimated to be around 42%, with just 26% working from businesses premises2.

Data shows that between pre-lockdown January and early lockdown March 2020, digital approaches almost instantaneously replaced physical contacts between pharma companies and healthcare professionals, with the use of remote meetings increasing by over 2000%3.

This acceleration of technological transformation has also seen a massive increase in virtual consultations, particularly in primary care. The UK’s Royal College of General Practitioners (RCGP) reports that between February 2019 and February 2020, more than 80% of appointments were face to face and less than 1% took place over video. At the height of lockdown in April, however, face to face consultations were estimated to have plummeted to between 7 and 8%, with technology picking up the slack. Further, the RCGP believes that up to 50% of all consultations will remain virtual after the pandemic4.

Transformation also goes beyond direct patient interaction, with an acceleration in the roll-out of innovations such as electronic patient records (EPR), which will see patients able to access and interrogate their own medical histories. Further, the UK Department of Health and Social Care is investigating how technology platforms can involve patients more directly in their own care and how advances such as wearables will begin to impact healthcare.

Pre-pandemic, these changes were in progress but integrating over time: postpandemic they have suddenly emerged as essential.

While the debate still rages around whether patients are, conceptually, customers or consumers – or neither — the argument is becoming moot. The reality is that COVID-19 is accelerating the trend that sees them increasingly behaving, and expecting to be treated, as such.

While these figures are likely to move once again as our responses evolve and life normalises, the pandemic will accelerate a permanent shift to home working for millions of people. What seemed futuristic in the spring is an established fact in the autumn.

Telescoping a decade’s worth of change into just a few months has led to unforeseen outcomes across a range of sectors, with impacts on real estate, transport infrastructure and the viability of previously robust commuter-dependent businesses.

With COVID-19 acceleration shaking so many foundations, are pharma and life sciences immune?

Research from a leading life sciences cloud platform provider suggests not.

32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Longer-term Impact This last statistic – with patients unwilling to go back to pre-pandemic norms – is perhaps the most interesting. Essentially, they have been given a glimpse of a more convenient future and don’t want to let it go. Research from a video consultation platform provider appears to support this interpretation, with levels of ‘happiness’ with virtual appointments rising to more than 70% by May 20205.

While a patient is not a direct customer of a pharma company, for example, they are the end user and ultimate ‘payer’. The increasing cost of healthcare, whether paid for through personal insurances or general taxation, means that patients want greater accountability and a greater say. Today, populations access finance, socialise, are entertained, shop and find life partners online – so why should healthcare be any different?

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Drug Discovery, Development & Delivery As COVID-19 ushers in a more consumerlike experience of healthcare, people’s interaction with it will also become more consumer-like. One of the most obvious iterations of this is crowd-sourced insight through review platforms. Few consumers today would think of purchasing anything online without first consulting the experiences of others.

With the emergence of online experience sharing platforms such as Trustpilot, personal opinions now have a significant financial and reputational impact for companies. These platforms may have caused initial panic in many businesses, but as they have matured, data-savvy organisations have quickly realised that opinion carries value. Near realtime feedback keeps a company focused on its customers; is an immediate and highly targetable engagement channel; and can be used to inform everything from product development to marketing and sales.

Some of the counter-arguments to embracing a more consumer-focused patient experience have centred on the fact that healthcare is different to every other form of consumption. The received wisdom is that a ‘patient-consumer’ could have the best possible service from a healthcare provider, but still suffer an adverse outcome – and that patient-consumers are not sufficiently qualified to make an objective judgement – so their feedback is of no value.

Demonstrable Improvement It is an attitude that harks back to an age that has already passed. An age of patrician healthcare where patients were to be treated and not heard. Change here isn’t driven by ‘trends’ or fashionable concepts of democratisation – it’s an acknowledgement that healthcare, if it’s to be successful, must be a dialogue between clinician and patient. It’s a realisation – on both sides – that there isn’t a pill for everything and that ongoing personal good health isn’t solely dependent on clinicians, but is also a personal responsibility.

“By involving people in decisions about their health and care we will improve health and wellbeing, improve the quality of care and ensure people make informed use of available healthcare resources. Involving people in their own health and care not only adds value to people’s lives, it creates value for the taxpayer. The challenge now is to shift the focus of care and support services from ‘what is the matter with you?’ towards ‘what matters to you?’.”

As a maturing approach to healthcare, it is now evolving into a new discipline, known as public engagement (PE). PE isn’t traditional ‘communications’ where organisations talk to try and change patient behaviours, rather it’s about listening to patients to change organisational behaviours.

Research6 demonstrates that this level of patient engagement works. Technologies – specifically a sophisticated form of ‘Trustpilot for medicines’ – already exist and will see significant improvements to healthcare generally and medicines specifically. A study that reviewed patients who had used an anonymised – regulatory compliant – medicines feedback app showed that, after two months: • • • • •

79% experienced an improvement in remembering to take their medications; three-quarters experienced an improvement in taking their medications as prescribed; close to half felt they better understood their medications; 69% felt more motivated to take their medications; while more than a third felt the effect of their medication actually improved.

In calling for further research, the study concluded that “Use of the DrugStars app improved clinically relevant indicators of adherence and impact and benefits were related to level of app usage.”

There is also recognition that, without greater patient engagement, some new forms of medicine will never achieve their true potential. The emergence of fields such as genomics blur and even dissolve the lines between healthcare and research.

Once upon a time, a patient who submitted a tissue sample gave tacit consent for this to be used in their care. Today, a tissue sample may well be used to provide care but also to be applied to a range of research purposes.

This is a completely different ball game and will require properly informed consent – which demands real engagement with the patient.

The Drug Development Cliff Edge Despite this acceptance of the patient voice in ongoing healthcare, pharma companies remain stubbornly resistant to feedback on medicines. In pharma, the harvesting of patient data is highly valued during the clinical trial stages of development – with the industry investing an estimated US$19 billion a year.

Post-licensing, this engagement drops off a cliff. Patients have virtually no outlet to share their day-to-day reality of often complex drugs and equally complicated regimens. The patient’s real-world experience of medicines is ignored by the very companies that developed – and continue to develop – them.

It’s a damaging omission that has led to a catastrophic collapse in trust. Research

The UK’s National Health Service (NHS), for example, has long embedded patient experience in its operations. Patient panels in various guises have existed for decades but have now become critical components of care.

Professor Alf Collins, NHS England’s Clinical Director, Personalised Care Group writes in the organisations’ statutory guidance for clinical commissioning groups, 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Spring 2021 Volume 13 Issue 1

Drug Discovery, Development & Delivery supports this conclusion. A 2020 survey of 3346 users of prescription and over-thecounter (OTC) medicines from the UK and the Nordics revealed that: • • •

more than three-quarters of patients do not trust advice from pharmaceutical companies about their medication; 81% feel the pharmaceutical industry influences prescription decisions; and 72% do not feel listened to by pharmaceutical companies.

Unlike virtually every other sector, pharma companies fail to see the value in listening to their end users (patients). These end users often report feeling confused and alone. Medicines information leaflets are one-size-fits-all documents that fail to reflect a patient’s individual circumstances and experiences; are obligated to list every possible side-effect (which can make them virtually meaningless): and patients have no opportunity whatsoever to feed back or pose questions to the company or – as critically – other users.

As one Crohn’s disease patient describes, “It can be difficult getting useful and reliable information on your medication, and leaflets that come with them can be scary. They have to list all of the possible side-effects, even the rarest. It is reassuring to read about other people’s real-life experience…it is important because it is by the people that actually take the medications. It makes me feel less alone….”7 It is frustrating that pharma fails to see the value in these opinions. Understanding, for example, the factors that heighten the risk of poor adherence to medication regimens can lead to solutions designed to mitigate them – and reduce patient drop-out. Further, with insight direct from users, pharma companies can optimise their patient support programmes and patient support materials, while they also have access to a continuous, near realtime market research resource made up of hundreds of thousands of highly engaged patients willing to share experiences.

Effective Pandemic Response As COVID-19 vaccines begin to emerge, patient insight will be critical to their success or failure. The Pfizer-BioNTech vaccine, which was the first to declare, has been found to be more than 90% effective in preventing COVID-19, tested on over 43,000 people in a Phase III trial. The EU has ordered 300 million doses of this vaccine, www.ipimediaworld.com

while the UK has ordered 40 million. The UK’s Department of Health and Social Care is preparing to roll out vaccinations from 1 December, with sites from GP practices to drive-through centres to football grounds to town halls earmarked to administer around 5000 jabs a week.

Perhaps most powerfully of all, patient power and the patient voice can strengthen and improve our response to COVID-19 – and help to ensure successful emergence from the pandemic.

This is a huge undertaking, with billions allocated to implementation. Hundreds of billions more, national economies, and the health and livelihoods of whole populations depend on effective deployment. In the age of the anti-vaxxer and widespread distrust in pharma, these efforts could fall at the first hurdle – public acceptance. In the UK, for example, more than half the public expressed an unwillingness to take a vaccine unless it had been tested for at least a year.

Further, close to three-quarters would be unwilling to allow their children to receive such a vaccine.

1.

This priceless public understanding – if pharma is prepared to listen – could allow industry to better support governments as they prepare to deploy the latest vaccines.

Embrace Patient Power Patient power is a shift in dynamic that shouldn’t be feared. It has long proven itself to be remarkably effective in helping health systems to better align services to need and deliver demonstrable improvements to clinical outcomes. It is a critical outlet for patients using medicines, allowing them to share experience, best practice and highlight problems that have only emerged post-licensing. Further, if pharma finally embraces a ‘medicines Trustpilot’, patient power will help to rebuild reputations, provide remarkable insight that can improve new and existing drugs, and improve pharma business models.

REFERENCES

2.

3.

4.

5.

6.

7.

https://www.census.gov/prod/2012pubs/p70132.pdf https://news.stanford.edu/2020/06/29/ snapshot-new-working-home-economy/ https://www.veeva.com/resources/veevaintroduces-new-capabilities-for-remote-drugsampling-in-veeva-crm-engage-meeting/ https://www.bbc.co.uk/news/uk-england52216222 https://visionable.com/wp-content/uploads/ 2020/09/CommunicationsTechInHealthcare_ WhitePaperSept2020_final.pdf Changes in patient reported outcomes, attitudes and health behaviors in 606 people with diabetes following 2 months use of the DrugStars health app. Skovlund SE, Moeldrup C: https://www.valueinhealthjournal.com/ action/showPdf?pii=S1098-3015%2818% 2934122-6 DrugsDisclosed User Case Study 2020

Claus Møldrup Claus Møldrup – Qualified pharmacist and former professor at the University of Copenhagen. Claus is the CEO of DrugStars, a patient management app, as well as the co-founder of DrugsDisclosed, a platform for patient medication reviews and of DrugsDiscovered, a new service designed to remove the red tape, to allow the pharma industry to take action on patient insights.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 35

Drug Discovery, Development & Delivery

Innovate UK Funded Project Results in Next-generation AI Drug Discovery Technology Introduction A promise of artificial intelligence (AI) is that it will gain more value from the complex and expensive data generated in drug discovery, by identifying hidden patterns and valuable conclusions that will guide better decisions when designing and selecting high-quality clinical candidates. To achieve this requires several factors to align: •

•

•

Algorithms – The latest deep learning algorithms have transformed many fields with their ability to capture complex data relationships. However, many of these methods fail in the context of drug discovery, due to the specific challenges of drug discovery data: what we consider 'big data' in our field is orders of magnitude smaller than many areas of notable success for these algorithms, and the available data have significant uncertainties due to the variability inherent in biological experiments. Robust and proven methods are required that make a genuine difference in drug discovery.

Data – High-quality and up-todate data are required as input, to distinguish genuine signals from the noise and provide timely insights as drug discovery projects progress.

Intuitive and interactive access – The results need to be readily accessible to the key decisionmakers in a project, who may not be computational experts, and presented in a way that will address their questions and drive better-informed decisions.

This article describes a successful publicprivate partnership, the DeepADMET project supported by Innovate UK, that addressed these challenges, delivering a 'next-generation' software platform. The project consortium combined the skills of Intellegens Limited, a Cambridge University spin-out developing unique deep learning imputation algorithms; 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The Alchemite method accepts compound descriptors (orange squares in a complete matrix), sparse assay data (green squares in a sparse matrix) and imputes the missing values (purple squares).

Medicines Discovery Catapult, which brought cutting-edge AI approaches to curation of high-quality data; and Optibrium Limited, a software company with a proven track record of innovation and delivery of elegant software that guides successful drug discovery. We will provide an overview of the underlying methods, proof-of-concept and implementation of this platform, and illustrate the unique ways it addresses critical challenges faced by drug discovery projects.

The Challenges of Drug Discovery Data Drug discovery data present challenges for the application of standard machine learning tools: in particular, the data are sparse, as not every compound is measured in every assay, and no assays are run for every compound in a pharmaceutical company’s collection. Drug discovery data are also noisy, as biological variability leads to (sometimes radically) different results when repeating the same experiment. These challenges are not unique to drug discovery and are found in many experimental sciences.

They are particularly acute in drug discovery, where it is not unusual for over 99% of possible compound/assay measurement results to be unavailable. To obtain the full potential of machine learning for drug discovery, it is necessary to use an approach designed for this complexity of data.

The Intellegens’ machine learning algorithm, Alchemite™, was originally developed for and successfully applied to materials science, optimising superalloy compositions for jet engine turbine blades. That field also suffers from sparse, noisy datasets, with the

expense of generating and testing samples limiting the amount of data available. The project partners identified the similarities between the data from these different experimental domains and suggested the adaptation of Alchemite™ for use in drug discovery.

This unique algorithm follows an imputation approach: it ‘fills in the gaps’ in sparse experimental data, utilising what little experimental data are available to help the imputation of the points that are not.

This has a high value in large drug discovery datasets, multiplying the amount of data available for basing project decisions by many folds. The model may also be applied for predicting the performance of ‘virtual’, unsynthesised, compounds, saving experimental effort by triaging results to identify those with a good chance of success against a broad range of endpoints and prioritising those compounds for synthesis.

The ability to leverage existing sparse experimental data in its models results in more accurate models for complex, heterogeneous endpoints, including absorption, distribution, metabolism, excretion, and toxicity (ADMET) endpoints, than is possible with conventional quantitative structureactivity relationship (QSAR) models that are based purely on compounds’ structures.

This increased accuracy enables more reliance on the model’s predictions for drug discovery project decisions, an increase which is furthered by the inclusion of reliable uncertainty quantification for each prediction. These uncertainty estimates enable a focus on the most confident Spring 2021 Volume 13 Issue 1

Drug Discovery, Development & Delivery predictions from the model, setting a tolerance for the uncertainty that is useful for ensuring decisions are based on only the best information available.

Accurate predictions and reliable uncertainty quantification also enable the construction of robust experimental designs, by proposing the next experiments to carry out that have the highest likelihood of improving the underlying model and future predictions. This is achieved using a probabilistic approach to identify which experiments are most likely to improve the model’s understanding of particular endpoints or regions of chemical space.

The Generation of Large-scale Data There have been several historical approaches to generating large-scale data for use in machine learning approaches to predict ADMET properties for novel potential drugs. Foremost of these efforts are the ChEMBL database of literature abstracted medicinal chemistry data (https://www.ebi. ac.uk/chembl) and deposited experimental screening data at PubChem Bioassay (https://pubchem.ncbi.nlm.nih.gov).

However, due to the need for novel data to predict novel target or property endpoints, to boost the domain of applicability or improve model accuracy, there is an ongoing need to develop approaches to identify, index and curate novel SAR data. Ideally, this data supply would be as automated as possible and supply ‘data on-demand’.

The current under-representation and use of supplementary data from journal articles focused initial studies on processing these data for relevant ADMET-related endpoints, leveraging existing specialist lexicons and data standards where possible, and directed the prioritisation of data towards a manually selected set of highinterest ADMET target genes, for example, drug transporters where advances in molecular science, screening, and experience of the industry in drug optimisation have highlighted the need for more predictive data. Specific heuristics were used to identify sections in supplementary data required, typically the presence of a relevant gene name (e.g. OCT1), a chemical structure (e.g. tamsulosin), numerical data (e.g. 13.14), and an assay endpoint description and unit (e.g. IC50, micromolar).

70 million diverse supplementary data documents were gathered from public sources, requiring ca. 35TB of storage space for storage and processing. On top of these www.ipimediaworld.com

data, a software pipeline was built, enabling parallelisation, a component-based architecture for best-in-class named entity recognition (NER) tools, and enhancement of compound, gene, assay endpoint, etc. dictionaries.

Further work was performed around image identification and segmentation, and for image data application of optical character recognition (OCR) technologies.

Optimisation of the software was required to minimise the false-positive rate in prioritised documents, and manage the complexities of handling Unicode characters across different stages of the process and sometimes corrupt source supplementary data. Expert review was performed to identify the causes of false positives and negatives, and the results were fed back into earlier stages to identify the most relevant subset of documents.

Once sufficient positive examples had been identified, a document-relevance classifier was developed to automatically assign a probability of a new document having information relevant to the subject area.

This used features from the document and boosted performance using interpublication author and citation linkages.

These processing steps led to a focused set of documents for processing into a set of consistently annotated bioassay data, similar in principle to the bioassay data stored in the ChEMBL database. Significant technical challenges still remain in achieving completely automated discovery and extraction of novel data, although this work provided significant steps towards this goal and ongoing research is underway to optimise the delivery of data-on-demand further.

Proven Success A vital element of DeepADMET was demonstrating the practical application of deep learning imputation to drug discovery data and projects. After an initial proof-ofconcept using public domain data published

by Whitehead et al.1, collaborations with pharmaceutical and biotech companies and academic groups enabled applications in real-world scenarios and across ongoing projects. These resulted in peer-reviewed publications and public presentations of the results.

A collaboration with Constellation Pharmaceuticals demonstrated an application to heterogeneous biological endpoints, including activities against biological targets and phenotypic screens, and a range

of absorption, distribution, metabolism and excretion (ADME) assays. A critical aspect of this project was that it validated the application of Intellegens' algorithm to small-scale data sets, typical of those encountered in individual drug discovery projects; in this case, the full data set comprised approximately 2500 compounds.

The success in this scenario contrasts with most deep learning methods, which typically require very large data sets to achieve an improvement over conventional machine learning methods. Full details of this project were published by Irwin et al.2 and described in a presentation that can be viewed at https://bit.ly/practical_deep_ learning.

Takeda Pharmaceutical Company Limited's collaboration involved an application to a data set of approximately 700,000 compounds and 2500 experimental endpoints. This demonstrated the scalability of the approach to global pharma-scale data sets and explored applications to predicting target activities in projects, a diverse range of ADME and toxicity (ADMET) properties, and highthroughput screening data. The presentation detailing the results is available to watch at: https://bit.ly/large_scale_imputation.

Translation of in vitro ADME data into in vivo disposition was the subject of a collaboration with AstraZeneca, (described in a presentation available to watch at http://bit.ly/PK_prediction). In this application, sparse in vitro ADME data and predictions from in silico models were used to impute pharmacokinetic parameters and concentration-time curves, achieving industryleading results.

Finally, an application to guiding the design of new compounds, by making predictions for 'virtual' compounds, was explored in collaboration with Open Source Malaria (OSM). A model of multiple antimalarial experimental endpoints was built and applied to prioritisation of new compound designs for synthesis and testing.

OSM ran this as a competition, and of the compounds proposed by the participants, and synthesised and tested in vitro by the OSM team, only the compound selected by our model was confirmed to have to be active against the malaria parasite Plasmodium falciparum with an IC50 better than 1 µM, as illustrated in Figure 1. Full details of this project were published by Tse et al.3 and Irwin et al.4 and can be viewed in a presentation at https://bit.ly/AI_guided_ design.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 37

Drug Discovery, Development & Delivery

Figure 1. The compound submitted by four organisations to the Open Source Malaria projects. For each, the structure and experimentally-measured activity against Plasmodium falciparum are shown. Data from Tse et al.3.

Delivering a Secure and Scalable Platform The final element of the DeepADMET project was developing a platform that would enable the deployment of deep learning imputation for interactive application on an ongoing basis. This development addressed several challenging and sometimes conflicting goals: •

The platform must be scalable from small data sets, for organisations pursuing only a small number of projects, to global pharma-scale data sets containing millions of compounds and tens of thousands of experimental endpoints.

•

The models should be updated regularly, to reflect the latest experimental data and enable 'active learning'.

•

Data within the system must be secure.

In particular, compound structures and details of the assays are critical intellectual property (IP) for drug discovery organisations.

The results must be intuitive and accessible interactively, enabling scientists to quickly answer relevant questions for their drug discovery

•

38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

projects and prioritise experimental and synthetics resources.

The requirements for scalability, regular model building and interactivity motivate a cloud deployment, providing access to large-scale computational resources in a cost-effective way to handle large data sets. However, there is an understandable reluctance to transfer information on the most sensitive IP to the cloud. The solution to this conflict was a unique hybrid onpremises/hybrid architecture, as illustrated in Figure 2. In this architecture, the most

sensitive information is processed only in the 'blue zone', hosted on the customer's private network. The platform connects directly to in-house databases, via a 'Query Interface', to refresh the data regularly, e.g. nightly. The raw data is pre-processed in the blue zone to clean and prepare them for modelling, remove compound structures and anonymise compound identifiers and assay information. The resulting, anonymised data are encrypted before transfer to the 'green zone' where the models are built and a matrix of results stored and searched. These results are

Figure 2. Schematic of the platform architecture. The 'blue zone' is hosted on-premises and manages sensitive information, such as compound structures and assay identifiers. The 'green zone' is hosted in a virtual private cloud, providing scalability for modelling, storage and searching of the 'massive matrix' of experimental and imputed data, but has no access to the most sensitive information.

Spring 2021 Volume 13 Issue 1

Drug Discovery, Development & Delivery true 'big data' for larger data sets because they can comprise tens of billions of data points. Rapid searching and retrieval from this 'massive matrix' and building of the underlying models require the scalability in the green zone provided by a cloud-hosted environment.

Users reside in the blue zone, on the organisation's private network, so results returned from the green zone to the blue zone are decrypted and matched back to the compound structures and assay information to which the data relate.

These results can be used to proactively highlight new opportunities to find highquality drug candidates, by 'filling in' missing data based on limited experimental results for existing compounds. For example, when a scientist performs a query to find compounds that meet their requirements, the massive matrix of imputed results can be searched in real time, in addition to experimental data in the company database, to find additional compounds based on confident predictions, as illustrated in Figure 3(a).

Where experimental measurements have been made, these can be compared with the probability distributions generated by the model to highlight unlikely results. Due to the variability of biological experiments, we know that experimental errors arise that can mislead optimisation projects or result in false negatives that result in missed opportunities. Automatically flagging unlikely results identifies valuable candidates for retesting, as illustrated in Figure 3(b).

Figure 3. Example workflows with which to use the results of an imputation model. (a) Querying a database for compounds with desired criteria can also return compounds with values that are imputed to meet the criteria (blue cells) as well as those that have already been experimentally measured (white cells). (b) An outlier (purple cell) can be investigated to compare the measured value (red line) with the probability distribution for the corresponding imputed value. (c) Selecting a target assay (dark blue column) for prediction and additional assays that can be performed suggests the most valuable assays and compounds to measure with which to make better predictions for the best compounds for the target assay. www.ipimediaworld.com

The models can also drive 'active learning', suggesting the most valuable data points which, if measured, will result in the greatest improvements in predictive accuracy and hence better selection of compounds for downstream, expensive experiments. Also known as 'design of experiments', this powerful approach is illustrated in Figure 3(c), whereby a scientist can select one or more 'target' assays, followed by lower-cost or higher-throughput assays that can be run as input to predict the target assays. The output highlights the most valuable experiments and compounds to measure, that will most accurately identify the best compounds for the target assay. This approach reduces the experimental effort required to progress compounds and make the best decisions quickly.

The workflows illustrated in Figure 3 demonstrate how the results from sophiINTERNATIONAL PHARMACEUTICAL INDUSTRY 39

Drug Discovery, Development & Delivery

John Overington

sticated AI algorithms can be used intuitively and interactively by scientists who are not expert data scientists.

Conclusion The DeepADMET project is an example of a successful collaboration, bringing together publicly-funded and SME organisations.

It illustrates how cutting-edge science, software engineering and drug discovery experience can come together to deliver state-of-the-art technology that will have a major impact on the discovery of new medicines.

REFERENCES 1.

2.

3.

4.

T. Whitehead, B. Irwin, P. S. M. Hunt and G. Conduit, "Imputation of Assay Bioactivity Data Using Deep Learning," J. Chem. Inf. Model., vol.

59, no. 3, pp. 1197-1204, 2019.

B. Irwin, J. Levell, T. Whitehead, M. Segall and G. Conduit, "Practical Applications of Deep Learning to Impute Heterogeneous Drug Discovery Data," J. Chem. Inf. Model., vol. 60, no. 6, pp. 2848-2857, 2020.

E. Tse, L. Aithani, M. Anderson, J. Cardoso-Silva, G. Cincilla, G. J. Conduit and e. al., "An Open Drug Discovery Competition: Experimental Validation of Predictive Models in a Series of Novel Antimalarials," (preprint), 2020.

B. Irwin, S. Mahmoud, T. Whitehead, G. Conduit

40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Professor John studied Chemistry and then completed a PhD in protein modelling and sequence-structure relationships, he then joined Pfizer, leading the Molecular Informatics Structure and Design department. This was followed by Inpharmatica, where he led the development of a series of computational and data platforms to improve drug discovery. In 2008 John was central to the transfer of this technology to the EMBL-EBI, as the ChEMBL database. John then joined Artificial Intelligence technology company – Stratified Medical (later renamed BenevolentAI), applying machine learning to the development of biomedical data extraction and integration strategies. In 2017 John joined the Medicine Discovery Catapult as CIO, where he leads the development and application of informatics approaches to promote and support application of informatics to drug discovery. and M. Segall, "Imputation versus prediction: applications in machine learning for drug discovery," Fut. Drug Discov., vol. 2, no. 2, 2020.

Matt Segall Tom Whitehead Tom is Head of Machine Learning at Intellegens, a machine learning spinout from the University of Cambridge that specialises in handling sparse and noisy experimental data. He has a PhD in theoretical physics from the University of Cambridge, and is now leading the application of Intellegens' novel deep learning approaches to a wide variety of industrial applications.

He is also developing a series of application-specific machine learning modules to address high-value data analysis bottlenecks and is interested in developing machine learning approaches to solve previously intractable problems in a range of scientific and engineering fields.

Matt has a Master of Science in computation from the University of Oxford and a PhD in theoretical physics from the University of Cambridge. As Associate Director at Camitro (UK), ArQule Inc. and then Inpharmatica, he led a team developing predictive ADME models and state-of-the-art intuitive decision and visualization tools for drug discovery and responsible for Inpharmatica's ADME business, including experimental ADME services and the StarDrop platform. Following the acquisition of Inpharmatica, Matt led a management buyout of the StarDrop business to found Optibrium which continues to develop research technologies and ground-breaking artificial intelligence services to improve the efficiency and productivity of drug discovery.

Spring 2021 Volume 13 Issue 1

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Drug Discovery, Development & Delivery

The Danish Approaches for Personalised Medicine – For the Benefit of Patients The term tailor-made or personalised medicine covers a form of drug treatment in which the use of drugs is adapted to the individual patient's very special disease situation and biological characteristics. The desire is to achieve a unique treatment result that best meets the individual patient's genetic profile. The Danish healthcare system offers unique possibilities for realising the potential of personalised medicine.

Based on a common national information infrastructure, the new genome centre in Denmark will ensure the entire setup for collecting samples from patients for genome sequencing and analysing data for research or treatment purposes.

The data and research will be used to identify medicines that have the best effect on different diseases and patient groups. Together with data from existing national registries and databases, as well as the national biobanks, Denmark has established a solid national framework to develop tailored personalised medicines to benefit patients.

Not All Medicine Benefits All Patient Groups Humans are not alike, which is why we often react differently to the same medicine.

One of the great benefits of personalised medicine is that the quality of treatment will increase significantly. It will be possible to give patients the treatment that gives the greatest possible effect the first time, while reducing the risk of side-effects. This will improve the patient's quality of life.

With personalised medicine, it is possible to achieve more health for the money, as patients receive correct medication the first time. Unnecessary money is not spent on costly medications that are not effective or perhaps even harmful to the patient.

A large proportion of the medicines offered in healthcare today do not work or are directly harmful to the patient. It is both stressful for the individual patient and a socio-economic challenge.

This is a global problem that is also manifesting itself in the United States, among other places. Figure 1 is from a US 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

study conducted by the US Food and Drug Administration (FDA) and illustrates the proportion of patients who do not benefit from the medication they receive for their disease.

Why Personalised Medicine The term "personalised medicine" was first used in April 1999 in an article in the Oncologist: "New era of Personalised Medicine - Targeting Drugs for Each Unique Genetic Profile"1. Since then, and especially in the last few years, the number of scientific articles specifically dealing with personal medicine has grown steadily, so that today hundreds of articles on the subject are published every year.

Figures from the United States compiled by the Food and Drug Administration (FDA) show that 12 out of the 48 new drugs approved in 2019 were in the personal medicine class – that is, 25 per cent of all new drug approvals2. While the total percentage of personalised medicines approved by FDA decreased from both 2018 (42%) and 2017 (36%), the FDA approved many new indications for existing, approved personalised medicines, providing new treatment options for many patients.

And furthermore, several biosimilars for personalised medicines were also approved.

The development in personal medicine is therefore not just a future scenario – it is reality here and now.

Diseases develop differently from patient to patient, who in turn respond differently to the same medication. Some need one tablet, while others need two tablets for it to have an effect. Some people benefit from a standard treatment – while others simply experience side-effects. One perspective when using personal medicine is that medicines are only given to those patients who are known to have an effect on the medicine – this is already seen today in connection with the use of certain cancer medicines.

Another perspective is that one can predict via molecular diagnostic tests whether a patient will have the desired effect or experience serious side-effects with a given drug treatment. One step is

therefore to have knowledge of a drug that is particularly effective in relation to patients with a particular genetic profile. Another step is to have a test that can determine if the specific patient has a genetic profile that matches the use of the desired drug.

Therefore, drug and concomitant diagnostic tests are usually closely related when talking about personal treatment – illustrated in Figure 2.

The use of personalised medicine was previously most prevalent in the treatment of cancers. This makes sense, since cancer is one of the therapeutic areas that has the most ineffective drugs for treatments (Figure 1). However, today the treatment principle is being transferred to many other disease areas. In 2019, there were a significant number of approvals for the treatment of non-cancer disease. Seven of the 12 new personalised medicines drugs, approved by the FDA in 2019, were for indications outside the field of oncology.

This includes the approval of ZolgensmaTM (onasemnogene abeparvovec-xioi) for the treatment of spinal muscular atrophy. This gene therapy corrects bi-allelic mutations in the SMN1 gene2.

The Danish Approach to Personalised Medicine Many countries, like Denmark, are in the process of developing strategies for personalised medicine. One of the first initiatives in the Danish Personalised Medicine Strategy was the establishment of a National Genome Center in May 2018.

The National Genome Center provides genomics-based analysis and insights related to diagnostics of relevant patient cases at Danish hospitals.

The establishment of the National Genome Center means that Denmark will be able to raise the overall effectiveness of personal medicine across the entire healthcare system to a level that would otherwise take a long time to achieve within individual hospitals. The Danish effort is unique in three areas. Denmark focuses on personal medicine benefiting patients immediately. In addition, the country has public control over the use of information from all Danish patients3. And finally, Spring 2021 Volume 13 Issue 1

Drug Discovery, Development & Delivery understand which treatments work, and which do not5. Users of the Danish healthcare system expect treatment that offers them the best possible outcomes. Therefore, another component of the personalised medicine strategy in Denmark involves the establishment of a Data Analytics Center, under the Danish Medicines Agency, which will open November 2020.

The Data Analytics Center will be the first of its kind in Europe, supporting regulatory decision-making as well as creating a globally unique research infrastructure to be used by industry partners. With the Data Analytics Center, the Danish Medicines Agency is able to offer more precise scientific advice to the pharmaceutical companies in the development of new medicines, including medicines for people with rare diseases or small patient groups.

Figure 1. Percentage of patients for whom drugs are ineffective

Denmark develops personal medicine nationally, which means that patients receive the same treatment opportunities, no matter where in Denmark they received healthcare services.

acts under two different legal frameworks: health legislation and personal data legislation.

Over 80 per cent of medical specialists today use genetic diagnostics4, and the National Genome Center will ensure that they can perform comprehensive genetic examinations at a uniformly high level of quality, no matter where in the country the patient receives treatment. With joint efforts, doctors and health researchers will have better conditions for improving the treatment of future patients.

Data is protected through two levels of security. First, at a system level, the core of the infrastructure is a supercomputer system with enhanced security features.

Second, at an individual level, patients must first be informed of the patient's right to self-determination over his or her genetic information, which is derived from biological material in connection with patient treatment and which is kept by the National Genome Center. The patient can decide for themselves whether to consent to having genetic information stored in the National Genome Center, which may only be used for one's own treatment and for purposes that have an immediate connection to it. Patients may also consent to have their data used for such activities as research. The National Genome Center again has no commercial interests, which means, among other things, that the information in the National Genome Center may not be used by insurance companies.

Is Data Secure?

A question that was very quickly asked by the Danish population was whether data from the National Genome Center is secure.

In the wrong hands, DNA could be misused and harm the individual citizen. For that reason, today the National Genome Center

Data Analytics Center – First of its Kind in Europe For many years, the Danish healthcare system has systematically collected data and knowledge about the Danish population's diseases and treatment. It has helped researchers and health authorities to better

The new National Genome Center’s supercomputer system has been established, and the centre has tested and prepared a new, national infrastructure, which consists of a national whole genome sequencing centre and a high performance computing centre. Selection is already underway for the first patient groups to be offered comprehensive genetic analyses (whole genome sequencing).

www.ipimediaworld.com

The new centre is especially relevant in Denmark, since the public health service system includes numerous comprehensive registers and statistical databases of extremely high quality – not least Denmark’s national personal identification number system6. This means all residents in Denmark are registered with the public health service system and other health organisations where they are receiving treatment.

The Danish national personal identification number system and the numerous statistical databases, disease registers and journal records offer unique opportunities for epidemiological research of extremely high quality. Given that the aforementioned registers have a long history in Denmark, Danish researchers also have a long tradition of performing register research, public health studies, and epidemiological research, all of which are important prerequisites for the identification and segmenting of relevant target segments and patient populations within personalised medicine.

With the development of the Data Analytics Center, the regions and universities will have obtained secure, confidential, and flexible access to the use of health data. This means more accurate diagnostics and better treatment for the patient. The goal is more use of personalised medicine in the Danish healthcare for the benefit of all patients.

The Danish National Biobanks Biobanks are an important component of personalised medicine, and strongly support scientific progress in the stratiINTERNATIONAL PHARMACEUTICAL INDUSTRY 43

Drug Discovery, Development & Delivery

Figure 2. Standard treatment vs. personalized medice

fication of the population, biomarker discovery, and validation to drive progress in personalised medicine. Furthermore, biobanks are also an essential tool for new drug discoveries and drug development and play an important role in the whole process of patient prevention and prediction, follow-up, and therapy monitoring and optimisation7.

Denmark has several national biobanks.

The aim of these is to provide an easy, transparent and safe entrance to biological material in Denmark. The Danish national biobanks create an infrastructure that supports diagnostics and research, based on collaboration across the country to help make personalised medicine a reality; another important factor in the Danish Personalised Medicine Strategy.

The Danish national biobanks contains register with detailed information on the specimens available in the biobanks, which are physically located in the pathology departments at the hospitals around in Denmark. Danish registers provide detailed

information about the entire population.

Linking biological specimens in the biobanks to information contained in the Danish registers creates unique possibilities for research.

Conclusion Being able to develop new pharmaceutical products is essential for successfully developing new therapies in the emerging paradigm of personalised medicine.

Individualised and tailored treatment is necessary for patients to receive the right treatment the first time, manufactured to fit optimally with any unique genetic profile. The Danish National Strategy for Personalised Medicine supports the use of genomic data to offer patients more targeted and efficient medicine. Denmark's electronic healthcare data for the entire population, which goes 40 years back in time, connects to the Danish Biobank Register of 25 million biological samples.

These linkages between these data sources generate a unique patient identifier system, a key enabler for personalised medicine at a national level in Denmark.

REFERENCES 1.

2.

3.

4.

5.

6.

7.

Langreth R, Waldholz M et al. New era of personalised medicine: targeting drugs for each unique genetic profile. Oncologist (1999) 4 (5) Mullard A. 2019 FDA drug approvals. Nature Reviews Drug Discovery (2020) January (19) Beedholm-Ebsen R. Denmark - The Heart of Life Sciences for Clinical Trials. International Pharmaceutical Industry (2013) 5 (1) Lundgren B, Løngreen P. www.altinget.dk/ sundhed/artikel/nationalt-genom-center (2019) September Beedholm-Ebsen R. Trends in Drug Development – In Denmark and Globally International Pharmaceutical Industry (2018) 10 (2) Sørensen HT, Pedersen L et al. Danish clinical quality databases - an important and untapped resource for clinical research. Clinical Epidemiology (2016) October (8) Kinkorová J. Biobanks in the era of personalized medicine. The EPMA Journal (2016) 7 (4)

Rasmus Beedholm-Ebsen Rasmus Beedholm-Ebsen is Special Advisor within Life Science, at Invest in Denmark, under the Ministry of Foreign Affairs of Denmark. Rasmus received his PhD in Medicine at Aarhus University, Denmark and worked as a post-doc at the Department of Medical Biochemistry at Aarhus University before joining Invest in Denmark.

Recently Rasmus received a Bachelor of Commerce degree and he holds a MBA. Besides, Rasmus is Scientific Expert Reviewer for the European Commission.

Email: rasbee@um.dk

44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 45

Drug Discovery, Development & Delivery

Key Considerations when Repositioning a Known Drug for Inhalation Therapy In recent years, the pharma industry has seen significant growth in finding new uses for old drugs. Geraldine Venthoye, Executive Vice President Product Development, Vectura, looks at the opportunities for inhaled drugs.

The repurposing and repositioning of existing drugs has become an increasingly common way to find new treatments in recent years. While the main purpose of this strategy in the past may have been to manage the lifecycle of a product by extending the intellectual property (IP) coverage, regulators are increasingly taking a negative view of repurposed projects whose sole benefit is IP extension. Rather, they expect there to be some form of therapeutic rationale, whether this is a new therapeutic application, or an improved method of drug delivery.

Repurposing involves taking a drug already approved for one indication and getting it approved for another. New indications are increasingly for an otherwise poorly-served, rare or neglected disease, where the potential patient population is small and there is little commercial incentive for de novo research. It might also be used for the same indication, but in a new formulation that allows administration via a different route. A repositioning project, meanwhile, might give an existing drug an improved or altered product profile, while keeping the same administration route. Drug repositioning and repurposing now accounts for almost a third of all new drug products, generating half a trillion dollars in annual sales across all dosage forms.1 Either way, there are advantages both for patients and for innovators.

For innovators, any drug repurposing or repositioning programme will need to offer a compelling commercial case. Every company will have a proprietary method for determining which potential projects are worth pursuing, but the broad principles are the same: decide whether there is an unmet clinical need, whether there is space in the market, and whether the potential revenues are likely to be sufficiently high to cover the 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

development outlay with a decent return on investment.

Inhaled Drug Opportunities A reasonable starting point for the number of potential repositioning and repurposing projects that might successfully use inhaled delivery would potentially be around 300.

Discounting those that do not fit with a company’s existing R&D strategy will typically reduce the list by about two-thirds, leaving at least 100 projects on the longlist (see Figure 1). The next step is to consider the potential for meeting clinical needs and filling a gap in the market. It is crucial that there should be a compelling scientific rationale for the new application; if it fulfils a true unmet medical need, then the project passes on to the next stage of the triage.

But even if it does not meet this criterion, if the patient population is sufficiently large, and the disease sufficiently widespread, there may still be a place for it in the market alongside existing products, particularly if there is the prospect of an improved delivery mechanism.

Projects deemed to have clinical potential are then assessed for their commercial possibilities, including whether there would be sufficient differentiation from any competition, and how crowded the marketplace for that indication is already.

The projected development timescale should also be considered; if it is too long it will have a big impact on the overall cost of the project, and the time required to recoup the costs of development may make the project unviable.

For projects that pass this hurdle, the next question is whether or not technical advantages are available. Applying proprietary technology, either from in-house or external sources, that will offer measurable improvements in functionality and performance will make the project more resistant to competition if it reaches the market, and will bring significant commercial advantages.

The final consideration is the overall feasibility of the project. There are numerous challenges involved in developing inhaled drug products, and a company needs to

be certain that it has established in due diligence that it has the research capabilities required to carry the project to a successful conclusion. Advice should be sought from key opinion leaders and expert scientific advisers as to whether there may be specific challenges within the development process, and importantly, whether it is likely that the project could take advantage of abbreviated regulatory pathways.

From the original list of more than 300 potential projects, the shortlist is likely to number fewer than 10. For inhaled products in particular, technical considerations will play a huge part in whether or not the project can achieve both technical and commercial success.

Figure 1: Key considerations in selecting an asset to develop

Advantages of Repurposing or Repositioning Repurposing or repositioning offers a number of commercial benefits. First, there is the prospect of a faster route to market than for a new molecule, as most of the necessary safety trials will already have been completed. Preclinical testing will, therefore, be limited to anything specific to a new mode of delivery and dosage level.

A repurposing or repositioning can usually be completed in less than 10 years, and often significantly faster, compared with the 10–15 years that a novel API or biologic drug typically takes from initial idea to marketing approval. This reduction in time is reflected in lower costs, and the rates of attrition will be lower as so much information is already known.

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Drug Discovery, Development & Delivery Second, there may also be the opportunity to resurrect programmes that never reached the commercial phase, either because they were deemed unviable or were withdrawn and halted for a lack of efficacy in late-stage clinical trials. Some or all of the development work may well have been done, making the repurposing or repositioning route a relatively fast and low-cost way to bring the product to market.

Both scenarios can be used to extend IP coverage, driving additional revenue for innovators. For example, a drug approved for an adult might undergo repositioning for the paediatric market, which may or may not include changing the delivery mechanism, such as moving from a metered dose inhaler to a smart nebuliser or a dry powder inhaler to suit the expanded patient population.

Having an effective delivery device can also provide an additional layer of market protection from competition.

Improving patient compliance may also be a source of commercial benefits for innovators; if patients take a drug correctly and therapeutic benefits are established, it is likely to be prescribed more widely.

Creating novel formulations that allow

for a different route of administration can improve delivery or compliance, and may also permit the treatment of further conditions. Alternatively, a new formulation may be administered via the same route, but changes or improvements to the product profile, perhaps by enabling extended release delivery, could reduce the dosage burden on the patient.

This is particularly true of inhalation drugs. Metered dose inhalers can be challenging for some patients to use correctly, because of the requirement to time the dose with breathing in, and if a patient fails to do this properly, the benefit of the drug may not be felt, leading to discontinuation of treatment. A device that removes this requirement for careful breath and dose synchronisation has compelling commercial advantages.

Modern nebulisers are not only smaller and easier to use than older models, but can also have smartphone connectivity built in, through Bluetooth, for example. This ability to monitor treatment can be invaluable, not only for compliance, but to allow physicians to keep track of how well the treatment is working. Some smart nebulisers use flow and

Figure 2: Sales growth in the respiratory market [source: WHO, British Lung Foundation, GSK, BI]

volume control to better target the nebulised aerosol to the correct part of the lung, or within a specific type of inhalation profile.

Such modern devices are designed to be breath-actuated, which means they only nebulise while the patient is actively inhaling and therefore less expensive drug is wasted.

For example, iloprost (Ventavis) is used to treat the rare, debilitating, fatal disease pulmonary arterial hypertension (PAH) and can extend life expectancy from approximately three years to 10–12 years.

However, the drug needed to be dosed nine times a day via a nebuliser, and each dose took 10 minutes to administer, representing a huge treatment burden to the patient.

Repositioning the drug to be delivered by an advanced smart nebuliser has allowed the dosing time to be reduced from ten minutes to three minutes. Although this must still be done up to nine times a day, it marks a substantial improvement in the patient's quality of life. The device also gives the patient feedback, leaving them feeling more in control of their treatment and their disease.

Unmet Market Needs There are a significant number of unmet clinical needs in respiratory medicine, besides PAH, that make the global respiratory market an attractive proposition for repurposing and repositioning drugs. These conditions include not only asthma and chronic obstructive pulmonary disease (COPD), which together comprise more than half the whole market value for inhaled products, but also more niche diseases such as cystic fibrosis (CF), pulmonary hypertension and idiopathic pulmonary fibrosis (see Figures 2 and 3). And although there have been significant advances in treatment for CF in recent years, these are effective only in a small sub-population of patients. Despite this, CF is outstripping the market with an annual growth rate of 10%, against a background of 6% growth overall.

These conditions may only have small patient populations, but they represent high-value opportunities. Furthermore, if a project is given orphan drug status, it may qualify for abbreviated approval processes and fast-track designation, as well as financial incentives such as fee waivers and tax credits, and even extended exclusivity, which is particularly important for a repurposed product.

Figure 3: Total respiratory market 2017-25 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Inhalation is most familiar as a route for administration for diseases and conditions that directly affect the lungs, including Spring 2021 Volume 13 Issue 1

Drug Discovery, Development & Delivery opportunities to develop combination products whereby two APIs are dosed together. One example is GSK's inhaled combination asthma product, Trelegy Ellipta, which treats COPD patients with a corticosteroid, a long-acting muscarinic antagonist as well as a long-acting beta agonist simultaneously.

Delivering drugs systemically via the lungs can also be of benefit. Inhaled delivery offers fast onset of action: a drug absorbed deep within the lungs can be taken up by the bloodstream almost as quickly as one that is injected subcutaneously. This extremely rapid onset of action would be hugely beneficial for time-sensitive applications such as pain relief, migraine treatment, or even schizophrenia. It can also be possible to dose within tight therapeutic windows, or to mimic the pharmacokinetic profiles that are achieved with more invasive delivery routes such as injection. Inhaled administration can also be potentially used to effect mucosal vaccination.

Inhalation also has a major advantage over oral administration, as the drug avoids the first pass metabolism of the liver. This can prevent the formation of problematic

metabolites, which may cause undesirable side-effects, and can also be advantageous if the drug is susceptible to being broken down by digestive enzymes in the gut.

REFERENCES 1.

Naylor, S. et al. Therapeutic drug repurposing, repositioning and rescue. Drug Discov. World Spring Edition 2015

Some drugs that use the lungs for systemic delivery have already reached the market, including levodopa, used to treat Parkinson’s disease, and MannKind’s inhaled insulin product, Affrezza, although take-up of the latter has been limited.

Future Opportunities The repurposing and repositioning of existing drugs for new applications is becoming increasingly appealing, given the escalating cost, risk and time involved in de novo development. While there is significant unmet medical need in conditions affecting the lung, both common and rare, there are other opportunities for harnessing inhalation technologies for systemic delivery and for combination drug products. Combining a differentiated enabling technology with an expedited approval pathway can provide both a rapid route to market and the concomitant commercial benefits to the pharma company, and, more importantly, significant benefits to patients.

Geraldine Venthoye Dr. Geraldine Venthoye leads Vectura’s Pharmaceutical Development and Medical Device Development departments, and is responsible for the strategic and technical advancement of the company’s products, development services and technology platforms. She joined Vectura in June 2016 upon completion of the merger with Skyepharma PLC, where she had been executive vice president pharmaceutical development since 2013, having joined Skyepharma as head of the inhalation business unit in September 2003. Dr. Venthoye is a UK registered pharmacist and holds a doctorate degree in pharmaceutics from the University of London.

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 49

Drug Discovery, Development & Delivery

A Greener Future for the Inhalation Industry: A Critical Year for our Climate The urgent threat of climate change is the age-defining issue of our generation, and we are reaching a defining moment for our industry. The inhalation industry is committed to reducing their carbon footprint and establishing processes which are more sustainable. A global commitment to establishing a greener future must happen now; the industry’s proactive approach will address the major environmental concerns of pMDI manufacture – the carbon footprint of the propellant.

The adverse effects of greenhouse gases on our climate are well documented.

This is not a new revelation, rather, this industry has gone through a similar issue before! The issue being adapting the way we formulate MDIs to develop more sustainable products, whilst maintaining the safety and functionality.

This article explores the legislative and economic drivers of why the industry needs to adapt, and crucially why now is the time to act. It is also important to ground ourselves and remember why we develop medicines; to better the health of the public and save lives. The effective delivery of medicines still remains the priority. The challenge to produce sustainable products cannot compromise the safety, efficacy and patient adherence of inhaled medicines.

The 1987 Montreal Agreement was the catalyst for the first-wave development of sustainable pMDIs. The successful phase out of CFCs with F-gases had a positive impact on ozone depletion and to some extent the carbon footprint1. Through significant investment by the industry, less ozonedepleting alternatives were developed (HFA-134a, HFA-227 & DPIs). Manufacturers of pMDIs understand that sustainable products cannot be developed on sentiment alone – it is the commitment to invest that ultimately allows the change to alternative propellant systems!

Two major pharmaceutical companies, Astra Zeneca and Chiesi Group, have recently 50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 1

committed to investing in alternative propellant pMDIs. Both companies have committed to launch a ‘greener’ inhaler by 20252,3. Other major companies have yet to publicise their commitment. Given the timelines for pharmaceutical product development and regulatory approval of new medicines, 2025 may seem challenging.

The importance of acting now is evident for both environmental and economic issues. It is clear the environmental crisis cannot wait; if and when the current propellant supply is phased out, commercial production of current inhalers becomes unrealistic.

As a producer of reliever medication, Pharmaserve North West has committed to future-proofing our facilities, products and processes. The importance of safeguarding the supply of critical medicines has been highlighted through the COVID-19 crisis. It is a collective responsibility to ensure global delivery of life-saving pMDIs. The issues and challenges posed by the investment into two prospective greener propellants have been addressed as a matter of urgency.

Working closely with industry leaders to ensure our approach to the ‘greener’ inhaler does not impact the health of the public.

Proposed Solutions HFO-1234ze and HFA-152a have been highlighted as potential replacements of

HFA-134a and HFA-227ea. Isobutane was also considered and is currently used in topical aerosols; the inhalation safety concerns make this a less favourable option1. Both propellants address the environmental concerns of pMDIs, however each has limitations and challenges which must be overcome before commercial production.

HFA-134a

HFA-152a

HFO-1234ze

Liquid Density (g/mL)

1.21

2.7

1.29

ODP GWP

0 1300

0 138

0 <1

Atmospheric Lifetime

13 years

1.4 years

18 days

Flammability

n/a

LFL 3.8%

n/a

Table 1

It has been well documented that HFA-152a is actively being developed for use in pMDIs. The properties are similar to those of HFA-134a – but critically for suspension formulations, the liquid density is significantly lower. Despite this, early formulation studies have shown that the performance is surprisingly good4.

Although the data is promising, it is critical that further studies are performed to understand the propellant performance for more inhaled APIs and also solution formulations. The performance of HFO1234ze may look more promising, given the closeness of its properties to HFA-134a. The transferability, due to these similarities, may expedite the development process.

Spring 2021 Volume 13 Issue 1

A SUSTAINABLE FUTURE FOR pMDIs Would you like to be involved in shaping the future of pMDI’s and safeguard your business and products?

Pharmaserve NW has developed an approach to rapidly assess the feasibility of alternative, low GWP propellant formulations. With nearly 50 years’ experience in inhaled medicines manufacture & development, we are using our knowledge and innovation to develop and manufacture the next generation of pMDI’s. By acting now, we you can safeguard your product(s) market share as the industry adapts to address the global warming crisis.

Whether it’s transferring from HFA-134a/HFA-227ea or developing a new product, we can combine your formulation knowledge and our expertise to bring your ‘greener’ products to market with prompt efficiency.

START DEVELOPING GREEN ALTERNATIVE PROPELLANTS NOW For more information on how we are investing in future proofing our products, visit: www.pharmaservenorthwest.co.uk/ shapethefuture To discuss how we can partner to bring your inhaled medicine to market with a green propellant, contact: www.ipimediaworld.com adam.kay@pharmaservenorthwest.co.uk

INTERNATIONAL PHARMACEUTICAL INDUSTRY 51

Drug Discovery, Development & Delivery Both propellants have been shown to have good compatibility with currently used materials in MDI componentry. Particular focus has been on the behaviour observed when the propellant contacts elastomer and polymer materials used in the valve constructions. In light of the change, the concern of compatibility is actively being addressed by componentry suppliers, with commitment to understanding and developing new ‘sustainable’ componentry.

The critical path activity of the development of a new propellant is the generation of long-term safety data. HFA-152a is expected to finalise the DMF in 2022; the FDA granted approval to proceed with clinical trials which began in February 20205. The generation of the toxicological data package is also backed by Chiesi to help achieve their target of a commercial product launch in 20253,6.

The current uses for HFO-1234ze are focused on commercial and industrial products, although the manufacturer does have a pharmaceutical division and patents for use as a medical propellant. The initial safety data shows that it has a low acute toxicity. Any timelines for extensive toxicological assessment have yet to be published and will no doubt be the ratelimiting step.

The appeal of HFO-1234ze is clear – due to its lower flammability the propellant can be directly transferred to existing equipment and facilities. Whereas, HFA-152a is considered flammable and significant investment is required to mitigate the flammability risks and ensure safe handling. Although the technology is established for topical sprays (historically this technology has been used to safely fill cans with isobutane), the timeline to scale up production is somewhat hindered by the safety requirements. Novel manufacturing methods using ‘tablet dispersion drug loading’ are also being considered, which form stable suspensions when the propellant is added – the separation of the propellant filling stages, reduced batch sizes and mixing requirement mitigates some safety concerns7.

It is also important to consider the DPI approach. Whilst the product, technology and processes are established today, there are considerations to be made to ensure the global access to inhaled medications to all demographics. The breathing ability of paediatric and geriatric patients makes DPIs less feasible, particularly in reliever medicines. The economic impact of a 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

wholesale switch was studied, showing the prescribing costs of the switch would increase around 10% on average8. It is also important to note this is not feasible for all patients – the pMDI must remain and hence the environmental challenge remains.

Legislative & Environmental Drivers With the rising concern in the urgency of the environmental crisis, the Kigali amendment to the Montreal protocol was signed in 2016 and presented the industry with a new challenge – tackling greenhouse gas emissions. The amendment aims to phase out global consumption of HFA by around 85% by 2047 to address the environmental concerns9,10.

There is currently no legal or regulatory requirement to change propellant outside of the Montreal agreement in the US. More and more pressure is being applied by environmental lobbyists to phase

out these high global warming potential propellants. The corporate responsibility to protect the environment is evident – however the ‘choice’ of the solution has commercial motivation. It is clear that all solutions are positive; for the environment and the enhancement to patient. Multiple therapeutic solutions allow additional factors to be considered when prescribing medicines: patient ability, preference, costs and adherence.

Economic Drivers Besides from the moral obligations as residents of this planet, there are also commercial incentives to act promptly.

The economic driving factors of propellant price increases and supply chain issue serve as a warning sign for currently marketed products.

Figure 3 (Koura) is based on probable phased withdrawal of ‘F’ gas quota exemption

Figure 2

Figure 3 Spring 2021 Volume 13 Issue 1

Drug Discovery, Development & Delivery by the EU commission over six years. The increase in cost is mainly due to the need, under the revised regulation, to purchase quotas. This also applies to HFA-227ea, which may lead to it becoming unavailable for medical use. This is a median case; there are more aggressive scenarios. This applies to both 134a and 227ea. In addition, regulation of industrial uses of 227ea may lead to it becoming unavailable for medical use.

By performing early-stage feasibility studies, a commercial strategy can be defined.

The translation of existing medicines can follow several routes (DPI, alternative propellant, nasal spray). It is critical for both the patient and business to have assurance that their current product portfolios are safeguarded against the industrial change.

The initial investment to assess the feasibility of product translations to sustainable alternatives is relatively small, with relatively big dividends. The focus on being the ‘firstto-market’ for each medicine is becoming more evident. The market share of current HFA-134a pMDIs cannot be maintained going forward. Capitalisation on this industrial change ensures businesses are not cannibalised by the lack of agility on this issue.

Safeguarding Approach Pharmaserve have outlined a safeguarding approach to streamline the development and supply of sustainable pMDIs. Through

working closely with industry leaders and suppliers, a suggested approach and timeline has been outlined, primarily to ensure the maintenance and supply of safe sustainable products, whilst maintaining a commercially viable operation within the inhalation industry.

REFERENCES 1.

2.

3.

4.

5.

6.

Medical and Chemical Technical Options Committee, 2018 report. Available from: https:// ozone.unep.org/sites/default/files/2019-04/ MCTOC-Assessment-Report-2018.pdf AstraZeneca. Investing in a sustainable future for patients with respiratory disease. Available from: https://www.astrazeneca.com/mediacentre/articles/2020/investing-in-a-sustainable-future-for-patients-with-respiratorydisease.html.

Farmaceutici C. Chiesi outlines €350 million investment and announces first carbon minimal pressurised metered dose inhaler (pMDI) for Asthma and COPD 04/ 12/2019.

Available from: https://www.chiesi.com/en/ chiesi-outlines-350-million-investment-andannounces-first-carbon-minimal-pressurisedmetered-dose-inhaler-pmdi-for-asthma-andcopd/.

Noakes T, Corr S. The future of propellants for pMDIs; Drug Delivery to the Lungs 27; pp.

61-64, 2016.

Koura. ‘Green’ medical propellant receives FDA approval to proceed to clinical trials.

Available from: https://www.prnewswire.com/ news-releases/green-medical-propellantreceives-fda-approval-to-proceed-to-clinicaltrials-300998598.html.

Corr S. Development of HFA-152a as an environ-

7.

8.

9.

10.

mentally sustainable propellant for pressurized metered dose inhalers; Inhalation 14; pp. 12-17, Oct 202.

Taylor G, Warren S, Tran C inventors; Cardiff Scintigraphics Ltd assignee. Pressurized metered dose inhalers and method of manufacture. United States Patent 9981092B2.

2018. May 29.

Pritchard JN. The Climate is Changing for Metered-Dose Inhalers and Action is Needed.

Drug Des Devel Ther. 2020 Jul 29;14:3043-3055. doi: 10.2147/DDDT.S262141. PMID: 32801643; PMCID: PMC7410333.

United Nations Environment Program. The Kigali Amendment to the Montreal Protocol: HFC Phase-Down. OzonAction Fact Sheet OZFS/16/ 11_1. Paris, France: United Nations Environmental Program; 2016.

European Commission. Regulation (EU) No 517/ 2014 of the European Parliament and of the Council of 16 April 2014 on Fluorinated Greenhouse Gases and Repealing Regulation (EC) No 842/2006 Text with EEA Relevance.

Available from: Https://eur-lex.europa.eu/legalcontent/EN/TXT/PDF/?Uri=CELEX:32006R0842& qid (10) =1594982827385&from=EN.

Adam Kay A chemical engineering graduate from the University of Leeds, Adam has spent 4+ years focusing on inhalation product development. His experience includes the end-to-end development of inhalation products, from formulation to commercialisation, leading EMA product submissions – as well as process development, optimisation and equipment commissioning. In 2020, Adam took the role of Business Development Manager to bring his technical expertise in product & process development to support the existing BD team.

Email: adam.kay@pharmaservenorthwest.co.uk Figure 4 www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 53

Clinical Devices Medical and Medical Research

Connectivity, Cybersecurity and Medical Devices: What are the Threats?

Developers of medical devices are taking inspiration from the use of connected technology in consumer products; realising that smarter devices offer huge benefits to patients, POC workers, and manufacturers.

Today’s medical devices can be connected within wider network infrastructure, perform remote upgrades to software with relative ease, and be accessed through smartphones.

Whilst these technologies can be used to increase the functionality of devices – for example, improving device usability, or allowing manufacturers to perform remote post-market surveillance – they can also open them up to cyber-threats.

We will look at ways to identify common risks and vulnerabilities in medical devices and how to defend against them, to help put you on the right development path.

An Overview of Cybersecurity Risks As medical device manufacturers, designers, and distributors, many of us are familiar with the concepts and processes of risk management throughout the lifecycle of a medical device, as described in ISO 14971.

During medical device development, risks are identified and subsequent mitigations are devised to reduce the probability, or severity, of these risks. Following this, manufacturers will then monitor the device throughout its lifecycle, to assess new threats and the effectiveness of any mitigations.

and manage, cybersecurity events; recover from events, minimising their impact.

Whilst not specific to medical technologies, the cybersecurity framework is targeted towards cybersecurity risks in critical infrastructure, in which we can include medical devices. It recognises that the impacts of security incidents can be wide-reaching and highly variable.

The risks relating to a device depend largely on its purpose and the specific design employed, however it is still possible to generalise some of the possible harms associated with cybersecurity across all medical devices.

Direct Patient Harm In the worst cases of cybersecurity incidents, an attacker could intentionally misuse your device in an attempt to cause harm to patients, caregivers, and others involved.

For example, if a wireless interface is used to control your device functionality and trigger therapeutic behaviour, an attacker could use this interface to control and manipulate the device. Without protection, the interface is directly vulnerable to attack.

Loss or Manipulation of Data Where sensitive or personal data is in transit, it can be exploited by attackers to steal identities, extort individuals, or sell to unscrupulous organisations. In many cases we already protect this data within our IT systems, as it falls under the scope of legislation such as GDPR.

Cybersecurity risks are handled in a similar way. In the United States, the National Institute of Standards and Technology (NIST) provide a cybersecurity framework1 which, in some ways, is similar to our understanding of ISO 14971.

Attackers may also manipulate critical data; medical data could be modified by attackers in a way which leads to changes in the patient’s treatment. In current times, consider the manipulation of COVID-19 test results. A false-negative test leads to potentially infectious patients continuing in their lives, with well-known consequences.

At a high level, the cybersecurity framework involves five over-arching activities.

Identify threats, assets, and impacts; protect assets against these threats using appropriate safeguards; detect cybersecurity events when they occur, and devise ways to detect events; respond to,

Denial of Service A “denial of service” (DOS) attack is one which is used to block your services. The most common takes the form of server downtime due to an enormous number of access requests in a short period. Alternatively, as we saw with the WannaCry

54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

attacks on health services, services can be blocked by ransomware which holds your system hostage.

The WannaCry attacks on healthcare providers showed the wide-reaching effects when critical services are inaccessible, with delays to surgeries and treatments for thousands of patients worldwide.

Leapfrog Attacks In connected systems, no point in a network stands in isolation. This allows the connected system to distribute information between nodes and improve patient outcomes.

Unfortunately, for attackers it also provides a mode of entry for a much wider system.

By attacking one poorly protected device, it may be possible to attack the wider system.

A system is only as secure as the least secure device within it. It is therefore imperative that all developers strive to make their devices as secure as possible.

Loss of Intellectual Property It is possible for your software to be read and interpreted directly from the device, allowing attackers to understand how your device works. In doing so, attackers may re-create your functionality; thus taking advantage of the development work your team has completed in order to reach the market in a significantly shorter period.

Identifying and Assessing Vulnerabilities While there is a wide array of cybersecurity risks in medical devices, it is important to remember that each individual device, system, and product line will introduce and observe unique risks.

When assessing risks associated with cybersecurity, it is important to assume that an attack will occur and that any vulnerability will be abused. It can be useful to consider these risks under the assumption that no mitigations are in place.

Where mitigations exist, we can assess the likelihood of them failing; for example, data encryption can fail if a weak encryption method is used.

The concept of “guaranteed” risks is applied commonly during medical device software development, with a similar Spring 2021 Volume 13 Issue 1

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talkfuture@pciservices.com INTERNATIONAL PHARMACEUTICAL INDUSTRY 55

Clinical Devices Medical and Medical Research rationale. This means ensuring that all cybersecurity risks are taken seriously and that mitigations are applied to prevent (as far as possible) these risks being exploited.

Such a rationale helps to account for the nature of some cyber attackers, who may attempt to break into a device “for fun”.

Similarly to device safety risks, we can examine risks from two directions; the top down, and the bottom up.

Top-down Top-down cybersecurity assessments look at the overview of the system, identifying higher-level features or resources which could be exploited, and then identifying how these could be accessed or manipulated. To start this, try asking yourself what could happen if an asset was stolen, corrupted, or misused.

Example assets include patient information being used to blackmail the patient.

High-power energy sources, such as X-Ray and RF, could be used to cause direct harm or disruption to nearby equipment. Clinical data such as test results or images, when manipulated or corrupted, could lead to an incorrect treatment regimen being applied.

Having understood our assets, we look to understand the routes of attack. A method of documenting this is to record an attack tree; as described by B. Scheneir2. Attack trees examine the different ways that an asset can be attacked or that an event can occur. This breakdown continues until we have exhausted the possibilities. Consider a sensitive data file on a device which currently has no protective measures. An attack tree diagram clearly illustrates how the file data can be stolen.

The top-down approach provides a robust way to identify potential weaknesses in the early stages of projects, focusing from a higher level and ensuring that we consider cyber-risks when identifying device requirements. It should be repeated regularly during device development, to ensure new assets are identified and managed throughout the lifecycle.

Bottom-up The bottom-up approach is commonly performed during the detailed design, and implementation, phases of the development cycle. The assessment begins from a finer level of detail than the top-down approach in order to identify harms caused, or assets accessed, when failure occurs. This can be considered similarly to a failure mode and effects analysis (FMEA), where teams examine the risk of failures of individual components from a design which is already well understood. Our mitigations focus on ways to prevent, or detect, failures of specific design elements.

If we take a computer as an example, we examine the details of our system to identify how it could be misused or attacked. We can identify that it has a network connection available for use, so the next step involves looking at how it could be exploited:

This bottom-up approach can help you to identify further risks which a top-down approach may miss, as you are examining the methods and interfaces which an attacker can use directly. By using both approaches, the goal is to discover as many security vulnerabilities as possible, and to then determine the mitigations for them.

Common Vulnerabilities and Mitigations It is rare to encounter an entirely new cybersecurity problem during design; this is where the common vulnerabilities list becomes useful. This highlights well understood vulnerabilities, such as specific network protocol exploits, which can be used by teams as a reference when identifying potential risks. The UL2900 cybersecurity standard expects that all common vulnerabilities which apply to your system have been mitigated against, so this is an important starting point.

So how can we mitigate against the risks we have identified? Whilst each application will have specific needs, we can consider some common concepts which should be considered during device development.

Data at Rest Many devices store data at rest which could be considered sensitive, for example user

passwords, clinical data, or platform data.

Attackers could access such data directly through a device’s hardware, or the user interface. The most common mitigation to protecting data is to encrypt the data, using robust encryption mechanisms such as AES256.

Encrypting data is a key way of reducing opportunities for attackers to understand it. This involves scrambling the data so that only a device with an encryption key can interpret it. It is important that encryption keys are, themselves, protected from attackers – you don’t leave the key to your house under a plant pot! Whilst in some cases, storing encryption keys in protected memory may be acceptable, in many cases 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Spring 2021 Volume 13 Issue 1

Medical Devices a trusted platform module (TPM) may be required to ensure that keys are protected adequately.

TPMs are bespoke hardware modules which provide a wide range of security functions, including managing cryptographic key storage and exchange, encryption and decryption of data, and the authentication of users and data. These can be integrated within your device to ensure high levels of device security. They are also produced by a wide range of manufacturers, allowing development teams to select the most appropriate device for their application’s needs.

Data in Transit Data in transit, meaning data transferred between devices, is vulnerable to eavesdropping, where an attacker can steal information while it is being sent. A simple solution, as discussed for data at rest, is to ensure that data in transit is encrypted from “end-to-end”. The principle of end-to-end encryption is simple; whenever data is being transferred between parties it is encrypted.

In a system which is encrypted end-toend, the encryption keys are only known by parties which need to use the data. Consider data transfer between two computers on a network which must be secure. The sender PC can encrypt the data before transfer using a key known only by the sender and recipient. This data is handled by the server but cannot be read as it does not understand the encryption keys.

Until now we have considered a system where the encryption key is shared by both the sender and recipient of data. In reality within this system (known as symmetric key encryption) the shared encryption key may act as a single point of failure for multiple devices. A more secure approach is to use asymmetric key encryption which, in brief, allows two devices to determine an encryption key which is unique to each communications session, without needing to know the encryption key ahead of time.

An example of asymmetric key exchange is the Diffie-Hellman protocol. Where feasible, developers should aim to use these asymmetric key exchange protocols for interdevice communications.

Data Authenticity Alongside data being observed, another option for attackers is to disrupt data in transit and to modify it. This can be performed through “man in the middle” type www.ipimediaworld.com

attacks, or through random data corruption from electromagnetic interference. Corrupted data can introduce significant risks, for example incorrect test records, or incorrect instructions to remote modules. We can identify corrupted data by attaching robust signatures (such as SHA256) to the data. With these, the recipient confirms that the data is valid by calculating the signature of the received data – if this does not match the provided signature then the data cannot be authenticated.

We have already examined the idea of encrypting our data during transit, but how do we know that the system providing our new software image is from a genuine source? This is the second part of authentication; determining if the data is valid and from a valid source.

Here we can take inspiration from website and server certificates, used to confirm that the communication is with the correct host.

Once an encrypted communication session has been established, we can exchange authentication data between devices, establishing that we are communicating with a valid recipient.

User Access Most of the examples we have discussed have been around remote attackers gaining access to data through networked interfaces, but in reality the simplest way to access data on a device is to gain access to the device itself. In most computer systems, we are familiar with the use of passwords to secure a device; however, these can become a point of entry for attackers if they are discovered.

The greatest protection here is to ensure that strong password policies are used on devices. Each device and device user should have a unique password, and access to data should be restricted where appropriate.

The use of system-wide default passwords for all devices is highly discouraged, as it offers attackers an opportunity to access all devices within an ecosystem. Devices will need some form of default password when configured, but this should always be a unique password to the given device.

In California this is a legal requirement3 for all internet connected devices, and should ideally be factored within all manufacturing and distribution processes.

In Summary In the modern, connected world of medical

devices, ensuring that the device remains secure must be considered part of the overall risk management process. We have discussed some of the risks associated with cyber-attacks, common vulnerabilities which can be exploited, and examples of mitigations which can be applied.

Unfortunately, even if we protect against all foreseeable methods of attacks, cybercriminals will find novel ways to break through your defences. The key to ensuring a secure device lies in starting the risk management process early, planning how security threats can be removed once they are understood, and continuously monitoring and evaluating the potential for new threats.

By recognising assets and mechanisms for attack in the early stages of design, your system architecture can include cybersecurity from the outset.

REFERENCES 1.

2.

3.

https://www.nist.gov/cyberframework/onlinelearning/five-functions https://www.schneier.com/academic/archives/ 1999/12/attack_trees.html https://techcrunch.com/2018/10/05/californiapasses-law-that-bans-default-passwords-inconnected-devices/

Thomas Watts Thomas is an electronics and software engineer at Team Consulting, where he specialises in embedded software development for medical devices.

Before joining Team, Thomas worked for SLE in London; a company focusing on neonatal ventilator systems. He has an MEng in Biomedical Engineering from Imperial College London.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 57

Clinical and Medical Research

Digital Medication Adherence in Clinical Trials

Drug developers work tirelessly progressing their compounds from the laboratory to the clinical phases, and rigorously assessing the medication use in Phase II and Phase III clinical trials is crucial to the future success of the treatment. Significant investment of time, resources and capital is employed in these developments – yet they are still, to a great degree, vulnerable to the risks associated with medication non-adherence.

There’s no one single reason for poor adherence during studies. Poor investigator / patient communication can leave participants unsure on how to use the drug, or on the protocol itself. Today’s increasingly complex clinical trials have complex, hardto-follow dosing regimens; some people stop taking the medication if they feel no benefit; and some people just forget. The fear of side-effects and protocol burdens can also play a part.

In order to address this pervasive problem of striking magnitude in clinical trials, solutions are needed that seamlessly measure and analyse patient medication adherence in clinical trials, research settings, and professional healthcare systems to support successful management of patient adherence to medication. To manage medication adherence in clinical trials, some sponsors use biased and imprecise measurement methods such as pill counting, blood sampling and patients’ self-reporting, while others have chosen digital medication adherence monitoring.

Electronic compilation of dosing history data, enabled by smart packages, has been proven to be the most effective way to monitor, identify, manage, and document the risks associated with poor patient adherence to medications in clinical trials. Overlooking medication nonadherence in planned clinical trials can lead to significant issues. However, they can be easily diminished by implementing a mitigation plan based on proven digital medication adherence monitoring systems.

58 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Key Risks Associated with Patient Nonadherence to Study Medications Poor medication adherence is a threat to drug development. Half of clinical trial participants do not adhere to the dosing regimen specified in the protocol. Studies have shown that 40% have stopped taking their medication as per the protocol by month 12. Additionally, a further 15% do not implement the study dosing regimen.

Such protocol deviations go undetected by traditional measures of adherence, such as pill counts, blood sampling and subjects’ self-report.

It’s hard to overestimate the impact of medication non-adherence across the healthcare ecosystem.

In terms of clinical trials, it can skew drug efficacy calculations and risk-benefit profiles. Sponsors often need to increase sample sizes to compensate for the adherence-related drain on study power, an expensive, time-consuming process that can significantly delay regulatory approvals.

For patients, risks include severe health complications, premature deaths, and lower quality of life. All of this can create increased healthcare services demand in addition to wasted medications. To that end, only 30% of approved drugs on the market are commercially successful.1 The variability in patient outcomes from medication nonadherence is a significant contributor to this low success rate.

The Perils of Unreliable Methods to Assess Medication Adherence The financial and practical implications of medication non-adherence are wideranging, but they are not new. Sponsors have grappled with these issues for decades.

Traditionally, they have employed methods such as directly observing the patient taking their medication or measuring drug titre levels in blood or urine. Other traditional methods include pill counts, patient diaries and questionnaires, or measuring prescription refill rates, clinical responses, and physiologic markers.

However, these methods do not compare to the accuracy and precision of digital medication adherence monitoring. In fact, electronic monitoring is the most objective, precise way to understand medication adherence during a clinical trial.

It typically involves an electronic microcircuit being placed within the medication packaging, which automatically generates a timestamp each time the patient takes their medication.2 The timestamps are then stored within the packaging’s ‘memory’ and then wirelessly transferred to a central, cloud-based software system where it’s downloaded and analysed.

Advanced digital medication adherence monitoring provides complete oversight of the adherence metrics and risk indicators that matter the most. According to studies, smart electronic packaging/device monitoring is 97% accurate, ahead of drug levels and markers (70%), pill counts (60%), healthcare professional ratings (50%) and patient self-reporting and electronic patient diaries (27%).3 Such digital solutions not only provide more reliable data, but also more detailed data about actual patient adherence behaviours, such as dose frequency, dose interval and medication dose timing – details that traditional methods do not capture. Electronic monitoring shows that medication non-adherence, especially dosage omission or changing intervals, is more prevalent than previously recognised.

Furthermore, this data is captured passively, as it does not require the patient to take any additional action. Solutions that do require an additional action, such as a digital diary on an app, will often be ignored by poorly adherent patients.

These digital monitoring systems enable sponsors to improve drug efficacy by managing patient adherence to the study medications. For typically less than 1% of the overall clinical study cost, pharmaceutical companies can safeguard their clinical trials and build a stronger argument about the efficacy of their medication from the development stage to commercialisation.

Spring 2021 Volume 13 Issue 1

Clinical and Medical Research Crucial Benefits in Using Digital Medication Adherence Monitoring The electronic compilation of dosing history data is enabled by smart packages, and is a highly effective way to passively monitor, identify, manage and document the risks associated with poor patient adherence to medications in clinical trials.

As well as improving adherence, data quality and integrity, medication adherence technology, including smart packaging, gives investigators all the information they need to intervene and change behaviour before the problem impacts on the quality of the study.

Adherence-informed clinical trials enable sponsors to optimise drug development by deploying proactive evidence-based risk mitigation strategies, which in turn boosts compliance with FDA and ICH guidance.

Crucially, the role of electronic adherence monitoring does not stop at study end. The collected data gives sponsors a window into how the product is used in the real world, and this key patient behavioural data can prove invaluable when developing a successful marketing strategy.

Digital medication adherence monitoring is straightforward and easy to implement in a clinical study without delays in the supply chain, and is applicable to all study participants without additional burden for the patients. Patients are empowered as the solution is usable without any necessary configuration by patients. Such innovations

are non-intrusive and completely frictionfree for patients. There is no need to combine an app and a phone, nor to recharge/change the battery.

The captured data is used to provide a proxy for drug intakes. In turn, this enables the patient’s actual medication adherence to be mapped and graphs and charts and other forms of tangible analysis to be produced that illustrate a patient’s medication intake over a given period of time.

Conclusions According to the World Health Organisation,4 up to half of patients with long-term conditions do not take their medications as prescribed, and numerous studies have shown that this problem extends to clinical trials.5 The impact is huge. It can lead to the underestimation of drug efficacy, delay market approval, and drain study power. In short, it is an expensive problem.6 Traditional measures, such as pill count, blood sampling and self-reporting, have done nothing to alleviate this problem.

Manual methods can be biased or just not sensitive enough to detect issues.

Experts acknowledge that digital medication adherence monitoring enables the most objective and precise medication adherence monitoring. Evidence-based digital medication adherence monitoring systems can help improve clinical results and conclusions, maximising the chances of success in clinical trials. Sponsors can

improve drug efficacy by managing patient adherence to the study medications. For clinical trials, the integration of this kind of tool will improve the speed and accuracy of medication adherence assessment and intervention efficacy. It will also potentially decrease the rate of unnecessary interventions. It very well can be the critical factor in a trial that fails or succeeds.

REFERENCES 1.

2.

3.

4.

5.

6.

www.syneoshealth.com/2019-health-trends https://www.oecd-ilibrary.org/social-issuesmigration-health/investing-in-medicationadherence-improves-health-outcomes-andhealth-system-efficiency_8178962c-en Blaschke TF, Osterberg L, Vrijens B, Urquhart J. Adherence to medications: insights arising from studies on the unreliable link between prescribed and actual drug dosing histories.

Annu Rev Pharmacol Toxicol. 2012;52:275-301 https://www.who.int/chp/knowledge/ publications/adherence_report/en/ https://www.oecd-ilibrary.org/social-issuesmigration-health/investing-in-medicationadherence-improves-health-outcomes-andhealth-system-efficiency_8178962c-en Breckenridge A, Aronson JK, Blaschke TF, Hartman D, Peck CC, Vrijens B. Poor medication adherence in clinical trials: consequences and solutions. Nat Rev Drug Discov. 2017 Mar;16(3):149-150. doi: 10.1038/nrd.2017.1. Epub 2017 Feb 3. PMID: 28154411.

Bernard Vrijens Dr. Vrijens holds a PhD from the Department of Applied Mathematics and Informatics at Ghent University, Belgium. He currently leads a research program investigating (a) the most common errors in dosing using a simple but robust taxonomy, (b) particular dosing errors that can jeopardize the efficacy of a drug, and (c) the optimal measurement-guided medication management program that can enhance adherence to medications and maintain long-term persistence. Dr. Vrijens is also the co-author of seven book chapters, over 100 peer-reviewed scientific papers, and named as inventor on 6 patents.

He is a founding member of the International Society for Medication Adherence (ESPACOMP), and an active member of several EU- and US-funded collaborative projects around the theme of adherence to medications.

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Clinical and Medical Research

Pharmacokinetic and Statistical Considerations in Firstin-human Clinical Trials – Case Study Article Given the exploratory nature of firstin-human (FIH) studies, the question of what – if any – statistical analysis is required for pharmacokinetics (PK) data has long been a contentious topic. This article, and corresponding case study, seeks to explore the topic in more depth.

A Bit of Background The purpose of FIH studies is to evaluate the pharmacology, tolerability, and safety of the drug or investigational medicinal product (IMP) in humans for the first time.

They are designed to reveal the best dose and dose regimen to be used in later Phase II studies. Typically, FIH studies include a single ascending dose (SAD) part, which is subsequently followed by a multiple ascending dose (MAD) part to investigate the dose proportionality and the drug accumulation and steady state, respectively.

FIH studies often investigate myriad drugs’ behaviour, and therefore other study elements are sometimes added to assess food effects, formulation effect, gender differences, drug-drug interaction (DDI), age effect, and more.

In this case study, however, the emphasis is on the assessment of dose proportionality, steady state and food effect. Let’s first examine the two key steps that need to be completed prior to performing any statistical analysis for pharmacokinetics (PK) data.

The Two Key Preparatory Steps 1. Create an Analysis Plan Clearly outline the different methods that you’ll be using in a detailed analysis plan before conducting any statistical analysis.

This should cover at least the PK parameters to be estimated, descriptive statistics, graphical presentation, and inferential statistical analysis.

Your analysis plan should detail the descriptive statistics that you’ll estimate on both PK concentrations and PK parameters. These might include mean, standard deviation, coefficient of variability (CV), 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

minimum, median, and maximum for PK concentrations and in addition, geometric mean and geometric CV for PK parameters (except for sampling time-related parameters like tmax, tmin and tlast where only minimum, median and maximum are presented).

Your analysis plan should also outline how your statistics will be graphically presented – in other words, the different tables, listings, and figures (TLFs) that you’ll be creating.

Individual and mean PK profile plots are created by plotting the concentrations in function of the time. The PK profile is best described in two different graphs; one plot on linear-linear scale to have a good visual evaluation on the peak concentrations and one on logarithmic-linear scale to clearly visualise the distribution and elimination phase.

Depending on the precise objective of the study, one or more inferential statistical analyses can be performed. That being said, remember to interpret the outcome of inferential statistical analyses in FIH studies with caution. The number of subjects is limited, so these analyses should only be thought of as exploratory – they’re not meant to prove any effect.

2. Review the Data Once you’ve thoroughly outlined your analysis plan, you can then begin defining the PK population of your PK analysis.

Thoroughly check for any abnormal concentrations or profiles, as these might be excluded from your PK population. There are a variety of reasons why this might occur. For example, there may be samples with a large time deviation from nominal time; samples that were switched; certain protocol deviations (e.g. incomplete dose); concomitant medications; or adverse effects (e.g. vomiting or diarrhoea for orally administered drugs). Furthermore, subjects might be poor or extensive metabolisers, which can significantly alter PK data.

The analysis plan should clearly define the rules surrounding which PK parameters

(e.g. terminal half-life and AUCinf) should be considered as reliable. The study design should foresee that the sampling time is long enough to reliably estimate the terminal half-life. However, be aware that if the bioanalytical method is not sensitive enough, the estimation of some parameters (like the extrapolated part of the AUCinf) can be inappropriate.

Finally, consider the impact of missing data on the reliability of parameters (e.g. data missing around the possible tmax of the profile).

Based on your data review, you can then begin to fine-tune the PK population if necessary, by removing any unreliable or unexpected data and/or subjects that might adversely affect the results of your PK analysis. Note: the rules for removing data should be defined in the analysis plan.

The Case Study This case study presents the data from a randomised, double-blind, placebocontrolled, dose-escalation study in healthy subjects. The study consists of two parts: a single ascending dose (SAD) as well as a multiple dose (MD) part. In the SAD part, five cohorts of eight subjects (of whom six received the active treatment and two received the placebo) received a single oral dose, ascending from 10 to 300 mg. In one cohort (150 mg), a two-period crossover substudy was performed to investigate the food effect. In the MD part, one cohort of eight subjects (of whom six received the active treatment and two received the placebo) received a 300 mg q.d. dose for seven days.

Analysis Plan The analysis plan clearly outlines: the PK parameters with their calculation rules, the list of the TLFs, and the descriptive and inferential analysis to be performed. Three different inferential statistical analyses are described: the dose proportionality (SAD part); the steady state (MD part) and the food effect (SAD part – cohort 150 mg).

Inferential Statistical Analyses Let’s dive into the various inferential statistical analyses in more depth.

Spring 2021 Volume 13 Issue 1

Clinical and Medical Research Dose Proportionality This examines the data from the SAD part of the study. In this article, only AUCinf is discussed. The dose proportionality of AUCinf is investigated using three different methods: linear model, power model and graphically.

The outcome of the inferential statistical analysis shows that one is not within the 90% CI of the slope (0.75–0.90). Based on this, it can be concluded that AUCinf increases less than dose proportionally over the dose range 10 to 300 mg.

Linear Model In the linear model, PK parameters are plotted against the dose, though no logtransformation of the PK parameters was performed. Note: a regression line with a confidence interval (CI) can also be included.

The graph (Figure 2) also includes a reference line in red with a slope equal to one – this highlights that the slope of the PK parameter is lower than one. Although the PK parameter seems to increase in a doseproportional manner, if no reference line is

similar. In Figure 3, it’s clearly visible that with higher doses, the dose-normalised PK parameters are lower – thus the PK parameter increases less than dose proportionally.

Figure 2: Dose Proportionality: Graphical evaluation: box plot

Conclusion: Dose Proportionality Analysis We’ve examined three different methods to evaluate dose proportionality: linear model, power model, and a box plot graphical representation.

Figure 1: Dose Proportionality: Linear Model

In the statistical model of the linear model, the PK parameter is the dependent, and the dose administered is the fixed effect. In addition, a quadratic term (dose*dose) can be included to investigate the non-linearity of the effect.

plotted, it’s not obvious from the graph that the slope is lower than one.

The models show different conclusions.

The linear model clearly shows that AUCinf is increasing in a linear way with increasing the dose. On the other hand, the second

The outcome of the inferential statistical analysis shows a significant (p-value <0.05) dose-effect and a non-significant (p-value >0.05) dose*dose-effect. Based on this, it can be concluded that there is a linear increase in PK parameters with increasing dose, and there is no quadratic effect.

Only use this model to draw conclusions about dose linearity – not about dose proportionality.

Figure 2: Dose Proportionality: Power Model

Power Model The power model can be used to conclude on dose proportionality. In this model, the log-transformed PK parameter is plotted against the log-transformed dose (Figure 2).

If the 90% CI of the slope contains one, dose proportionality can be concluded.

Graphical Evaluation The simplest way to evaluate if the PK parameters increase dose proportionally is to plot the dose-normalised parameters in function of the dose. In this article, a box plot is presented (Figure 3), although other types of graphs are also suitable.

The statistical model for the dose proportionality analysis has the logtransformed PK parameter as dependent and the log-transformed dose as a fixed effect.

Note that the axis with the dose is categorical in these types of graphs.

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Dose proportionality can be concluded if the dose-normalised PK parameters are

method (power model), shows that this is no dose-proportional increase in AUCinf – rather, that AUCinf increases less than dose proportionally. The simple box plot provides the same conclusion.

The key message is that you need to understand what you plot to draw the correct conclusion: is it a linear or doseproportional increase? For example, we can clearly see that while the data looks nicely scattered in the power model, this doesn’t necessarily mean that there is a doseINTERNATIONAL PHARMACEUTICAL INDUSTRY 61

Clinical and Medical Research proportional increase in PK parameters. For this to be the case, one would need to be included in the CI of the slope.

Steady State The data of the MD part is available, i.e. one cohort with six subjects that received active treatment (daily dose of 300 mg for seven days). For the steady state, the trough concentrations are considered, and it’s investigated using three different methods: linear trend, pairwise comparison, and graphically.

Linear Trend Log-transformed trough concentrations are tested in repeated measures ANOVA (Analysis of Variance). Attainment of steady state is determined by stepwise testing for linear trends over successive ranges of days.

Orthogonal polynomial coefficients are used for the contrasts (e.g. Day six to eight: -1 0 1). Steady state can be concluded when the 95% CI of the slope of the day range contains zero.

Based on the results from the ANOVA model (Table 1), steady state is reached by Day three.

Figure 4: Steady State: GRaphical Evaluation: mean (+/-SD) and individual through concentrations

Since multiple comparisons are done, adjusted p-values are considered. Based on the results from the ANOVA model (Table 2), steady state is reached by Day four.

Table 1: Steady State: Linear Trend

Conclusion: Steady State Analysis For the steady state assessment, three different methods are discussed. Based on the first method (linear trend), steady state is reached by Day three. The second method (pairwise comparisons) shows that steady state is reached by Day four. The same conclusion could be drawn from the graphical presentation.

The first two methods require intensive SAS programming. The latter method, a simple plot, has a more subjective way of drawing a conclusion. Nevertheless, a similar estimate on steady state achievement can be taken as with the inferential statistical methods described above.

Food Effect The food effect is evaluated in one cohort (Cohort four -150 mg) of the SAD part. In this cohort, six subjects received the treatment in a fed or fasted state following a two-way crossover regimen. In this article, however, only AUCinf is discussed.

Table 2: Steady State: Pairwise Comparison

Pairwise Comparison Alternatively, you could use pairwise comparison to conclude on steady state between days. When comparing trough concentrations day by day, steady state achievement can be concluded when there is no longer a significant difference between the days.

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Graphical Evaluation Lastly, steady state can also be evaluated using a graphical presentation of the trough concentrations in function of the day (Figure 4). Steady state achievement can be concluded when the trough concentrations are practically stable. Based on the mean profile, steady state is reached by Day four.

The food effect of AUCinf is investigated using both inferential statistical analysis and a graphical evaluation.

Inferential Statistical Models Two different inferential statistical models are tested. The first is described in the protocol by client and included treatment as fixed effect and subject as random effect (Model A).

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Clinical and Medical Research The second model followed the FDA guidance1, including treatment, period, sequence and subject nested within sequence as fixed effects (Model B).

The outcome of both models is quite similar (Table 3).

Graphical Evaluation Just as before, the food effect can also easily be evaluated using graphs (Figure 5). Here, two types of graphs are proposed. In the first graph, mean (+/- SD) and individual data are presented versus the food condition (fasted or fed), with different symbols assigned

Table 3: Food effect: Inferential Statistical Models

to potentially exclude unreliable or unexpected results prior to starting with the analysis. It then went on to explore graphical presentation and clearly outlined why inferential analyses should only be thought of as exploratory.

REFERENCES 1.

FDA guidance “Food-Effect Bioavailability and Fed Bioequivalence Studies”

Figure 5: Food Effect: Graphical Evaluation: mean (+/-SD) and individual data and boxplot

The LSM and LSM ratio are similar, with minor differences in the CI. The p-values are not discussed as the study is not powered to perform this food effect.

The results of the food effect also demonstrate the importance of the correct interpretation of the results. Solely based on the LSM ratio, one can conclude that there is a statistically significant food effect, given that 100% is not included in the LSM ratio CI. Although this may be true, the LSM ratio is about 91% and thus this is not a clinically relevant decrease. It’s better to instead consider the bioequivalence limits, i.e. that 90% CI of the LSM ratio should fall within 80 to 125%. Based on this, it can be concluded that there is no difference between administration under fed or fasted conditions. www.ipimediaworld.com

per subject. In the second one, the data is presented in a box plot.

We could conclude a significant effect from the food conditions if there were no (or limited) overlap between the treatment data. In both graphs, however, the two food conditions still overlap – meaning there's no impact on the food conditions.

Conclusion: Food Effect Analysis For the food effect analysis, both inferential statistical methods and the graphical evaluation gave a similar outcome.

Conclusion This article explored different statistical analysis methods for pharmacokinetic data in FIH studies. It delved into the importance of preparing properly – of making sure to develop a detailed statistical analysis plan and to review the data thoroughly

Joanna Magielse After completing her PhD in Pharmaceutical Sciences at the University of Antwerp (Belgium), Joanna Magielse started working at SGS as Pharmacokineticist in 2012. Over the years, pharmacokinetic knowledge has been gathered and now, Joanna leads the pharmacokinetics team as Team Manager Pharmacokinetics. The SGS Pharmacokinetics team has a wide range of experience in Phase I clinical trials. Joanna and her team have presented various pharmacokinetic related topics at PhUSE and CDISC conferences over the past years.

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Clinical and Medical Research

How Approaches to Clinical Research are Set to Change in the ‘New Normal’ 2020 was an extraordinary year for the whole of humanity. But for one sector, it proved to be particularly defining – clinical research.

Even before the COVID-19 pandemic, the world of clinical research was undergoing large-scale changes, utilising new technologies and moving towards a more patient-centric approach to attract volunteers, increase efficiency, protect patient safety and speed up the delivery of new medicines.

Then, in March 2020, as societies all but shut down, the scientific community faced their biggest challenge yet – to identify treatments and develop new vaccines for the novel coronavirus – while the world collectively held its breath.

But while unprecedented feats were achieved in clinical research for COVID-19, many other important projects focusing on a wide range of diseases and conditions, including cancer, were halted and patient recruitment stopped entirely.

In fact, a survey showed that more than 75 per cent of pharma and biotech companies faced significant disruption in their clinical trials last year – the full effects of which we are yet to understand.

In this story of two halves, there are winners and losers. But what do the events of 2020, confounded with other forces such as political shifts and innovative technologies, mean for the future of clinical research, both in the UK and globally?

The Lasting Impact of COVID-19 Vaccine Trials on Clinical Research Developing and delivering new vaccines for COVID-19 worldwide has been – and continues to be – one of the greatest challenges faced by modern pharma.

It’s been over 13 months since the Chinese health authorities and the WHO announced the discovery of a novel coronavirus on 9th January 2020, followed by the full sequence of the coronavirus 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

genome being shared over the weekend of 11th–12th January.

According to the COVID-19 vaccine tracker, at the time of writing, there are currently 10 authorised and approved vaccines being delivered to patients worldwide, and many more remain in development.

Israel is currently leading the way with its vaccination campaign and is already witnessing the positive real-world impact – falling infection, hospitalisation and death rates.

It’s quite remarkable writing these words only a year on since the pandemic became a worldwide public health emergency. The international scientific community, investors and governments alike have come together at this time of crisis for the good of mankind.

It’s not an overstatement to say this feat was only made possible by the flexibility and ingenuity demonstrated by those in the clinical research field and the goodwill of trial participants. And the hard work continues to this day, as more treatments are being tested and other vaccines make their way through the clinical trials process.

The research sector should be applauded for adopting new approaches at rapid speed in order to cope with the challenges presented by COVID-19. Many of these transitioned to virtual approaches overnight to interact with and monitor trial patients, made possible by a range of innovative technologies.

Moving forwards, it’s important these lessons learned during the pandemic are remembered and adaptations are made to protect the research process against future emergencies.

What’s clear is that COVID-19 will permanently accelerate the use of remote technologies in clinical trials, reducing the need for in-person visits, to drive efficiency and uphold the highest levels of patient safety.

Realising the Potential of Patient-centric Clinical Trial Design Clinical research is the heartbeat of pharma-

ceutical drug development; a rigorous process of testing and analysing real-world data to be certain a treatment or device achieves what it set out to do in a safe way.

However, a fundamental flaw continues to affect the trial process’s biggest stakeholder – the patient.

Limited patient-centredness is cited as causing or contributing to a number of issues, including non-response bias in surveys where candidates are left unable to respond to a question because the answers do not reflect their position; key populations being omitted from clinical trials (on the grounds of age, ethnicity, gender or socioeconomic group, for example) can reduce the accuracy of and actionable findings from trial results; and a lack of understanding over the trial findings and outcomes which are often only published in medical journals.

Not paying due attention to or collecting information about the patient experience, including the recruitment process, is also a missed opportunity for researchers to improve trial design a step at a time. For example, asking patients for feedback on how useable informed consent documents can give clear insights into how that particular part of the process can be made smoother early on.

Over recent years, there has been a growing movement towards patientcentredness in clinical trial design. Patient advisory groups dedicated to helping tailor clinical trial design are becoming more commonplace, offering first-hand guidance on ethical and procedural components and identifying pain points that could be affecting patient recruitment and retainment efforts.

A literature review by the Patient-Centered Outcomes Research Institute (PCORI) in 2019 found evidence that consulting with patient advisers during a clinical trial has a positive effect on studies – including valuable contributions to research feasibility, acceptability, rigour and relevance.

It’s clear patient engagement can support more relevant research through Spring 2021 Volume 13 Issue 1

Clinical and Medical Research Similarly, telemedicine is now frequently used for routine patient monitoring and follow-ups, particularly in Phase I studies.

The method can also be used to measure select objective outcome measures; however, the data collected isn’t likely to receive regulatory approval. Until this point is reached, we’re unlikely to see a full switch from in-person monitoring to virtual.

Another exciting area of development is intelligent devices and packaging, creating secure two-way communication pathways between patients and clinicians during trials, and helping to decentralise them. Perennial encryption technology is protecting the sensitive data being collected and shared with trial leaders. better alignment with patients’, as well as clinicians’, real-world needs and concerns.

medical advancement forward and encourage more volunteers to join (and stay in) trials.

As such, funders and research institutions need to establish engagement policies and provide resources to support research that is more fully responsive to end users’ needs. Two-way communication is also vitally important, rather than simply using patient involvement and feedback as a one-way input. Ultimately, evidence will be more useful and relevant to decisionmaking when patients and stakeholders are fuller participants in the research process.

Perhaps the simplest step in moving towards a more patient-centric trial is the routine use of eConsent and telemedicine methods.

The Potential of Technology to Transform Clinical Trial Design Advancements in healthcare and monitoring technologies are accelerating this cultural shift towards patient-centredness and their application has been a key driver of success in recent COVID-19 clinical trials.

For over three years now, the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK has allowed the use of electronic methods for seeking, confirming and documenting informed consent for participation in research.

It enables potential research participants to be provided with the information they need to make a decision via a tablet, smartphone or digital multimedia. This digitalisation is credited with improving understanding, providing feedback on how consent materials can be improved, reducing dropout rates and enabling process efficiencies.

Wearable devices worn by the patients during trials is one component of this new digitalised approach, allowing clinicians to track and analyse health information such as heart rate and pulse, temperature, blood oxygen levels, stress levels, breathing rate, and even different types of brain activity in real time outside of a hospital setting.

Essentially, the device (usually a bracelet) acts as a personal assistant during the patient’s everyday life at home, monitoring their health status and alerting them about abnormal conditions, medication reminders and medication tracking. The device can also facilitate tracking of many outdoor and indoor activities to give a greater sense of their lifestyle during the trial.

A second component is the integration of intelligent technology into existing medical

The global pandemic forced the international clinical research community to accelerate the use of digital technologies to alleviate disruptions, mitigate risks and develop new treatments and vaccines under extreme time pressure.

In the “new normal” which is still being disrupted by the novel coronavirus over a year on since the first cases were reported around the world, we expect to see a mass adoption of virtual introductions and check-ups which will minimise the need for patients to travel to investigative sites, as well as increased device integrations with consumer and medical data capture tools.

This, in turn, will simplify patients’ participation in clinical trials and improve their overall engagement, helping to drive www.ipimediaworld.com

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Clinical and Medical Research and extract maximum value from existing data, from anywhere in the world.

Additionally, cloud-based clinical trial platforms enhance collaboration between sponsors and investigators and allow information to be shared and managed quickly and securely, which leads to increased productivity.

To summarise, the key benefits of moving towards a cloud-based model for data capture, analysis and storage are as follows: • • packaging (such as blister packs) or devices.

This is chipped with a wireless electronic component that allows tracking of drug usage as soon as the tablet is ejected from the blister or the device is used. In most cases, contact materials are not affected and the digital enablement, along with options for child resistance, are added as additional layers requiring no regulatory approval.

Each time a tablet is removed, or a medical device is used or activated, a signal is sent from the packaging or device to the bracelet. The bracelet will then send its information to clinical trial administrator team either directly, or via a smartphone to the cloud, then to the host. This transmission of data can be programmed to occur in real time or as a scheduled event.

Research organisations across the board are experimenting with new technologies such as these to streamline clinical research design and improve the patient experience.

Generally, organisational agility is a major contributing factor to how widely and how quickly these technologies are trialled and adopted, with smaller, flatter organisations less hindered by bureaucracy.

guidance on how they will interpret the data and insights gained during the approval process that we truly start to leverage the power of these remote technologies.

Moving Towards a Cloud-based Model As trials become decentralised, more and more sensitive patient data is being collected, analysed, shared and stored.

While this is a necessity from a scientific development and patient experience perspective, it does create security concerns over how data in clinical trials is being handled and these concerns risk slowing innovation and adoption if left unresolved.

Other concerns include false ownership of shared data and invalid secondary analyses.

Cloud-based solutions offer the greatest level of security and accuracy in secondary analysis, as well as simplifying the process of uploading, analysing and sharing data gained from remote healthcare technologies and onboarding stages. Cloud software can also help the community use anonymising techniques more efficiently, upholding patient privacy standards when dealing with extraordinarily sensitive data.

Larger organisations, on the other hand, are more likely to establish a task force to prepare and monitor new trial designs using remote technologies without significant oversight from senior leadership. Piloting, however, is common in both scenarios before a technology is widely rolled out.

To solve this inherent problem of balancing data sharing while ensuring that patient privacy is protected, cloud technologies allow researchers to handle both synthetically generated and real clinical datasets to conduct both exploratory and hypothesis-driven research without compromising patient privacy.

It won’t be until regulators catch up with these advancements and offer clear

This means researchers can gain meaningful insights earlier in development

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• • • •

Increased transparency and real-time visibility into clinical trial operations and data Enhanced collaboration between investigators, sponsors, and partners Increased efficiency and speed to conduct trials Streamlining processes, improving the patient experience and candidate retention Reduced costs in completing trials End-to-end visibility for security

Rising financial and time pressures on the life sciences industry will continue to drive changes in how clinical trials are conducted for many years to come and the COVID-19 pandemic has certainly accelerated digitalisation in the sector – a positive to come out of an extremely challenging year, professionally and personally.

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 ground-breaking pharmaceutical packaging devices, as well as offering a unique supply chain model which is disrupting the pharma industry. Established over 55 years ago, Origin offers customers a remarkable range of versatile packaging solutions that respond to the unique needs of the global pharmaceutical marketplace. Origin engages in the design, manufacture, and consolidated supply of pharmaceutical packaging, partnering with licence holders and CMOs.

Spring 2021 Volume 13 Issue 1

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Clinical and Medical Research

Beta Glucans and Endotoxin Testing

The presence of bacterial endotoxins in different media, solutions and laboratory materials can be determined by utilising the limulus amebocyte lysate (LAL) test.

This assay, which is the compendia test for the examination of bacterial endotoxin in pharmaceutical products, has become an essential tool for both industry and research over the last few decades, and the most reliable test for the detection of pyrogens.

The biochemical basis of the LAL test involves the unique clotting mechanism initiated by amoebocytes from the blood of the Atlantic horseshoe crab (Limulus polyphemus) when exposed to gramnegative bacterial endotoxin. There is a specific cascade associated with LAL that makes it possible to observe either qualitative or quantitative effects when endotoxin is present. The enzymatic reactions that occur along this cascade result in the conversion of amoebocyte coagulogen into a fibrinogen-like clotting protein, which forms a coagulin gel.1 A more detailed review of these reactions shows that the endotoxin interaction initiates Factor C (first serine protease precursor) from its inactivated form, which in turn activates Factor B (second serine protease precursor). The activated Factor B stimulates the clotting enzyme, converting it from a proclotting enzyme.

The clotting enzyme then cleaves peptide bonds within coagulogen to yield coagulin, the insoluble gel-forming protein produced in the gel clot assay. There are, however, other compounds which also cause the gelation in the amoebocyte lysate from the horseshoe crab, leading to an interference in the test of bacterial endotoxins. Some of these compounds are known as (1,3)-β-Dglucans, which can lead to false positives in the LAL test due to initiation of the clotting cascade when the glucans trigger the protease enzyme Factor G. To overcome this interference, the assay can be modified to include a wide range of glucan-blocking reagents.

The (1,3)-β-D-glucans are polysaccharide compounds consisting of glucose monomers, particularly the monomers of D-glucose, linked via β-glycosidic bonds, which are produced by many prokaryotic and eukaryotic organisms. One of the main sources of glucan contamination in laboratories comes from paper cellulose as these compounds are found in the cellular walls of tree cells. As filtering operations are a common process in most laboratories and are conducted on many occasions using cellulose filter paper, it is not unusual to find that samples being tested for the presence of bacterial endotoxins contain (1,3)-β-Dglucans introduced by the fibres of these same filters. In many cases, an examination of the filters fails to be completed prior to testing, allowing for the glucans to be

leached from certain types that ultimately end up in the filtrate. Often, this problem is only detected through routine testing performed on the finished product using the LAL assay. The samples can also be contaminated upon contact with other organisms which produce glucans. The contaminant glucans can come from different sources, such as the zymosan of yeast, the laminarin from algae, lentinan from the shiitake mushrooms (often used as an antitumoral drug) and curdlan that is produced by bacteria. β-glucans have also been regarded as pathogens in mammals and thus a serious concern of possible contamination in both bioprocessing and in blood products. High amounts of β-glucans in pharmaceutical end-products can illicit an immune response and so it is necessary to control their levels to prevent any associated reactions from occurring within the general public. The β-D-glucans, which have various effects on mammals, mediate the immune response by activating different receptors involved in proinflammatory reactions, such as those found on lymphocytes, macrophages and within the complement cascade. Generally, they are not digested in the intestine. They are substances that serve as an energy source for different microorganisms that live in the

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Spring 2021 Volume 13 Issue 1

Clinical and Medical Research gastrointestinal tract through fermentation.

These molecules have been used as a method of diagnosis for fungal infections in humans, as a food additive for their properties as prebiotics, and as immunomodulators. Studies have been conducted for their use as potential drugs due to their anti-carcinogenic effects and as cholesterol reducers through their ability to prevent the absorption of cholesterol from food in the stomach and intestines. Some of the β-glucans most widely studied are paramylon from Euglena gracilis and the curdlan, originating from Alcaligenes faecalis, for which a triple helix structure has been suggested.

In practice, a researcher or technician will often need to know the concentration of bacterial endotoxins without the interference of glucans; most notably when the LAL test is used as a method of pyrogen detection, since glucans in general are substances that do not cause fever.

This can be of particular importance in the processes associated with haemodialysis treatment. Patients undergoing conventional haemodialysis three times per week are typically exposed to 300–600 litres of water depending on their prescription (Coulliette, 2013), with water comprising more than 90% of the dialysate (Layman-Amato, 2013).

Therefore, the presence of contamination by gram-negative bacteria or associated endotoxin, in either the dialysis water or the dialysate itself, can certainly threaten the life and health of the patient. The presence of bacterial microorganisms in these fluids can result in chronic inflammation, which can contribute to the emergence of cardiovascular disease, the leading cause of death for dialysis patients. On the other hand, fragments of endotoxins in the dialysate bath may pass through the dialyser membranes and result in symptoms of septicaemia, or give a pyrogenic reaction (Coulliette, 2013). Since the source of water used in haemodialysis consists basically of drinking water which has been carried through various levels of purification, being able to accurately monitor its quality is a vital aspect of haemodialysis treatment.2 When considering organ or stem cell transplant recipients who are commonly treated with immunosuppressive drugs, a significant level of morbidity and mortality has been shown to result from invasive fungal infections where the determination of β-D-glucan levels has been shown to be a useful tool in the presumptive diagnosis of these types of infections.3 www.ipimediaworld.com

for the determination of acceptable levels.

Nevertheless, there is a growing trend in the industry and among regulatory authorities worldwide to detect and quantify (1,3)-β-Dglucans, and to understand their true levels of safety.4

When attempting to test for the presence of glucan, there are three widely recognised methods that are routinely utilised by industry today: base hydrolysis method, subtraction method or direct measurement.

When utilising base hydrolysis, sodium hydroxide is added to the test sample which is then held at 37°C for 12–15 hours to destroy any endotoxin that may be present.

After adjusting the pH of the mixture with HCL, the sample can then be tested. If the subsequent LAL assay gives a positive result, then it would indicate that glucans and not endotoxin are present.

With the subtraction method, two different assays are utilised for the determination of endotoxin. One assay will incorporate a lysate that is either inherently endotoxinspecific or has been treated with a commercially available glucan blocker that will render the reagent unreactive to (1,3)-β-D-glucan interference by effectively blocking the Factor G pathway of the endotoxin clotting cascade. The other assay uses an untreated or unmodified lysate product. The difference between the two results is proportional to the amount of glucan present in the sample.

The direct measurement method, as the name implies, is a specific and quantitative determination of the (1,3)-β-D-glucans through methods which inactivate endotoxin such as the use of a non-ionic detergent and polymyxin B or of a specially designed monoclonal antibody test against activated Factor C.1 Regardless of the testing method used, the research surrounding β-glucans continues to be of interest to pharmaceutical scientists around the world from both a clinical and manufacturing perspective. Unlike bacterial endotoxins, the levels of (1,3)-β-Dglucan contaminants in pharmaceutical products are currently not regulated and there is no compendial standard for their detection. In addition, there exists no fully harmonised approach available that allows

The significance of β-glucans as tools in the determination of fungal infections, as troublesome contaminants in pharmaceutical manufacturing processes and as possible active ingredients in both current and future medications, has placed these diverse group of polysaccharides in a unique category that warrants further investigation.

For routine testing in the quality control laboratory, it remains of vital importance to establish a reliable and reproducible method of testing so that any reaction can be examined to determine if the cause is indeed due to endotoxin or to the presence of (1,3)-β-D-glucan.1 REFERENCES 1.

2.

3.

4.

Sandle, T. PhD., “Pharmaceutical Product Impurities: Considering Beta Glucans”, American Pharmaceutical Review. 2013 Aug 31, online addition “Dialysate Water System Microbiology & Endotoxin Sampling”, Provincial Standards and Guidelines, 2016 Aug; BCPRA Hemodialysis Committee Theel, E.S. and Doern, C.D. “β-d-Glucan Testing Is Important for Diagnosis of Invasive Fungal Infections”, J Clin Microbiol. 2013 Nov; 51(11): 3478–3483.

Neun, B.W., Cedrone, E., Potter, T.M., Crist, R.M. and Dobrovolskaia, M.A., “Detection of BetaGlucan Contamination in NanotechnologyBased Formulations”, Molecules. 2020 Aug; 25(15): 3367, Published online 2020 Jul 24. doi: 10.3390/molecules25153367

Lisa Komski Lisa Komski is the Sales General Manager for the LAL Division of FUJIFILM Wako Chemicals U.S.A. Corporation.

With a nearly 30-year career of working in the Chemicals and Life Science industries, she has established herself as a strong business development professional skilled in U.S. Food and Drug Administration (FDA) requirements and cGMP. Lisa holds degrees in Biology and Medical Technology.

Email: lisa.komski@fujifilm.com

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Whitepaper: Together Beyond COVID-19 – A Look at the Future Introduction The year 2020 has been challenging.

COVID-19 struck, causing a global crisis, and people worldwide were forced to adapt to the new normal brought on by the pandemic. The current situation has affected industries differently, benefiting some and disrupting, even sidelining, others.

In a short time, COVID-19 has increased our dependency on technology. Companies are actively investigating the role of digital transformation. In developing digital strategies, the focus must be on increasing efficiency while minimising risk. When adopting new technologies, it is important to have a clear strategy in place. This process will require more efforts in terms of change of management skills because, at its core, digital transformation is all about people. It requires the system composed of people and technology to be well organised and aligned for the future. Consequently, COVID-19 has been a catalyst for innovation and digital transformation.

To understand the challenges that the pharmaceutical industry faces during COVID-19, open-ended interviews were conducted with top pharmaceutical companies around Europe. The methodology followed during the interviews was semirestrictive, using a general outline of questions that led to other topics based on the spontaneous response of the interviewees, but always in relation to the general topic: COVID-19 and digital transformation. Some of the companies interviewed were Roche, AstraZeneca, Cinfa, Neuraxpharm, Amryt Pharma, Almirall, Alcala Pharma, and Dompé, amongst several other pharmaceutical companies. As a result of the interviews, meaningful qualitative data was collected.

This paper summarises the main highlights, together with the future vision.

Digital Tools and Data Analytics Digitalisation is causing upheaval. Since COVID-19 hit, companies have been forced to upgrade their systems and learn how to facilitate employees working from home.

This change, which was projected to occur 70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

in the next 5-10 years, has happened over a matter of months. During this pandemic, the use of digital health has become more popular amongst physicians as many patients do not feel as safe going to doctor appointments in person as they did before COVID-19. In addition, virtual medicine has been crucial in reducing the spread of the virus and the pressure on emergency rooms. Before COVID-19, the percentage of patients using remote consultation was very low (only 6%). However, digital health has gained momentum, and at least 19% of consultations are expected to continue remotely after the pandemic subsides (Source: Statista).

Pharmaceutical companies have also considered digitalisation as an opportunity to improve their business models. It provides a new potential stakeholder journey that enables them to communicate directly with clients. During the pandemic, many pharmaceutical companies have strengthened their efforts by offering patients and physicians information via digital communications, remote clinical monitoring, and video consultations. As an example, one of the pharmaceutical companies interviewed created a digital package for physicians and patients including a Q&A with relevant information about how to manage the new COVID-19 situation. This new way of engaging with the different stakeholders requires constant marketing efforts to differentiate from competitors.

Digital analytics is another key component of digitalisation. Artificial intelligence and data analytics are crucial to defending against future public health crises. Data analytics could help companies more accurately predict supply chain disruptions and forecast demand to avoid potential drug shortages. Surprisingly, of the pharmaceutical companies interviewed, none experienced any critical disruption in their supply chain, thanks to accurate forecasting. Using big data in healthcare can provide a 360-degree view of physician, patient, and consumer trends, which will help improve personalisation and efficiency of treatments within organisations. COVID-19 has emphasised the importance of trans-

lating data into a digital format for the creation of global databases. These databases store large amounts of data to help scientists and physicians increase understanding of both medications and patients in order to promote innovation.

This infrastructure will facilitate open collaborations within the industry that lead to better outcomes.

An essential piece of the puzzle for many of the pharmaceutical companies interviewed is the implementation of a digital tracking system to follow up treatments and create the history of each patient to predict future treatment trends.

These trends could, for example, help predict recurrence of symptoms. The use of data can help track high-risk patients, show trends and patterns of the disease, or even track the hospital capacity in a specific territory.

Big data facilitates the restructuring of the healthcare industry. Various electronic tools are being used in companies to identify and inform physicians about patients who need specific therapies. These cases are discovered through the analysis of trends.

Along with patient information, global databases can function as product registries.

With access to digital information, doctors would be able to access patients’ medical records from anywhere in the world to provide the right prescriptions and care.

Digital health and big data solutions raise some ethical issues, mainly related to the confidentiality of personal information. As mentioned in one of the interviews, there are some significant aspects that should be taken into consideration, such as the fear stakeholders might feel towards the technological side of things. A key point to consider when using these tracking systems and data is the need for patients to grant approval for the use of their personal information.

Moreover, patients and physicians are still concerned about the quality of medical services provided electronically. In routine care, digital health is most useful for patients who have chronic conditions or who utilise psychotherapy as a part of behavioural healthcare. Both areas have been important during the pandemic. The classification of Spring 2021 Volume 13 Issue 1

Technology patients and specialities is key to increasing the efficiency of digital health, which would normally be focused on primary care and pre- and post-surgical visits.

Digitisation Towards Sales and Marketing Pharmaceutical companies have had difficulties attracting specific target audiences during COVID-19. It remains unclear how relationships will be built between pharmaceutical companies and different stakeholders such as physicians and patients. These sudden societal lockdowns and restrictions are driving new, meaningful ways of building personal connection through digital interactions. COVID-19 has forced pharmaceutical companies to implement reactive, rather than proactive, commercial strategies focused on the crisis and short-term solutions. In the long term, pharmaceutical companies must tailor their marketing strategies with new appealing commercial models. They must adapt and help their employees maintain relationships while building new ones with the same level of quality and engagement.

Communication should be detailed, concise, and frequent. Companies must add value to demonstrate why they are the best option.

As the strategy changes to be more patientcentric, companies will need to add more communication-specific roles, encourage digital marketing, have employees focused on e-learning, and much more. Sales representatives must be persuasive online to keep physicians’ attention while contacting them remotely.

Pharmaceutical companies have also reacted quickly to digitalising marketing promotional materials in order to engage clients. Both physicians and patients have been overwhelmed with content from multiple sources. Therefore, the management of an efficient content development strategy has been critical for commercial success.

Companies have been focusing on sending multiple, varied messages which included only short, critical pieces of information.

Some of the interviewees have also used the COVID-19 pandemic as an opportunity to improve their marketing strategies in the long term by building an omnichannel experience to engage with patients and physicians. As discussed during one of the interviews, companies should reconsider how to provide an integrated experience that includes a mix of channels with the right content and a personalised approach to communicate with the client. To make the experience more engaging, each client should be contacted through their preferred www.ipimediaworld.com

platform and sent both personalised and branded documents. The creation of an omnichannel strategy permits pharmaceutical companies to be flexible and prepared for any change in customers’ behaviour or requests. Organisations will need to facilitate an agile decision-making process to adapt quickly to each audience and to tailor the content to their needs.

Some pharmaceutical companies have explored the use of free messaging apps during COVID-19 to exchange information amongst users. These tools have proven to be a great channel. They facilitate the interactions between healthcare professionals and patients while maintaining personal interaction. However, security and data protection policies must be considered.

To offer a customised solution for healthcare professionals, specific systems with additional security and privacy standards are required as an alternative to free apps.

Additionally, it is important to properly track customer engagement to measure the effectiveness of different marketing initiatives. Analytics should be used and the right key performance indicators (KPIs) established. Engagement could be easily tracked by integrating the platforms used for communication between patients and physicians with customer relationship management (CRM) systems.

New Ways of Operating for Clinical Trials and Specific Therapies COVID-19 has initiated new ways of carrying out clinical trials safely and effectively.

Ongoing clinical trials with recruited patients continue, but recruiting new patients presents a challenge. Increased exposure to COVID-19 during recruitment has caused significant delays in trials. Moreover, highrisk patients are reluctant to go to hospitals to get the necessary treatment.

To overcome this situation, some pharmaceutical companies interviewed used electronic tools and additional remote medical options in homes to monitor progress. Remote clinical trials allow patients to participate without barriers such as COVID-19 exposure or mobility limitations.

These services also benefit patients for treatments outside of clinical trials.

Companies have started delivering treatment products to patients’ homes. In addition, nursing care has been provided at home for specific therapies in order to conduct the necessary physical examinations and to

supply the appropriate medications. These new services maintain the special care provided by nurses at the hospital. They also allow pharmaceutical companies to be in direct contact with patients and to explore innovative potential stakeholder journeys.

For instance, nursing care can be a valueadded service separate from the product.

Individual monitoring and analysis of the data can anticipate future health problems to put the right preventive measures in place. Another way to combat the barriers of COVID-19 is to ship treatments directly to patients. This allows delivery routes to be both simplified and shortened. As a result, the supply chain carries fewer risks, and this new distribution model reduces cost and time.

As additional services are included in the stakeholder journey, the pricing strategy and potential tax implications will be affected.

For instance, regulators do not consider the services or the accompanying devices when pricing a medicine, which leads to significant debate about reimbursement. To correctly adjust pricing, regulations regarding price reimbursement must be changed to prove the cost-benefit value of this service to the client. Standard measurements must be considered, such as efficiency, security, and cost-benefit analysis. During one of the interviews, it was discussed how, in order to drive long-term competitiveness and sustainability, companies will need to either focus on price or improve the overall safety of the patients by efficiently delivering home services. It is imperative that pharmaceutical companies have open conversations with authorities in order to implement these new stakeholder journeys with the appropriate restructured reimbursement policies.

The New Digital Era for Regulatory Affairs and Compliance Regulatory authorities have been flexible about many processes during this emergency period. They have accepted document formats that would not have been considered under normal conditions. Authorities have agreed to facilitate marketing authorisations, mainly for medicines and medical devices that are considered crucial during the pandemic. Acceptable documentation in alternative formats has prompted regulators to establish new processes for review.

Agencies now review dossiers more quickly than before without sacrificing quality, safety, or the efficacy of the information.

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Technology of working to be efficient. Consequently, authorities should consider keeping these procedures in the future and establishing similar measures with the same flexibility for all marketing authorisations including other drugs and medical devices.

During the pandemic, most of the companies interviewed have felt the support of the authorities more than ever.

Companies have been able to contact regulators, especially in emergencies, to get advice on reducing problems with supply chain, safety, regulatory issues, and much more. The support and flexibility from the authorities have reduced time and costs.

As a result of this agile approach from the regulators, pharmaceutical companies are wondering how this collaboration will continue post-COVID-19. They feel that COVID-19 has brought an opportunity to enhance these relationships and establish new ways of working and developing new procedures. Round tables with the involvement of the pharmaceutical leaders and regulatory authorities, together with the support of external consultants, could facilitate alignment and agreement to bring innovative solutions that benefit all stakeholders.

One of the companies interviewed highlighted the need for open discussions with the authorities about advancing digital technologies. New formalised health information for patients could be created through websites with approved technical content from the health authorities. This approach would facilitate compliance, provide patients and physicians with reliable information about products and services, and allow information to be accessed from anywhere.

Another consequence of COVID-19 is the use of alternative methods to approve documents that previously required wet ink signatures in the pharmaceutical industry. To validate protocols and reports, risk assessments, technical reports, or signing documents often meant ink on paper, including printing and scanning, to be able to send the signed document by email. During COVID-19, many organisations interviewed mentioned that their processes for approving paper documents with wet ink signature are no longer achievable and have been replaced by e-signatures. Authorities have been understanding regarding this new situation, and many have eased restrictions while maintaining control to avoid potential risks. An electronic signature is generally 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

permitted; however, for the signature to be valid, it needs to be unique and linked only to the signatory. In addition, the method used to sign must be reliable. Depending on the nature of the transaction, the use of the electronic signature could have additional requirements. Therefore, it would be beneficial to design an electronic system for controlling certain sensitive transactions.

Further considerations to increase control are the implementation of workflows within the organisation for the review and approval of the electronic documentation.

Human Resources to Support the Move Towards Digitisation The human resources (HR) department of every organisation plays an important role in supporting business continuity during COVID-19. Working remotely is a potential new normal with a new mindset that needs to be driven by HR. One of the most challenging things HR has had to manage is helping employees balance their work and life in the new situation. Companies quickly pulled together workshops to educate employees on good practices such as stress management. Webinars and online teambuilding activities have also been carried out during the pandemic to keep employees engaged. Compared with 2019, participation in webinars has increased by 60%. Most companies interviewed mentioned that efficiency and productivity have increased during the pandemic, as many employees are working during time previously used for commuting.

One of the challenges that management is facing is keeping employees engaged, efficient, and satisfied with this new style of working in order to keep high productivity levels. One of the companies interviewed mentioned that timetables of the employees during COVID-19 are not controlled any more, and they mainly focus on the end results that are achieved. The acceptance level of more open schedules has given employees more freedom to manage and balance their personal and working lives more adequately and contributed to achieve the expected efficiency levels and even higher. Although efficiency and productivity have not decreased, it will be important to continue monitoring the effectiveness of remote working to evaluate the future of “working from home” beyond the pandemic.

Establishing the right KPIs is crucial to keep track of employees’ performance while working from home. Some of the interviewees have implemented ways to

check-in and check-out for monitoring where employees are located and when they are available. This technique facilitates effective communication between employees, as timetables are different for some personnel due to family obligations. Constant communication is critical to engage with employees, to ensure knowledge-sharing across the organisation, and to make employees feel supported and valued within the company. With the implementation of KPIs, a well-planned incentive programme, and strong company policies, employees feel motivated and grateful, which increases their productivity levels. It is also vital for HR to closely monitor employment policies and benefits and more importantly, working practices. HR will also need to keep abreast of the latest changes in local employment laws, which may be adjusted to account for the new work environment.

Conclusion Before the pandemic, digital transformation was a long-term goal within the pharmaceutical industry. Now it is a necessity that comprises having open and more meaningful interactions with authorities, patients, doctors, and colleagues within our own organisations. The companies interviewed perceived COVID-19 as an opportunity to accelerate their digitalisation plans both externally and internally.

Externally, the go-to-market strategy is evolving towards new potential stakeholder journeys that are patient-centric. They lead to the use and creation of digital tools and care services that aim to connect people within and across our healthcare systems.

The new stakeholder journeys require additional marketing efforts to create omnichannel strategies, which also contain secured online platforms for the rapid and personalised exchange of information with selective content. The use of digital health during the pandemic has been encouraged amongst physicians and their patients to maintain contact. If used correctly, a combination of data analytics and digital health could achieve universal health coverage at a cost-effective rate, preventing many diseases and saving many lives. As a result of COVID-19, new emerging healthcare journeys are becoming more relevant to explore and demonstrate the need for honest conversations with the authorities and the health community regarding the potential impact on public policies.

Additionally, the regulatory authorities have been flexible and have implemented efficient procedures for pharmaceutical Spring 2021 Volume 13 Issue 1

Technology companies. This agility shows that there is room for change and digitalisation beyond the pandemic.

Internally, every company’s human resources department plays an important role in accommodating employees in their new working environment. HR should develop the right programmes to enable employees and help them master the new situation, guaranteeing the least amount of impact to their lives. Accordingly, HR and management should continue working on business continuity plans while exploring future new ways of working. Plans should emphasise the use of an agile change management approach with special focus on delivering a consistent communication strategy that makes employees feel involved and supported.

Adaptations by organisations to the circumstances surrounding COVID-19 have demonstrated that there are always solutions when there is a need. The future challenge to this new digitalisation era is to ensure that what has been advanced will remain once the COVID-19 limitations are lifted. EY and PharmaLex will be delighted to support the pharmaceutical companies to continue advancing towards the future designing and implementing the right strategies and tools to achieve their objectives.

Marta Vila Ramos VP Corporate Development, Business Strategy and Innovation, PharmaLex.

Baltasar Lobato Beleiro Health & Life Science Partner, EY

Manuel Gonzalez Fernandez Managing Partner of Finance Transformation, EY

Miguel Gallo Martinez Lead Partner of Business Design, EY

Jacobo de Silva Urquijo Supply Chain and Operations Partner, EY

www.ipimediaworld.com

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Technology

Redefining Healthcare: Digital Trends in 2021

2020 has redefined healthcare for good. As with many industries, the impact of COVID-19 cannot be understated, as healthcare was placed at the centre of the global agenda. In the same way that in 2020, every company wanting to thrive has had to become a tech company, led by remote working and data, so every company has become a healthcare business; safeguarding people and customers becoming a core business focus.

It’s also been a year of rapid acceleration as pharma companies raced to develop the COVID-19 vaccine. Behind the scenes, we’ve seen pharma leaders develop new strategies to ensure clinical trials stay on track, adapting trial designs and recruitment techniques amongst an increasingly savvy candidate pool to enable a rapid recovery and vitally, get new drugs to market. Meanwhile, frontline healthcare providers innovated “new normal” ways of delivering patient care from digital dashboards through to virtual consultations.

Digital transformation has underpinned every aspect of healthcare this year – from how global teams can collaborate on vaccine projects through to minimising disruption to patient care. In this piece, I’ll explore the new trends set to change the landscape of healthcare on 2021.

Start with Patient Experience The pandemic has highlighted the need for real consistency in patient experience – and how as a society, we empower more patients to manage their care. With the gap in access to healthcare at the centre of COVID-19, improving patient experience and engagement has become essential. We expect 2021 to bring a renewed commitment to patient experience placed at every touch point of healthcare, redefining this through remote, tele health and m-health technologies to drive engagement throughout their treatment. This in turn will foster more innovation across all areas of healthcare.

Chatbots Drive Personalised Patient Care We expect to see more AI-led applications 74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

than ever in 2021. Let’s start at the front end with chatbots and digital dashboards, as providers adapt to new ways to deliver healthcare. First off, from an efficiency and admin perspective, they’ll increasingly be used to track appointments and contacts alongside monitoring patient activities.

Moving into clinical, there’s real potential to offer a more personalised patient experience too – medication management, for instance.

The Move to Virtual Trials Connected AI and virtual technologies are on track to transform clinical trials too.

2020 highlighted the need for speed, safety, effectiveness and vitally, patient-centricity in trials. And as the industry seeks to bring other trials back into play, cost reduction and increased productivity are more important than ever.

Where AI will come into its own is in the process of patient pre-selection and prescreening, coupled with the need to make trial enrolment easier for patients. AI and predictive analytics can help us unpack these deeper insights. By understanding key data points such as motivators, previous experiences, even behavioural tendencies, trial owners can weigh the patients most suited, and support recruitment and successful retention. At the same time, AI can filter out existing biases, creating a far more accurate, richer picture.

With these foundational elements at play and the changing trial eco-system, we expect to see more investment in virtual trials coming through next year.

Virtual Healthcare as the New Normal The parameters of lockdowns, certainly in the UK, have shaped the way so much patient care is delivered – from GP consultations through to pharmacy check-ins. The number of virtual visits, particularly for minor and routine appointments, has surged during the pandemic; Forrester predicted this is set to hit one billion by the end of the year.

While virtual visits have been driven by necessity, to reduce the risk of infections, this style of remote patient care has driven new levels of efficiencies for frontline medical professionals, and we expect this

to stay in place, well after the pandemic’s over.

A Rise in Mobile Health Again, the groundswell is gathering pace for mobile healthcare devices, as they continue to revolutionise the face of healthcare, from instant and virtual consultations and diagnosis through to appointment management and medical supplies processes.

Today there are nearly 320,000 mobile health apps in the leading app stores, with 200 new health apps coming to market every day.

It’s an empowering move for consumers, looking to take more control of their own health too, be it through fitness, meditation or wellbeing apps. A key employer trend in the wake of lockdowns has been for businesses to partner with mobile health apps to provide their teams with access to wellbeing support. The aforementioned Forrester report cites that during 2021, one third of virtual care appointments will be related to mental health, so ensuring patients have access to resources, tools and support will be essential.

Integrating Wearable Technology to the Next Level Tying into m-health are wearables, already gaining real patient attention and transforming the way consumers engage with their healthcare. As with m-health, we expect this to go beyond the fitness, sleep and calorie tracking generally associated with wearables, as they’re increasingly integrated with EHRs, and new ways to improve the quality of patient care. The potential to shape preventive action through smart use of devices will be significant, feeding into more sophisticated health solutions, especially as 5G internet is rolled out.

Next-gen APIs and Interoperability Secure, efficient data exchanges have been at the centre of effective healthcare, as care is delivered through multiple channels, be it in person or telemedicine. We expect to see next-gen APIs enabling impactful data exchanges between EHR platforms and devices in a more significant way in 2021.

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Technology

For patients, this means improved accuracy and quicker diagnoses, as well as efficient care plans.

New Levels of Efficiency in Clinical Trials Focusing in on clinical trials, there’s an industry movement suggesting the end of SDV (source data verification) could be in sight. SDV has long ensured the quality and integrity of data but increasingly, real weaknesses have been identified in terms of quality control, cost and ROI. Also the resource – the healthcare man hours lost to manual transcription and checking of data in an industry as sophisticated as ours, is incongruous at best. We’re spending billions of dollars to re-enter and then re-check data that already exists.

Again, COVID-19 has accelerated new questions around the efficacy of SDV, not least due to the challenges around placing monitors onsite to manage data. As more sophisticated alternatives emerge, we expect to see a rise in digihealth applications that enhance the interoperability of EHR and supporting research applications, EDC (electronic data capture) for example. This new level of efficiency will drive a paradigm www.ipimediaworld.com

shift in clinical research, reducing costs and freeing up staff resources.

Deliver Faster Patient Recruitment with Technology Another clinical trial-focused trend is the transformation of patient recruitment strategies via a data-led approach. Let’s think about how the potential of electronic health records (EHRs) here; 70% of clinical studies data can be found in patient records, but the process remains primarily manual.

The previously untapped sources of eligible patients open up larger and new patient pools. And, with pre-screening, you have even more control over the final patient recruitment process. Using this data resource smartly gives trial managers a multi-layered understanding of patients supporting a more predictable trial outcome and manages costs.

2021 will see more in remote, datadriven approaches, more automation, more efficient study delivery. Additional benefits include allowing for greater levels of safety and more accurate forecasting. Because bottlenecks are minimised too, trials start quicker, delivering valid results faster – essential in a post COVID-19 world.

2020 has changed the face of healthcare.

And digital transformation is enabling growth in the delivery of faster, better quality options, revolutionising how patients engage in and access their healthcare. And with increased personalisation and greater efficiencies, this supports the collective goal of ensuring that patient experience always comes first.

For more information: https://www.ignitedata.co.uk/

Richard Yeatman Richard is CTO at IgniteData, the healthtech startup shaping the future of clinical data. Through its innovative digihealth platform, Archer, IgniteData is on a mission to revolutionise clinical research. Richard has spent most of his career helping to deliver the next innovations in healthcare IT.

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Technology

Next-generation Aseptic Tech Needed to Cut Contamination Risk The need for sterile manufacturing conditions in the pharma space continues to rise, increasing industry demand for solutions to help achieve aseptic processing goals without compromising on manufacturing efficiency.

We spoke to Christian Dunne, Head of Sterile Solutions, ChargePoint Technology to find out more about the next generation of equipment designed to help balance the asepticefficiency equation.

The Rise in Aseptic Demand One of the key trends rocking the pharmaceutical industry in recent years has been the booming demand for sterile processing – which rose again this year, despite the economic turmoil of the COVID-19 pandemic.

In 2020, the global market for aseptic processing was estimated to be worth $62.2 billion and is expected to reach a value of $73.6 billion by 20271.

There are a number of reasons for this growing need for aseptic pharmaceutical processing. Chief among them is the rise of parenteral treatments and injectables in particular which, by their nature, must be subject to aseptic manufacturing and packaging in order to safeguard the health and wellbeing of patients. MarketsandMarkets projects the injectable drug delivery market to grow from $362.4 billion in 2016 to $624.5 billion by 2021, at a compound annual growth rate (CAGR) of 11.5% during the period2.

The rise in demand for these treatments is being driven by growing diagnoses worldwide of chronic conditions, such as diabetes and cancer. As populations in North America and Europe age, and as long-term healthcare becomes increasingly affordable and accessible in emerging economies, such as China and India, we can expect the demand for parenterals to increase further.

In addition, the drive for more patientcentric parenterals is leading to innovations, such as prefilled syringes and autoinjectables, which are further increasing 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the popularity of injectable products.

Fortune Business Insights’ report “Prefilled Syringes Market Size, Share & Covid-19 Impact Analysis,” projects the global prefilled syringes market will reach $10.57 billion by 2027, climbing at a compound annual growth rate of 10.5% during the forecast period3.

These prefilled products also have specific aseptic manufacturing and packaging requirements, which must be met to ensure safety and product integrity.

All of this is driving significant increases in demand for aseptic processing across the pharmaceutical industry. We can expect the need for expanded sterile capacity to continue to rise well into the next decade.

Balancing Aseptic and Efficiency Needs A major challenge facing pharmaceutical companies looking to meet this new market demand for sterile treatments is how to achieve an aseptic processing environment without compromising on efficiency and productivity.

Failure to reconcile both these challenges could increase manufacturing costs, lowering revenue. Worse, it could impact on return on investment for product innovation, with potential repercussions in terms of resource and appetite for future product development.

With this in mind, there has been considerable innovation in recent years in the technology used in aseptic processing, as well as evolution in drug developer behaviours when it comes to commercialising and manufacturing their sterile treatments.

Both of these developments are playing a major part in enhancing the efficiency of sterile manufacturing while optimising product quality.

Outsourcing On the Up In order to meet growing demand for sterile manufacturing, more and more drug developers are outsourcing to the contract services space.

Contract development and manufacturing organisations (CDMOs) have a unique flexibility to meet aseptic processing goals.

They have the financial resources, specialist expertise, infrastructure and capabilities that many drug developers do not possess in house. This means that they can quickly launch aseptic development, and scale up manufacturing and packaging, helping to achieve the stringent quality standards required while minimising time-to-market.

As a result, many sterile drug development projects are now being outsourced to partners.

While such contract partners offer plenty of benefits to drug developers when it comes to expert guidance and support, the outsourcing of production can bring a layer of complexity to the manufacturing process. For example, when outsourcing, drug substances and products often need to be transferred between different facilities and different geographies, all while maintaining sterility. This necessarily creates new potential points of failure that need to be controlled to protect the material from contamination. As a result, manufacturers are increasingly investigating the viability of logistic innovation to ensure the integrity of sensitive ingredients and products during the transport process between sites.

Advances in Aseptic Transit A number of solutions have been investigated in recent years to support the safe and secure transit of sterile materials between drug development and manufacturing sites.

One of the solutions currently widely used to transport APIs and intermediates is fibre or plastic drums with flexible liners.

Despite the benefits they may offer in terms of transit efficiency, these drums do pose challenges when it comes to maintaining sterility during key processes, such as filling, sealing, handling and emptying.

In addition, the processes needed to maintain sterility within the drum during transit require considerable and costly time and resource. This stands in opposition to the overwhelming market need for speedier, more efficient procedures and lower production costs.

In response, drug developers are calling for a new generation of equipment and Spring 2021 Volume 13 Issue 1

Technology

processes designed to achieve optimum sterility without any of the efficiency drawbacks of these fibre or plastic drums and other current procedures.

The Benefits of Single-use Technology For a growing number of drug developers and their partners, the answer to this conundrum is the use of hybrid, single-use technologies in their aseptic processing.

There are a number of key advantages to single-use equipment in sterile pharmaceutical development. They are generally easy to use, with minimal training or production line upgrades required. As they are designed to be used once prior to disposal, they can significantly streamline the hygiene procedures needed to maintain sterility, reducing production downtime and enhancing efficiency. In addition, they can ensure the integrity of products during transit as well as within manufacturing facilities. All of this allows firms to ensure optimum product quality, while helping to maximise process efficiency and reduce production costs.

One key example of a single-use technology that is helping to tackle the twin issues of sterility and efficiency is the split butterfly valve (SBV). These offer a solution for the sterile transfer of powders, www.ipimediaworld.com

including drug substance and drug product, during the pharmaceutical development and manufacturing process.

SBV technology is made up of two components: an active half and a passive half. The active component is connected to the production line equipment, while the passive half attaches to a filling container.

When the two halves of the valve are fitted together, a single plate is created, which allows product to flow from the line into the container via the interior surface of each half, without it coming into contact with the surrounding environment, maintaining the aseptic integrity of the product.

A new disposable version of the passive component of the SBV now exists, which can help achieve the same stringent level of sterile processing while significantly enhancing efficiency. This disposable passive half can be connected to a single-use flexible bag to enable the contained and sterile transfer of pharmaceutical powders between each step in the manufacturing process, as well as between facilities. The passive half doesn’t need to be cleaned after use as it can simply be disposed of between fillings, increasing productivity.

These disposable SBV variants are manufactured within an ISO6 cleanroom

environment and are gamma-sterilised prior to use. As such, they are suitable for use in the most rigorous aseptic processing environments.

This new generation of hybrid re-usable and single-use sterile technology can provide a flexible and effective means of aseptic powder transfer, while significantly reducing the costly downtime associated with cleaning, maintenance and validation to maintain a contaminant-free environment.

The Future of Aseptic Processing This is just one key example of how the pharmaceutical industry is harnessing the benefits of single-use technology to deliver sterile manufacturing while enhancing production line efficiency.

However, there are other exciting areas where innovations are happening to help drug developers and their contract partners to achieve both aseptic and productivity goals. For example, smart monitoring technology is now being integrated into pharmaceutical production lines in order to provide rich real-time data on key equipment performance.

There are two key advantages to this.

Having this real-time line performance data can help drug developers generate a rich INTERNATIONAL PHARMACEUTICAL INDUSTRY 77

Technology world. Armed with the unique convenience, productivity and control benefits of singleuse technology, they can ensure they can continue to be competitive and successful well into the future.

REFERENCES 1.

2.

3.

audit trail much more quickly. This can allow health and safety teams, and individuals responsible for regulatory compliance to proactively manage the validation programmes for their aseptic lines.

The arrival of smart monitoring technology in the pharmaceutical space has the potential to go even further. It can revolutionise the containment strategies traditionally used in drug manufacturing, by providing manufacturers with a reliable and fully-automated means of understanding the health status of their valves, or other components on their production lines.

This real-time information about every aspect of the production line can help line operatives to identify areas of the production line that need maintenance before they begin to affect productivity, helping them to plan preventative action in a way that minimises downtime. In addition, this data can help them identify where improvements can be made on the production line to enhance product quality and line speeds.

Users can access data from their device or using an online dashboard. This can allow for remote data access, so operatives can monitor their lines on the move, or even monitor lines they don’t have immediate access to.

Taking all of this into account, it is clear that smart monitoring has the potential to transform operational performance for the better, boosting line productivity while also helping drug developers and their contract 78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

partners to manage risk more effectively.

They also offer exciting opportunities to automate and achieve genuine real-time, real-world validation and equipment performance monitoring, giving developers the tools they need to maximise sterility on their drug production lines.

Harnessing the Power of Innovation to Maximise Aseptic Efficiency The aseptic market has enjoyed robust growth over the last few years, and this shows no sign of slowing down any time soon. A key challenge facing drug developers and their manufacturing partners over the next half decade will be how to meet this demand for sterile production while achieving enhanced manufacturing efficiency.

The pharmaceutical industry is evolving all the time, producing exciting and innovative new therapies and technologies. The question of how to balance sterility and efficiency will only grow more pressing as novel therapies with strict new sterility requirements enter the market, and regulations in key markets evolve to accommodate them.

Drug developers will need to be mindful of these and take steps now to future-proof their aseptic processes in order to ensure they continue to meet ever more stringent regulatory requirements.

However, through the use of advanced pre-validated, ready to use singleuse solutions which can be effortlessly integrated into their current processes, drug developers and contract manufacturers can be confident they are ready to face this new

https://www.globenewswire.com/news-release/ 2020/10/27/2114839/0/en/Global-AsepticProcessing-Industry.html https://www.marketsandmarkets.com/MarketReports/injectable-drug-delivery-market-150. html https://www.fortunebusinessinsights.com/ industry-reports/prefilled-syringes-market101946

Christian Dunne Christian Dunne is the global product manager at ChargePoint Technology for the sterile containment solutions.

For the past 20 years Christian has been creating innovative solutions for the pharmaceutical, biotech, cell therapy and fine chemical industries to overcome high potency containment and aseptic processing challenges.

His technical expertise spans high containment isolators, grade A (ISO5) sampling & dispensing facilities, together with R&D and production filling line restricted access barrier systems (RABS) and isolators. For the past six years, Christian has been working with ChargePoint Technology on the advancement of its split butterfly valve technology, designed to handle highly potent/sterile powders and small-scale components, where both product and operator protection are paramount. While working on many aseptic applications, Christian integrated a number of different biodecontamination systems and consequently has an in-depth understanding of their performance and application. This knowledge was key to the development of the now established ChargePoint AseptiSafe Bio®, used for the transfer of sterile powders in the industry. Christian is an active member of the International Society for Pharmaceutical Engineering (ISPE) and The Pharmaceutical Healthcare Sciences Society (PHSS).

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 79

Technology

Adopting Connected Drug Delivery Devices: Top Tips for Pharmaceutical Companies It has long been recognised that there are serious shortages in the healthcare workforce across all settings and disciplines, as demand for healthcare increases. By 2030, one in six people will be 60 years of age or older1 and with that comes a range of long-term health conditions such as diabetes, heart disease, osteoarthritis and dementia. At the same time, the WHO estimates a projected shortfall of 18 million health workers by 2030.2 The pandemic has magnified these long-standing problems and put health services and their staff under increasing and unprecedented strain and demand.

In this context of staff shortages and increased demand for healthcare, pharmaceutical companies are going beyond simply manufacturing drugs; they are increasingly providing holistic service packages that include training and education around their medicines.

Connected drug delivery could significantly enhance such services, by producing valuable data insights on medication compliance, which can then be used to improve therapy management. This article will address the benefits that clinicians, patients and pharmaceutical companies stand to gain from connected drug delivery devices, and later provide pharmaceutical companies with top tips to ensuring the market’s sustained growth and successful implementation.

medication in the home, which is invaluable at a time where healthcare services are under so much strain. Projections for the connected drug delivery device market are unsurprisingly positive, with our own analysis4 estimating the global market both for injection and inhalation to be $706 million by 2025, up from $225 million in 2020 – that is to say a CAGR of over 25%.

For digitally-enabled remote healthcare services to provide maximum value to patients, however, pharmaceutical companies must ensure they meet a number of key capabilities. Principally, these digital tools must provide patients with access to clinicians while allowing clinicians to verify that the right dosage at the right frequency is being administered by patients for prescribed therapies and ultimately to monitor their patients’ condition and its evolution. Bearing influence over the development and adoption of the area of connected drug delivery devices are a number of key stakeholders, most importantly clinicians and patients themselves. It will therefore be vital to consider

their needs and expectations first, as will be discussed below.

Consider Your Audience: Clinicians The benefit of connected drug delivery devices for clinicians is two-fold. From a patient benefit perspective, clinicians recognise the value of remote monitoring as a means to improve patient adherence, and in turn optimise patient outcomes.

Having observed the benefits that remote consultation has had for patients with chronic diseases such as rheumatoid arthritis, Crohns’ disease and multiple sclerosis, clinicians are likely to see the value-add of bringing connectivity to the area of drug delivery. Using embedded electronics and sensors, connected drug delivery devices provide benefits such as dosage reminders and dose confirmation as well as adherence tracking. This would, for example, enable a diabetic’s blood glucose to be monitored remotely, while also recording all adjustments and their reactions in a clinical database. For clinicians, the other concrete benefit of remote monitoring is that it helps to alleviate some of the pressure on

Responding to Demand for Remote Patient Monitoring Remote consultations have gained traction within the context of the current health crisis, but even before the crisis, remote services were considered one of the three top benefits of digitalisation, according to healthcare stakeholders.3 Remote patient monitoring is already in practice for chronic respiratory conditions and diabetes, but data exchange via digitally connected drug delivery devices is still relatively new.

With this comes the possibility of remotely monitoring patients who self-administer 80 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Spring 2021 Volume 13 Issue 1

Technology them and their colleagues, helping to tackle the staff shortages and limited resources faced by healthcare services.

Think of the End-user: Patients As the end-user of connected drug delivery devices, the patient will encounter a number of benefits also. Connectivity opens the door to greater personalisation, potentially providing patients with access to treatment that is tailored to their specific health indicators, which can be adjusted as needed over time. Getting patients more involved with their own treatment through connected devices can strengthen their understanding of their condition and its management. By providing access to and greater transparency of treatment data, patients can easily follow their own progress and fully comprehend the importance of adhering to their prescribed therapy. Where patients are less compliant, they can access training and support tools to help improve adherence to their therapy regimens.

Boundless Potential: Pharmaceutical Companies Pharmaceutical companies can also benefit from the possibilities created from the

rollout of connected drug delivery devices. In the industry, providing demonstrable value for money has become a critical competitive differentiator. As discussed earlier, dosage reminders can help to improve adherence and most likely outcomes, thereby improving the overall success of a drug using connected devices. Furthermore, knowing that clinicians can keep a careful eye on patient compliance and intervene where administration may not be occurring properly is a huge asset to pharmaceutical companies.

Going further, safely stored and anonymised patient data around outcomes and adherence will be an invaluable tool to demonstrating the efficacy of their drug through concrete, data-backed real-world evidence. Conversely, where outcomes aren’t as expected, manufacturers may be able to address instances of patient non-compliance in a more informed way. This data will also be of central importance for the training, adherence monitoring and benefit tracking services that are increasingly being offered by pharmaceutical companies. With these benefits in mind, here are some top tips to consider when implementing connected drug delivery devices:

•

Ensure regulatory compliance and address security risks: Working in partnership with health-care authorities and providers, pharmaceutical companies must ensure that data derived from devices are interoperable with standard clinical record systems, and they must also provide robust protection from data breaches. Ensuring that patient privacy is respected and protected, and being able to demonstrate this to stakeholders, is essential to the success of connected drug delivery devices. In a cloud-based world, collaboration between regulators and market players will be essential to data security.

•

Prioritise comfort and ease-of-use: While connected functionalities offer new opportunities for self-tracking to patients, they typically find comfort and ease-of-use to be the most important deciding factors. For a connected device to be accepted by patients, it will have had to undergo thorough human factors studies to ensure that non-professional users’ needs have been considered and addressed.

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Technology

•

•

•

Stick with simplicity: Since patients may already struggle with remembering to administer medication or the administration procedure itself, new products should ideally avoid introducing new challenges or complexities.

Similarly, the perception that a device is complicated to use may lead to resistance from clinicians or carers. This can be a particular challenge for connected devices which require charging, pairing and data transfer.

Raise awareness among patients: With patients taking on a bigger or potentially more complex role in their own treatment regime, it may be helpful for pharmaceutical companies to raise patient awareness of the benefits of connected drug delivery devices and their capacity to provide a more tailored treatment regime in order to encourage adoption and use.

Regulate information load and offer training: It may take some adjusting for patients to feel confident using new digital features and apps. To avoid users feeling overwhelmed or distressed, pharmaceutical companies can offer training and support programmes which address concerns and promote the benefits of digitalisation. For this same reason, it may be worth limiting the frequency of notifications and the load of information at patients’

82 INTERNATIONAL PHARMACEUTICAL INDUSTRY

disposal and keeping alerts to a minimum.

Conclusion As the connected drug delivery market moves to empower patients to take a more informed and active role in their own treatment, pharmaceutical manufacturers are embracing the opportunities these new connected devices will bring, to help deliver the greatest health outcomes to patients.

Connected devices equip physicians and care professionals with data they would not otherwise have, and in a timely manner, meaning that they can provide more informed advice, take quicker action when needed, and adjust treatments to specific patient needs. Likewise, patient data can provide invaluable insight into drug efficacy and can serve as the foundation for offering training and education services around therapy management. In future, we are likely to see more sophisticated monitoring and reporting capabilities, and it is more important than ever that clinicians and patients are at the very heart of decisions over new product development to help prevent health services becoming overwhelmed in years to come.

REFERENCES 1.

2.

3.

WHO, Decade of healthy ageing report, 2020 WHO, Addressing the 18 million health worker shortfall, 28 May 2019 Siemens Financial Services, Priority Investment, 2019: https://new.siemens.

4.

com/global/en/products/financing/ whitepapers/whitepaper-healthcarepriority-investment.html Referencing proprietary data, along with third party reports such as: GrandView Research, Connected Drug Delivery Devices Market Analysis, Dec 2018; Acumen Research, Connected Drug Delivery Devices Market, Nov 2019; Future Market Insights, Connected Drug Delivery Devices Market, Dec 2019.

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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Manufacturing

The Effects of Heat from Electro-mechanical Components in Critical Instrumentation Heat in electronic and fluidic control systems such as those seen in analytical, scientific and medical instruments will in many cases be an unwanted byproduct of the excessive power required to initially operate electro-magnetic devices such as solenoid valves and electro-mechanical devices. Although the initial power is unavoidable, the need to maintain full power when the device has been energised becomes excess to requirement in many instances. In the majority of cases, it is possible to reduce the power to a level that maintains the required function but reduces the excessive currents being drawn, and in doing so there is less heat and a lower overall power requirement that can be considerable, depending on the number of devices present.

Reducing power consumption is both cost-effective and desirable in this day and age of carbon-footprint awareness.

Solenoid valves in particular are a source of localised heat which, if unchecked, can transfer to the media passing through them and in doing so can elevate the temperature beyond the desired limits, and can be a particular problem if the media is a physiological fluid or is heat-sensitive.

However, any electro-magnetic device can emit heat and draw higher than necessary current if not intelligently controlled.

Such devices can be as simple as electromagnetic clamps, locks and sorting devices.

Figure 1. Typical solenoid valve

Figure 2. Sample electro-magnet

One of the many laws of physics states that energy is the quantitative property that must be transferred to an object in order to perform work on, or to heat, the object.

Energy is a conserved quantity; the law of conservation of energy states that energy can be converted in form, but not created or destroyed.

Simplistically speaking, that is all there is to it; however, each time there is a transfer from one form of power/energy to another, there will be some losses that are inherent in the device. The most wasteful phase is after the mechanical movement has been achieved and the magnetic circuit has been completed, the power to hold the device in position is considerably reduced.

Assuming that the instrument’s design allows the same power to flow through the device, the excess power is liberated as heat and it is this heat build-up that should be addressed.

In the real world, we are more likely to think of the concept of power rather than pure energy as it is more relative to the tasks we need to perform. For electro-magnetic devices, the subject of this editorial, the principle is simple: Electricity In = Electro-Magnetic Field = Magnetic Attraction = Mechanical Movement.

Wasting power may not appear to be a major consideration for mains-powered

Figure 4. Sample power savings

equipment, but what if there is need for a battery-operated instrument with a long field life? Even mains-operated instruments can benefit from power reduction, savings on the cost of electronic power supplies and reduction in physical size and weight of the final instrument.

Figure 3. Temperature traces for a high-pressure solenoid valve 84 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Electro-mechanical devices are designated to have specific duty ratings which will greatly affect their potential to generate excessive heat, and particular care needs to be taken when selecting such devices to match the application in hand. A 100% Spring 2021 Volume 13 Issue 1

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Manufacturing duty coil may happily remain energised for 24/7 but it will still get warm, possibly higher than the actual application can comfortably tolerate. Whereas, a 50% duty coil when energised then held at a reduced power setting will remain cool even at 24/7, and will more than likely be physically smaller and more cost-effective too.

Mitigation of the impact of heat from electro-mechanical devices is a two-fold problem, as not only can the heat be detrimental to chemists and other users of analytical instruments, it is also a design conundrum for the designers of the devices themselves.

There are a multitude of solenoid valves used in laboratory instruments and process systems. What they have in common is that heat can be detrimental to their performance and reliability, and can directly affect the materials of construction and promote premature failure.

Most solenoid valves for analytical and scientific use are designed to be small and inert and have low internal volumes.

However, many do not have 100% duty rated coils – something that is often overlooked when the valves are being used and, as a result, the performance can be compromised.

Because of this, applications that may well have worked well using manual valves during the development phase can have unwelcome results when solenoid valves are substituted for their counterparts and energised for long periods. Vaporising of media and formation of crystalline structures within valves is a particular problem.

The duty rating is also important when it comes down to basic physics, as noted earlier in this article: put power in and heat will come out somewhere along the line if nothing is done to control the device efficiently.

The coil in the solenoid is designed to develop sufficient force to operate the valve at a specified voltage by attracting the armature and completing the magnetic circuit. Once the armature has moved and completes the magnet circuit between itself and the core, the power required to keep the valve energised is reduced. However, the coil is still drawing the same current as it did to initially energise as the resistance of the coil remains the same and the excess power is dissipated as heat. Once again, physics is the reason for this; the attraction of the magnetic field is calculated as the square 86 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 5. Typical driver implementations

of the distance the armature must move, double the distance, quadruple the power requirement. Therefore, as the air gap in the magnetic field of the device closes, the power requirement reduces.

What can be done to reduce the heat and power requirements of solenoid valves?

There are a number of options available to the system designer, the two most common being latching valves and the use of strikeand-hold drivers.

Latching valves are devices that are bistable, only being energised to change state but then held in position by mechanical means. More often than not, this is achieved with at least one permanent magnet or a mechanical latch. The advantages include excellent power-saving, as no power is required once the desired state is achieved and they maintain position even when there is no power available at all. Their holding is limited only by the magnetic force or latch designed into the device, and they are ideal for use on battery-operated portable equipment.

The disadvantages of latching valves are the facts that they are more expensive than standard valves, in most cases physically larger than standard products, and always need a specific driver to operate them.

Care must also be taken when designing systems and instruments using bi-stable latching valves to be mindful of the fact that a recovery sequence must be programmed in to the control software to ensure the valve is in a known position when re-starting the system, health and safety always being a priority.

With regard to strike-and-hold drivers, this refers to energising valves using an electronic driver to first apply a pull-in voltage and then a lower voltage to hold the valve in the energised state. This type of operating system is in general use, but the methods used to attain the function vary widely. One of the advantages of this

approach is that it is possible to power boost the strike voltage by over driving a coil for a short period of time before reducing the voltage to hold the device. Three of the methods generally used are voltage control, current control and pulse width modulation (PWM).

The advantages of strike-and-hold drivers include the fact that they can use standard valves at no extra cost, and they can also work on pinch valves.

Power-saving can typically be 68 per cent (but will vary between manufacturers) and they provide improved battery life when used on portable equipment. There are only two main disadvantages associated with strike-and-hold drivers: they need a driver for switching and some pinch valves need increased holding currents as they need to maintain compression, so less power savings are attained.

Voltage-controlled drivers, as the name suggests, work on the principle that after initially energising the device, the voltage is dropped to the holding voltage. This is a simple approach, but in most cases a resistor is used to drop the voltage and in doing so the total heat emissions are not always reduced, just transferred to the resistor and in doing so, there is minimal power-saving.

Current controlled drivers operate similarly to the voltage-controlled circuits, but reduce the current instead.

Far more efficient and cost-effective are pulse width modulation drivers as there is virtually no resistance in the path of the current flow and as such, little or no heat is generated within the driver circuitry. By switching the power on and off at a set frequency with variable duty cycles, it is possible to generate precise holding states.

This method of voltage/current generation is variable from 0–100% duty within a simple circuit and with readily available components.

Spring 2021 Volume 13 Issue 1

Manufacturing

Figure 6. Modular drivers

Figure 7. Integrated driver and connector

Implementation of drivers for energising solenoid valves and electro-magnets is a matter of manufacturer’s preference, and can be anything from integral circuits on the main mother boards or as single drivers, modular, multiple assemblies, integrated within or mounted on the device or incorporated in an electrical connector.

Some drivers will incorporate visual aids such as LEDs indicating they are energised

or a fault condition. There is such a variety available, the choice is whatever fulfils your specific requirements best.

Figure 8. DIN connector driver

Whatever method is ultimately chosen to mitigate heat-rise and promote costeffective and efficient control of your electro-magnetic devices, rest assured just switching them on and off is not the best option.

Gary Stevens Gary Stevens is Managing Director of NResearch UK Limited and has over 40 years of experience in the fluidic valve control market. Specialising in the application of pinch valves, solenoid operated isolation valves and precision metering pumps for scientific and analytical instruments. In addition to the supply of proprietary products, Mr. Stevens also designs bespoke components for embedded manifold assemblies and devices for electronically interfacing and driving solenoid valves. Visit www.nresearch. com for more information.

Email: gstevens@nresearch.com

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Manufacturing

Are Plant-based Softgels the New Gold Standard for Pharma?

Softgel capsules are gaining popularity throughout the nutraceutical and pharmaceutical industries. As well as safely facilitating the delivery of poorly-soluble active pharmaceutical ingredients (APIs), softgel technology offers a number of benefits over other oral dosage forms, including versatility and rapid absorption. Moreover, they are widely accepted amongst the growing global population – who are taking more supplements and medications than ever before to maintain their health – thanks to ease of swallowing, convenience and quick onset of action, making them the preferred dosage form for manufacturers, consumers and patients alike.

Driven by their wide approval as a delivery format, continued innovation in soft capsule formulation, and the thriving pharmaceutical and supplement industries, the global market for softgel applications is predicted to grow at a CAGR of 5.4% between 2018–2023 – reaching $316.6 billion by 2025.1 Gelatin-based softgels are the current gold standard in the pharmaceutical industry.

But with new high-performing plantbased softgel solutions on the market, will vegetarian alternatives take the spotlight?

Below, we outline the challenges associated with gelatin softgels, the rise in vegetarian options and how manufacturers can tap into the plant-based trend.

Gelatin: The Current Gold Standard for Softgels With interest in soft capsules increasing across the consumer healthcare market, the pharmaceutical and nutraceutical industries have made it their priority to develop the perfect softgel delivery system. To date, this has typically involved gelatin. Derived from animal sources, gelatin has become the shell forming material of choice for soft capsule formulation because of its excellent filmforming properties and mechanical stability.

Gelatin-based capsules are also much easier to manufacture than other drug delivery systems, due to their thermo-reversibility properties and pH-independent gelling, and do not require complex formulations 88 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to produce. Moreover, gelatin softgels are exceptionally versatile, enabling producers to customise their capsules based on colour, shape and/or size. Not only does this help to meet the requirements of different active fills, but it also allows manufacturers to create capsules in line with their own brand and consumer preferences.

As a drug delivery format, gelatin softgels help to provide incredibly accurate unit doses safely to patients. When consumed, gelatin-based softgels are easy to digest, dissolving within minutes in the human body. Compared to tablets, hard capsules and powders, they help to improve the bioavailability of poorly water-soluble active ingredients, increasing overall effectiveness of the drug. They also support a range of release profiles – from slow release of the API for delayed drug delivery, to fast or immediate release – facilitating optimal drug activity based on patient needs.

In addition to helping manufacturers achieve capsules with consistent quality and integrity, that fulfil the end-use requirements of the application and meet stringent and evolving industry regulations,

gelatin softgels are popular amongst the individuals taking them too. Reasons for this include swallowability, no taste and convenience – factors which also help to improve patient compliance. This is especially important for medications or ingredients that have a strong odour or unpleasant taste, like fish oil, which can be easily masked when encapsulated within a softgel.

These benefits make gelatin softgels a popular choice amongst manufacturers and patients alike, and have enabled gelatin to dominate the soft capsule market for several decades.

But What About the Drawbacks?

Like most delivery formats, gelatin-based softgels have some limitations. A major constraint is that gelatin is highly watersoluble, depending on temperature. This is an advantage in some respects as it allows for disintegration of the capsule shortly after ingestion, which is essential for the delivery of fast-acting drugs. However, it can mean that gelatin softgels are more sensitive to heat and humidity. As a result, the shelf-life of gelatin softgel formulations Spring 2021 Volume 13 Issue 1

Pointed in the right direction.

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 89

Manufacturing

can vary considerably, depending on the conditions in which the capsules are stored.

An additional challenge with gelatin capsules is cross-linking. Capsule shell cross-linking arises from gelatin polymerisation – a process facilitated by high temperature, high humidity or UV light. The main impact of cross-linking is prolonged capsule disintegration time, whereby the active ingredients are released much more slowly than intended, leading to lower efficacy of the drug.

Therefore, despite gelatin’s numerous plus points, drug-makers are exploring alternative capsule materials that will help to overcome these challenges, including synthetic polymers and plant-derived or natural origin ingredients, like carrageenan and starches.

The Rise in Plant-based Alternatives Gelatin alternatives tap into the growing market for plant-based products, driven by the mega plant-based trend. Vegetarians and vegans are opting to minimise, or even completely eliminate, their consumption of animal-derived gelatin, increasing demand for alternative options in the pharmaceutical and nutraceutical markets. But it is not just lifestyle choices that determine demand for plant-based alternatives. Derived from the bones and skin of pigs and cows, the inclusion of gelatin means some individuals cannot consume traditional softgels for religious reasons. Meanwhile, the increased awareness of environmental and health concerns regarding meat consumption is also fuelling the global drive toward plantbased solutions. Because of these trends, the vegetarian softgel manufacturer value is expected to reach $650 million by 2025, growing at a CAGR of 7.2%.2 90 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Compared to gelatin-based softgels, vegetarian soft capsules obtained from plant-based, natural origin sources offer similar benefits, and more. Like gelatin softgels, they are easy to swallow, have a desirable texture and offer some flexibility in terms of capsule size, shape and colour.

Additional advantages of plant-based capsules include purity, safety, clarity, tastelessness and no odour. But, unlike gelatin, high-performing plant-based technologies are able to overcome some of the limitations associated with softgels.

This includes enabling higher temperature encapsulation, allowing better capsule stability in different temperature and humidity ranges. Plant-based soft capsules are also ideal for manufacturers who want to meet claims for vegetarian, halal and kosher, as well as non-GMO. For some, such characteristics make veggie softgels superior to traditional gelatin-based capsules.

The Formulation Challenge Although veggie capsules bring several advantages for manufacturers, their formulation is difficult to perfect and not without its challenges. They are typically more expensive and challenging to formulate, requiring unique gel mass preparations. Some formulators have

experienced leakers, low capsule hardness or slower dissolution of the polymer shell, for example, whereas other plant-based soft capsules do not comply with disintegration time criteria when submitted to accelerated stability. This means that many veggie formulations do not meet the necessary performance standards, with formulators undergoing many rounds of trial and error to get veggie soft capsules right. The manufacturing procedure for vegetarian soft capsules can be more complicated than their gelatin counterpart too, because of the solution’s higher viscosity and processing temperatures, which requires specialised features – the adoption of which can incur costs. And some manufacturers also believe that the manufacturing process is much slower and inefficient for plant-based softgels, and therefore more expensive, preventing them from exploring veggie soft capsules further.

Pea Starch Technology: Unlocking Nature’s Potential Their formulation may be complex, but increasing innovation in softgel technology means that more advanced vegetarian options are becoming available and they are rapidly gaining a foothold in the market.

Pea starch technology – a recent development – supports the formulation of highperforming and attractive softgel solutions, with capsule characteristics including minimal leakage and no sticking. Unlike gelatin though, hydroxypropyl (HP) pea starch alone does not possess the gelling properties required to cast a homogenous film and seal seamlessly a capsule. For this reason, the pea starch must be combined with other ingredients, like carrageenan, to achieve gelling characteristics. However, when mixed together, pea starch and carrageenan systems are more viscous than gelatin and jellify at temperatures below about 85°C, meaning that these types of soft capsules should be prepared at a higher temperature compared to gelatin.

Gelatin softgel capsules

Plant-based soft capsules (incl. pea starch capsules)

Created using gelatin, an animal by-product

Created using vegetable by-products

Highly susceptible to cross-linking, leading to reduced solubility

Not susceptible to cross-linking

Integrity affected at higher temperatures and humid conditions

Maintains integrity at higher temperatures and humidity

Table 1. Gelatin vs plant-based soft capsules.5 Spring 2021 Volume 13 Issue 1

Manufacturing

This offers formulators further advantage as it removes temperature limitations associated with gelatin, enabling multiingredient, complex formulations, and the flexibility to include ingredients that require higher processing temperatures, like pastes or waxes. In addition, pea starch-based soft capsules are able to maintain their integrity during production and throughout storage at temperatures higher than gelatin. One study in a high-performing pea starch formulation, where capsules were packaged in aluminium or PVC blister packs, showed that capsules retained a hardness of 19.1 N after six months at 25°C/60% relative humidity (RH) and 17.3 N after 12 months at 20°C.3 Moreover, unlike gelatin softgels, pea starch soft capsules exhibit no cross-linking, maintaining efficacy of the drug. A recent capsule performance study confirmed this, demonstrating a disintegration time of <8 minute after 12 months at 20°C and six months at 40°C/75% RH due to no cross-linking.4 Table 1 summarises the key differences between gelatin-based capsules and plant-based alternatives.

Time to Make the Switch to Plant-based?

Plant-based solutions – like pea starch and carrageenan formulations – require higher temperatures to mix, transfer and encapsulate. However, making the switch to plant-based capsules is relatively easy. Pharmaceutical manufacturers can incorporate vegetarian soft capsules into their existing gelatin operations with minimum capital investment by simply www.ipimediaworld.com

adding heat and temperature control systems to existing equipment. Contrary to popular belief, manufacturing times and encapsulation speeds for pea starch capsules are also demonstrated to be equivalent to gelatin, with gel preparation of pea starch capsules equating to approximately two hours, and equipment speed set to 2–5 rpm.

Drying times for pea starch capsules are similar too at 4-5 days, compared to 3–4 days observed with traditional gelatin softgels.

The Complete Solution Gelatin is an age-old technology. But, with demand for plant-based alternatives showing no signs of slowing down, offering a veggie soft capsule option could help differentiate pharmaceutical and nutraceutical manufacturers from their competition – all while meeting consumer preferences for sustainable, non-animalderived ingredients. Roquette’s pea starch technology – LYCAGEL™ – brings together the strength of nature with leading scientific expertise to create a nutraceutical and pharma grade-ready application with advanced performance characteristics, including excellent film-forming properties and easy drying with no stickiness.

Ready to unlock nature’s potential? Learn more at: https://roquette.campaign.page/ lycagel?utm_source=international-pharmaceutical-industry&utm_medium=text&utm_ campaign=lycagel&utm_term=vegetariansoftgels&utm_content=feature-article-link

REFERENCES 1.

2.

3.

4.

5.

Research and Markets, 2016, Softgel Capsules Market Analysis & Trends — Application (Health supplement, Vitamins & Dietary Supplements, Cardiovascular Drugs, Anti-Inflammatory Drugs and Antibiotic & Antibacterial Drugs), End-User — Forecast to 2025.

Market Study Report. Global vegetarian softgel capsules market growth 2020–2025. [report].

Roquette pea starch performance study, 2020.

Ibid.

Roquette data, 2020.

Steve AmoussouGuenou Steve Amoussou-Guenou is a Global Technical Developer with Roquette.

With more than 12 years of experience in the pharmaceutical industry, Steve leads all aspects of technical support for Roquette pharma customers, including helping them in the use of Roquette excipients for their pharmaceutical development projects, offering technical guidance in formulation/ process development, quality and regulatory affairs, and contributing to the development of innovative solutions.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 91

Manufacturing

Granulation in Pharmaceutical Technology

Flexible and Efficient Applications for Solids Production Granulation plays a key role in the production of solid dosage forms in the pharmaceutical industry. Particularly due to the pressure of rising costs, fast and efficient granulation processes are becoming increasingly important.

Granulation aims to form coarser agglomerates from fine powder. Agglomerates may consist of fixed, dry grains, and each grain is an agglomeration of powder particles of sufficient strength. Granules are used directly as pharmaceuticals or can serve as an intermediate in the production of tablets or capsules.

Beside wet granulation, which is the oldest and most common granulation technique and can be accomplished using different types of equipment, dry granulation is becoming more and more famous.

The German Technology Company L.B. Bohle Maschinen und Verfahren GmbH (Ennigerloh) offer a wide range of granulation solutions. The Bohle portfolio for manufacturing oral solids includes complete production systems as well as stand-alone machines. In addition, the mechanical engineering company specialist has developed and delivered many containment applications for the pharmaceutical and nutraceutical industries.

This report gives a first introduction to the different granulation techniques and names some product examples.

Dry Granulation Continuous dry granulation or roller compaction is an established process in the pharmaceutical industry and is required when wet granulation may be unsuitable as a manufacturing method. Roller compaction is used for more than just moisture- or temperature-sensitive products. Compared with wet granulation, no energy-intensive drying processes are required. This reduces the need for large investments in equipment and production facilities and results in a lower cost per batch by reducing the energy costs. Because no drying is required, no 92 INTERNATIONAL PHARMACEUTICAL INDUSTRY

solvents need to be stocked, extracted or disposed of.

Dry granulators ensure a compacting process with high material throughput.

A single machine can produce different products and batch sizes.

Roller compactors are distinguished based on their roller arrangement. Types include horizontal, vertical and inclined rollers. The press rollers also vary in width, diameter and surface texture, and there is a choice between fixed or variable gaps. Dry granulators with a variable gap are preferred because they ensure consistent granule porosity at a constant pressing force.

The aim is to process the powder’s freeflowing granules with a defined density or porosity that allows for immediate pelletising after compacting.

The powder is compacted between two rollers with specified gap widths. The impact on the rollers, as well as the gap width, is monitored via sensors and there is also the option to install process analytical technology (PAT). All data are integrated into a control circuit to ensure continuous process quality, while an electro-mechanical drive provides precise and fast control. The chopper unit below the compacting rollers processes flakes into a granule at a defined granular size, and the unit is equipped with a conical sieve with replaceable inserts for different particle sizes. Even at high material throughputs, the coneshaped sieve and its inserts gently crush the ribbons into granules with the desired particle size distribution. Each Bohle BRC can be mounted with a different rotary sieve within minutes to adjust to new process and ribbon requirements.

L.B. Bohle’s BRC series combines a high level of product capacity with minimum material loss. This system outclasses rival solutions by generating force through purely electromechanical means to ensure consistent ribbon properties. The BRC controls the compacting force and ribbon thickness very innovatively. It produces the even compacting of material over a production range of <1–400 kg/h. The

sophisticated system design facilitates the handling and shortens the assembly process.

The hygienic design and the integrated washing nozzles, fitted as standard, allow for an effective WIP process.

Thanks to its functional GMP-compliant design and PAT tool support, the compactor meets the requirements of the pharmaceutical “quality by design”.

Fluid Bed Granulation Fluid bed granulators and dryers have been used in the pharmaceutical industry for many decades. Adding an aqueous or alcoholic granulation medium compresses the mixture of dry powder particles. The fluid contains a volatile solvent which can be removed by drying.

Originally used only as a dryer after a wet granulation process, it replaced step-wisely the classical oven drying in pharmaceutical production. Today, fluid bed drying can still be considered state-of-the-art within pharmaceutical drying processes. With the additional implementation of spray nozzles, fluid bed dryers became fluid bed granulators - thus wet granulation could be smoothly performed in one discrete device. In these applications, the nozzles were mounted on the top in order to spray onto the wet particles (top spray setup). Further development used the same apparatus for coating of tablets or other particles with an additional insert, whereby the spray nozzles were placed at the bottom of the fluid bed (bottom spray setup). This type has been used for decades in the pharmaceutical industry. The most promising change was the development of the fluid bed apparatus with tangentially mounted nozzles. The benefits of systems with tangential spray nozzles are becoming more and more apparent and these systems are now tending to take over from top-spray granulators.

Since the fluidised particles or granules move tangentially at relatively low fluidisation height, they do not require a high-volume expansion. This reduces the required installation height, saving costs Spring 2021 Volume 13 Issue 1

Manufacturing integrates the individual components of the GMA high-shear granulator, BTS wet

The compact granulation unit with the BFS fluid bed system and the patented Bohle Uni Cone BUC® process sets new standards.

and production space. Another advantage of L.B. Bohle´s tangential design is that granulation, coating and drying can be carried out in a single system without altering the equipment setup.

L.B. Bohle developed the BFS fluid bed system with tangentially mounted spray nozzles and the patented Bohle Uni Cone BUC®, a specially slotted air distributor plate with a conical displacement cone for batches of 1 to 500 kg. Its pressure shock resistance of up to 12 bar makes the BFS the ideal choice for organic methods. Short product transfer times and efficient cleaning procedures offer additional potential savings in production time and cost. The geometrically similar structure simplifies scaling-up.

A newly developed, protected multipurpose valve directly above the distributor plate facilitates the dust-free suction and draining of the product container. This implicates clear benefits with regard to ergonomics and cleaning that make the BFS stand out significantly from other fluid bed systems on the market.

Benefits of the fluidised bed granulator

by L.B. Bohle: • • •

• • •

Complete fluidisation of particles Even film coating, no twin formation Integration of PAT (process analytical technology), NIR (near-infrared spectroscopy) and WIP (washing in place) Patented filter cleaning Lowering of filters via electric drive enables easy inspection Easy-to-remove distributor plate

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• •

Low installation height, efficient space utilisation Optimum conditions for containment applications

High-shear Granulation High-shear granulation is a form shaping process for granulation that has been optimised for the oral solids production, which guarantees best mixing quality with minimum mechanical stress on the product.

With high-shear granulation, a binding fluid is added to the powdery particles in a closed container that has an agitator blade and chopper. The agitator blade with its high shear and compaction guarantees effective granulation. Dense granules are formed. The chopper prevents excessive granule growth and distributes the granulation medium throughout the product.

The Bohle fluid bed system is a multi-purpose system for drying, granulating and coating and offers numerous advantages over systems in the top spray or bottom spray process.

L.B. Bohle’s single-pot granulation portfolio includes R&D systems for small production volumes as well as productionscale systems.

The GMA high-shear granulator system has been specially optimised for pharmaceutical applications and is designed for through-the-wall mounting. The advantages at a glance: • • • • •

Low fluid consumption Easy unloading Closed system Granulation can be controlled according to the time, quantity or output Easy cleaning and short cleaning cycles.

Water is drained completely

Compact Module The number of integrated granulation lines increased in recent years. Integrated production systems improve the productivity through automation, increased yields and fast and efficient cleaning procedures.

The Bohle compact granulation module

The BRC series, here in combination with a lifting column, guarantees extremely consistent ribbon properties by generating force through purely electromechanical means.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 93

Manufacturing sieve, BFS Bohle fluid bed system, Bohle Uni Cone BUC®, cyclone separator and BTS dry sieve perfectly into one unit. In doing so, the process, cleaning, control, explosion protection, zone concept and qualification are closely coordinated with each other.

The compact granulation suite allows for extremely space-saving installation due to the components being arranged right next to each other. In addition, direct product transfer is possible from the GMA’s outlet valve to the BFS suction valve through a stainless steel pipe. The tangential sieve can also be integrated into this pipe. An additional drain valve is integrated in the BFS process tank so that the transfer and drain lines do not have to be modified during the process.

The compact granulation system is an effective solution when it comes to optimising classic wet granulation in an economical and ergonomic way. The system sets new industry standards due to its many technological advances and logical safety concept.

Advantages: • • • • • •

High-shear granulator and fluid-bed system are installed into the wall right next to each other Low space requirement and minimal installation height Multi-purpose use for a variety of processes One single control panel is used to control both machines WIP cleaning guarantees fast cleaning times Low space requirement, high quality

Single-pot Granulation Single-pot granulation has been used in the pharmaceutical industry for many decades.

The single-pot granulator features classic single-pot granulators with agitator and chopper units and a top drive. The shearing action is performed by two stirrers which loosen the product and prevent clumping.

The GMP-compliant process bowl with a double shell is at the centre of the singlepot granulator. The production outcome of this technology is a granule of optimum quality.

With L.B. Bohle´s VMA granulator, mixing, high-shear wet granulation and drying (vacuum drying, carrier-gas drying, or drying by microwave heat) are all carried out in one bowl.

94 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The process bowl is emptied through a cone-shaped sieve via the floor outlet into a container (IBC). Recipe-controlled cleaning is carried out automatically.

The single-pot granulator VMA offer the following benefits: • • • • • •

Secure production within a closed container in a vacuum High mixing and granulation efficiency (even for low doses of active agents at < 1%) Drying at low temperatures Small product contact surface for fast, easy cleaning and fast product changeover Efficient solvent recovery through cooling water Compact footprint for low space requirements

Twin-screw Granulation Twin-screw granulation (TSG) is an established method and emerging technology for wet granulation of solids. In the beginning of the 2000s and in the years that followed, the process was described and followed up by several research groups. TSG is a fully continuous process by design and can be a starting point for pharmaceutical companies to launch activities related to continuous manufacturing. Compared to batch granulation, continuous granulation is characterised by a constant in- and output of material through the processing zone.

The powder to be granulated is fed onto two so-called screws, which rotate in the same direction in a cylinder, thereby transporting the material through the process zone and kneading and mixing it at the same time.

Intelligent control concepts are used in combination with PAT (process analytical technology) such as NIR (near-infrared spectroscopy) for in-line content analysis or continuous particle size analysis, or

Raman spectroscopy to produce granules of consistently high quality.

The major difference between TSG and extrusion is the missing die plate at the end of the machine. Consequently, the wet material does not experience a strong densification, but solely falls out of the granulator.

This TSG design results in several advantages: • Short dwell times for the material in the process (< 1 minute – a few seconds) • Fast and efficient reactions to process and quality deviations • Reduction in the space for the required machines and associated GMP areas • Mixing and granulation in one step and in the shortest time possible • Introduction of instruments for 100% in-line quality control • No more discarding of whole batches necessary as inferior quality products can be selectively ejected • Implementation of experimental test plans in the shortest possible time A TSG provides plenty of adjustable parameters and possibilities to vary the setup. Furthermore, different machines, mainly feeders, can be employed alongside the process, which increases the degree of freedom of the system even further. The TSG BCG, developed by L.B. Bohle, can be used as a stand-alone unit or integrated in a continuous production line.

Due to the flexibility, simple implementation of the process and potential, the TSG is the perfect, versatile machine for continuous manufacturing processes in research and development and in production.

Tobias Borgers Tobias Borgers is a Marketing Professional, with a huge experience of multi-channel marketing initiatives. Proven abilities in creating successful exhibitions, integrated digital and traditional marketing campaigns, social media marketing, content management, lead generation, event and project management. Tobias holds a B.A. from University of Duisburg-Essen and joined L.B. Bohle in 2012.

Spring 2021 Volume 13 Issue 1

INSIGHT / KNOWLEDGE / FORESIGHT

SUPER PUBLICATIONS FOR SUPER PHARMACEUTICALS IPI

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

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 95

Logistics & Supply Chain Management

Deploying AI in the War on Counterfeit Drugs

Introduction To provide patients with timely access to novel and effective therapeutics, pharmaceutical organisations must maintain robust, trustworthy supply chains. But this is no mean feat.

Creating and managing a reliable supply chain is essential for many reasons, including success in the market, to protect consumer safety, and to comply with mandatory regulations. However, supply chains are growing increasingly global and complex, opening them up to dangerous quality control and safety issues like theft, fraud, and counterfeiting. These issues have only been compounded during the COVID-19 pandemic due to associated supply chain restrictions, product shortages, price increases, and a disrupted pace of production and distribution.

Advanced technologies, such as blockchain and artificial intelligence (AI), can help to overcome the challenges of supply chain fraud and theft, and ensure that global supply chains remain safe, agile, visible, and reliable. The resiliency offered by such technologies is essential to maintain consumer access to potentially life-saving new therapies and better protect an organisation from disruptive events like COVID-19.

The Dangers of Counterfeiting and Theft Combating the presence of substandard drugs in supply chains is a priority for the pharmaceutical industry and a topic of significant concern for associated health officials and regulatory bodies.

Substances can leave supply chains via theft or enter them in substandard or fraudulent forms as a result of counterfeiting. Counterfeit products have a range of potential health impacts and can lead to preventable deaths. Approximately one million people die annually as a result of toxic or ineffective counterfeit products2.

In contrast, others are denied effective treatment as they unknowingly administer a substandard and less effective medicine 96 INTERNATIONAL PHARMACEUTICAL INDUSTRY

that will fail to treat or prevent disease.

In the case of Malaria, for example, up to 450,000 people die annually due to reliance upon counterfeit pills3.

Additionally, in times of disruption, such as during the ongoing COVID-19 pandemic, it’s not unusual for patients, governments, and even health organisations to stockpile medicinal supplies, sometimes in substantial quantities. However, this causes the prices of raw ingredients to skyrocket. As an example, this year, the raw ingredients of the anti-malarial drug hydroxychloroquine recently rose from $100 to $1150 per kilogram in Pakistan1, resulting in some companies trying to source alternatives.

Counterfeit medicines are a significant concern on a global scale. Falsification of medicine disproportionately affects poorer and more vulnerable nations, which have reduced access to high-quality medicines.

In 2017, the World Health Organization estimated that one in 10 medical products circulating in low- and middle-income countries is either falsified or substandard4.

Further, up to 30% of medicines sold in Asia, Africa, and Latin America and 64% of the anti-malarials sold in Nigeria are thought to be counterfeit5.

Complex distribution networks create more opportunities for counterfeits to enter legitimate supply chains, too, making them increasingly difficult to detect. Supply chains are growing in scale and intricacy, with numerous different interacting steps and components. Many third parties are involved in processing vast volumes of transactions, with each link in the chain offering another chance for fraud or theft – whether opportunistic or planned. This situation has worsened amid COVID-19related disruptions, as volatility has brought vulnerability; emphasis has shifted to progressing essential medicines to market, resulting in an easing of some enforcement guidelines. Consequently, the industry has experienced more supply chain restrictions and shortages than expected. Some oversight and approval procedures have also weakened, workforces are reduced and low on morale, and supply shortages are piling on the pressure. The result is an

upsurge in attempted fraud, bribery, and corruption across the globe6.

Tracking and Tracing Global Supply Chains Efforts to battle counterfeiting and theft in pharmaceutical supply chains are ongoing.

For example, under the US Drug Supply Chain Security Act (DSCSA), manufacturers have employed serialisation to achieve individual unit and lot-level traceability since 2018. By 2023, DSCSA mandates complete product traceability from manufacturer to dispenser – from plant to patient.

In working to meet these goals and regulations, the industry is making significant progress. Globally, over 40 countries are now implementing a ‘track and trace’ regime. Track and trace solutions record all information generated at each step throughout the distribution chain and store this in a traceable, transparent, and secure central database. Packaging and distribution chains have complete traceability due to the application of batch coding, serialisation, and aggregation to product packs as they prepare to leave a facility. As supply chains become less linear and more collaborative and network-like, track and trace assures complete knowledge of product provenance, location, interactions, and other essential characteristics.

Implementation of track and trace is also a significant stride towards achieving something essential for robust, efficient supply chains: interoperability. However, it is hugely challenging to make track and trace systems globally interoperable and to unify global supply chain regulation as more countries and companies get involved. For example, many drug companies feed into a single distributor, which in turn distributes to many outlets. To minimise the number of systems they must implement, pharma companies may tend toward complying with the most comprehensive or strictest policies.

A globally interoperable system would minimise such considerations, allowing different distributors and regulatory regions to work collaboratively with full transparency and integrity.

The Benefits of Advanced Technology Advanced digital solutions offer a way forward Spring 2021 Volume 13 Issue 1

Manufacturing & Recycling of thermal packaging Europe - USA

Thermal Blankets for the temperature protection of ambient pharmaceuticals in airfreight (+15°C +25°C) / (+59°F +77°F) - High temperature protec�on in HOT and COLD - Very light weight + water resistant - Tailor made for Euro pallets / Block / Airplane pallets - Protocols and S.O.P.’s available Qualifica�ons & Valida�ons - Ambients (+15°C/+25°C) in stress test 8% products mass - Qualifica�on tests according to EN-12546-2 - Tarmac summer profile tests (+46°C) during 6 hours - Tarmac winter profile tests (-15°C) during 6 hours - Solar power tests + Greenhouse effect qualifica�on Ecological notes - UNIQUE = Recyclable due to non-laminated composi�on - Re-use of recycled compounds = LOW Ecological footprint - Recycle machines in Temax manufacturing plants Also used in REEFER container transports for unplugged temperature protec�on

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Customer dedicated storage + QA

Temax fleet / 11 trucks-trailers INTERNATIONAL PHARMACEUTICAL INDUSTRY 97

Logistics & Supply Chain Management for effective supply chain management.

Blockchain is the leading example of such technology currently implemented by the industry and is being implemented in the aforementioned track and trace systems to help companies meet DSCSA and other regulations.

With blockchain, as a substance or product travels through the supply chain, data are generated at each step and an unchangeable code is added to the entry.

If one step is broken, then the system can flag for investigation, assuring that accuracy, traceability, and authenticity are upheld for every product and process step, and weak points in the chain can be addressed. Notably, blockchain maintains a trackable chain of custody in a permanent ledger that is visible to and governed by all stakeholders within a network.

Such a system also enables ‘proofs of data’ to stand in for actual data, allowing competitors to collaborate on a shared platform to assure drug safety without compromising sensitive or proprietary information. With the kind of ‘granular visibility’ enabled by blockchain – in other words, visibility and control over a supply chain at a point-by-point level – organisations can gain a full understanding of the state of their supply chain operations and efficiently identify areas of current or potential risk.

Enter AI The data gathered by blockchain technology can, in turn, be used to feed analytics and solutions powered by AI. AI offers real-time data availability and accessibility across the supply chain. It enables companies to manage silos of data more effectively, collate data from a wide range of sources, and implement ‘big data’ and machine learning applications to unlock the full power of their data. Big data and machine learning allow multiple, large datasets to be aggregated and analysed intelligently to reveal subtle patterns and rich insights.

Identifying such patterns and areas of concern ahead of time can help inventory management, excessive inventory financing, holding, waste, recalls, and crucially, protect against fraud in vulnerable parts of the supply chain.

Overall, the modelling and analytics capabilities brought by AI enable more informed decision-making – a critical factor in managing risk and product quality, as well as harmonising and optimising supply chain management.

98 INTERNATIONAL PHARMACEUTICAL INDUSTRY

From Hesitancy to Data Integrity: The Hurdles to AI Rollout Despite their promise, several challenges face the widespread adoption of AI solutions. For one, the pharmaceutical industry is riskaverse, with many companies adopting a ‘wait-and-see’ approach to implementing innovation, and technology is also outpacing regulators’ ability to manage it, complicating the current and future compliance landscape. Important considerations also concern the integrity of the data itself: the pharmaceutical industry generates data in vast volumes and at differing qualities. But how can organisations manage such large amounts of data and be confident that each data point is reliable? And how do we determine which data are useful to collect, and which are not? While data are undeniably valuable, not every data point must or should be kept – and those who fall into this trap run the risk of becoming ‘digital hoarders’, making their systems more challenging to manage and optimise as a result.

Ensuring data quality and integrity are prominent (if not the most important) challenges in the implementation of AI. Regardless of the power of an AI tool, rubbish in equals rubbish out – high-quality data inputs are fundamental for achieving robust models and unlocking the full predictive potential of AI. Models must then also be checked against high-quality data to verify predictivity, so a pool of robust verification data must be accessible and available for the context within which the AI tool is operating.

Conversely, machine learning applications – by which a system is fed data to learn and generate novel output — require more data to self-improve. Still, organisations have been hesitant to share relevant datasets (and some organisations may lack the data needed to generate appropriate models without collaboration). Datasets that could be immensely valuable, if used in concert with others, are often closely guarded as part of efforts to protect organisational secrecy and data security, making data collaboration a significant hurdle to overcome. However, blockchain is enabling companies to share material while maintaining their proprietary information, opening up new avenues for cooperation. By moving towards a more open, decentralised model for data collaboration, organisations can build and share the kind of verified, high-quality datasets needed to deploy valuable AI solutions effectively.

The Future Power of AI Despite these challenges, AI has the power to increase the agility and visibility of pharmaceutical supply chains. This is essential for protecting patients worldwide and making the industry more resilient so it can better respond to events such as the COVID-19 pandemic. For instance, AI can be used to predict where disease outbreaks will occur using contact tracing data. Such knowledge would be vital to monitoring the spread of the disease to ensure the timely delivery of a presumptive vaccine or PPE to at-risk locations.

The predictive power of AI holds exceptional promise in the realm of supply chain management. For instance, AI tools can predict where a supply chain is likely to be disrupted by traffic, extreme weather, or geopolitical events such as protests or pandemics, and pre-emptively reroute medicine deliveries to avoid disruption.

Such tools could also be leveraged in exploratory or diagnostic ways to protect supply chains, e.g., identifying weak points during distribution or likely sources of counterfeits. Additionally, by modelling whether orders could be consolidated in the production and distribution chain, AI-based tools for logistics and fulfilment can seek areas where increased efficiency can protect profit margins and improve performance.

Conclusion From manufacture through to packaging and distribution, pharmaceutical supply chains can stretch across numerous countries and continents. Optimising these long, complex supply chains and associated distribution networks is vital in ensuring that legitimate, high-quality medicines reach patients faster.

Advanced tools based on AI and blockchain are aiding global efforts to manage complex supply chains and protect them from safety issues like counterfeiting and theft. Although many challenges must be overcome to enable the widespread implementation of AI-based solutions, these tools promise significant benefits for a wide range of supply chain processes, including forecasting, inventory management, procurement automation, and production optimisation.

Advanced technologies enable a fuller understanding of the dynamics and processes at play across a complicated supply chain, enabling better assessment and monitoring Spring 2021 Volume 13 Issue 1

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2.

3.

4.

5.

6.

Service. https://www.bbc.co.uk/news/ health-52201077 Shujath, J. (2018) How tackling counterfeit drugs will drive improvements in the pharma supply chain, Pharmaceutical Commerce. https:// pharmaceuticalcommerce.com/brandmarketing-communications/howtackling-counterfeit-drugs-will-driveimprovements-in-the-pharma-supplychain/ Karunamoorthi, K. (2014) The counterfeit anti-malarial is a crime against humanity: a systematic review of the scientific evidence. Malar J. 2014; 13: 209.

World Health Organization (2017) 1 in 10 medical products in developing countries is substandard or falsified. https://www. who.int/news-room/detail/28-11-2017-1in-10-medical-products-in-developingcountries-is-substandard-or-falsified Blackstone, E., Fuhr Jr., J. P. and Pociask, S. (2014) The Health and Economic Effects of Counterfeit Drugs. Am Health Drug Benefits. 2014 Jun; 7(4): 216–224.

Geschonneck, A. (2020) The supply chain fraud pandemic. KPMG, 7 May 2020. https://home.kpmg/xx/en/blogs/ home/posts/2020/05/supply-chainfraud-pandemic.htmltion to COVID-19.

Jaleel Shujath

of risk, protection of profits and performance, and optimised operations. They also open up new opportunities for predictive modelling of potential disruption and triangulation of counterfeit products, helping pharmaceutical organisations prevent supply chain fraud and protect both the www.ipimediaworld.com

integrity of their products and the safety of the patient.

REFERENCES 1.

Piranty, S. (2020) Coronavirus fuels a surge in fake medicines, BBC World

Jaleel Shujath is the VP of Marketing at Absorption Systems. A 30-year veteran of the industry, Jaleel has worked in all areas of the life sciences value chain, focusing on leveraging new technologies to enhance processes and regulatory compliance. Jaleel has a Regulatory Affairs Certificate: Medical Devices and Pharmaceuticals from RAPS, and is a member of the Editorial Board of the American Pharmaceutical Review. Absorption Systems is a fullservice non-clinical contract research organisation (CRO) developing innovative services and solutions for the pharmaceutical, biotech, medical device, and regenerative medicine industry. The company's mission is to continually develop innovative research tools that can be used to predict human outcomes more accurately or to explain unanticipated outcomes when they occur.

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Cold Chain in 2021: COVID-19’s Continued Influence As we eagerly enter 2021 and prepare this year’s cold chain industry predictions, we reflect on the events of 2020. Nowhere leading into the year did we predict a global pandemic.

Yet its impact crosses all facets of business, causing companies to pivot and adapt. Some were able to harness new opportunities to serve our everchanging way of life and others struggle to stay the course.

The pharmaceutical and cold chain industries were pushed this previous year to innovate through vaccine development, temperature-controlled packaging that met the needs of new deep frozen vaccine storage and increased demand for existing products. They rose to the challenge, working in unprecedented ways to make 2021 a brighter year.

Though there is hope for a return to a more normal environment in 2021, COVID-19 will continue to drive business operations.

This is certainly true for pharmaceutical and cold chain companies. Our three predictions below all show how COVID-19’s influence persists, and in some instances, may have a long-term ripple effect.

Return to Refrigerated Temperatures for COVID-19 Vaccines As of December 8, 2020, 78 different COVID-19 vaccines are in clinical trials, under regulatory review for approval or approved for limited use. Though two vaccine candidates show strong promise, with one approved for emergency use in the United Kingdom, we expect the number of viable, approved COVID-19 vaccines will continue to grow in 2021.

All else equal, it is likely the market will favour vaccines that require refrigerated temperatures of 2–8 degrees Celsius.

Existing infrastructure exists to more easily transport and store these vaccines around the world. Additionally, refrigerated temperatures eliminate concerns around shortages of dry ice and concerns about how it reduces the amount of available cargo space on aircraft.

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This preference for refrigerated vaccines could push pharmaceutical companies with deep frozen vaccines to determine how to maintain efficacy of the vaccine at a refrigerated temperature. If this happens, we will gain knowledge that will move pharmaceuticals’ current storage and distribution temperature from -80°C to easier to distribute ranges of -50°C, -20°C or even refrigerated.

COVID-19 also increases the chances home-based offerings will grow outside of clinical trials. Over the past year, healthcare companies and consumers learned that it is possible to receive healthcare at home.

We expect that a subset of the population will continue to prefer home-based healthcare for its convenience, driving more companies to offer this service.

Outsourcing the Cold Chain Pharmaceutical supply chains continue to reach new levels of complexity that challenge even the most seasoned logistics and supply chain professionals. Contract manufacturing organisations (CMOs) and contract development and manufacturing organisations (CDMOs) offer expertise in manufacturing and development of therapies, allowing pharmaceutical companies to focus on their areas of expertise.

Services like phlebotomy, drug administration and sample collection that require refrigeration will require cold chain solutions.

We anticipate a drive toward solutions that require little training and are easy for home healthcare professionals and patients to operate. We should also see more assessment and evaluation of the cold chain for home-based care in 2021.

This year we expect to see even more pharmaceutical companies outsource these capabilities to CMOs and CDMOs, which will help them reduce overall costs.

We also believe CMOs and CDMOs will expand to include more services. This will include cold chain, working with partners like us. Offering end-to-end expertise will help reduce complexity by standardising as many pieces of the supply chain as possible.

Growth in Direct-to-patient and Direct-frompatient Brings Cold Chain to the Last Mile Over the past several years, clinical trials have become increasingly complex. They require extensive data collection, utilise complicated drug regimens and enrol global patient populations. Frequent travel to a clinical site for routine drug administration, sample collection and simple tests can deter patients from participating. This is especially true when patients do not live close to a medical facility.

Currently, 24 per cent of clinical trials offer home-based solutions that allow patients to receive medical care in their homes or ship study samples from their homes to a medical facility. We expect to see this number increase out of necessity, but also out of a desire for continued convenience.

Dave Williams Dave Williams is the President of Peli BioThermal, a division of Pelican Products, Inc. In this role, he is responsible for the strategic growth of product and service offerings to serve Peli BioThermal’s worldwide clients and partners. Throughout his 30 year career, Williams has held many management and engineering positions. Prior to being appointed President of Peli BioThermal, he held the position of Vice President of Strategic Initiatives at Pelican Products, where he was responsible for the oversight and coordination of evaluating and enhancing the company's systemic strengths and minimising weaknesses for maximum efficiency and profitability, as well as executing approved growth strategies. Previously he served as Vice President of Capital and Engineering at Technicolor and as Project Director for compact disc pioneer, Nimbus. Williams attended Harvard University in Boston, Massachusetts. He was a 2007 graduate of the Harvard Business School's Executive Strategy Leadership Program and the Thomson Executive Leadership Program.

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The Life-saving Technology that will Securely Deliver Vaccines Around the Globe The COVID-19 pandemic is retightening its grip in many parts of the world as case numbers rise again and the longdreaded second wave takes shape.

This has heightened focus on vaccine development, as the difficulty of suppressing the virus for prolonged periods without causing significant economic impact becomes increasingly apparent. That has in turn thrust global pharmaceutical distribution into the spotlight, and it seems clear that the typical in-transit spoilage rate of pharmaceuticals – as much as 12 per cent – can no longer be accepted when the stakes are as high as they are now.

The use of innovative technologies holds the key to minimising spoilage rates and saving lives.

From the gruelling heat of Middle Eastern runways to the freezing tarmac of Russia, air freight containers are regularly left in adverse conditions – and once in the air or on the road, turbulence and uneven surfaces present further dangers to the viability of their life-saving cargo. Vaccines are very sensitive to high and low temperatures as they have large molecules that are activated when temperatures deviate outside a narrow range. Any excursion outside 2 to 8°C could render doses useless on arrival at the destination. Given that external temperatures can easily vary from lows of -20°C to highs of +50°C during transit, this poses a significant challenge for logistics firms. On top of this, the need for the fast delivery of vaccines means that air freight – despite it being an expensive, complex, and polluting way to move goods – is the only feasible way to distribute these treatments.

A solution using a combination of hardware and software means that the transportation of vaccines is now safer, less expensive, and less polluting. The use of hybrid containers and detailed advanced AI to plan journeys has allowed logistics companies to reduce the spoilage rate from as high as 12 per cent to less than 0.1 per cent.

The Hybrid Container Historically, air freight containers have 102 INTERNATIONAL PHARMACEUTICAL INDUSTRY

either been active – for example, refrigerant units – or passive – normally boxes filled with dry ice. However, the hybrid design combines the best features of both – the refrigeration capacity of the active solution and the cooling and insulation of the passive solution – and doesn't require human interaction or the use of mechanical components. It can also recharge itself when it detects the steady 5°C conditions of a warehouse or refrigerated lorry.

This means that the average runtime of a hybrid container is much longer than existing solutions. While passive containers can typically run for anything from 24 to 90 hours between charges, and active containers can achieve runtime between 30 and 40 hours, a hybrid container can run on average for 202 hours without charging – and, due to its ability to recharge on the move, can be used for transporting pharmaceuticals for weeks.

The units are better insulated, allowing for superior temperature control. Indeed, recent audits recorded that there were less than 0.1 per cent temperature excursions even at the height of the global COVID-19 lockdown. With the application of IoT sensors, the containers can be tracked across the world with near realtime monitoring of internal and external temperatures, vibrations, time, and location, making them more secure than other forms of container.

On top of this, the containers are 98 per cent recyclable, thanks to advanced material development. The lightweight design also reduces CO2 emissions during transit by up to 50 per cent. This not only reduces lifetime costs, but also enables the containers to be designed to the highest quality, rather than planned obsolescence being factored into the design process.

Advanced AI and Design To design such a container, a manufacturer must use advanced software and AI to model the efficiency of the design in close to real-world situations. Understanding the energy flows from sources such as the sun – and treating them as an energy source rather than just thinking about temperature

– is vital to understanding how to insulate the cargo. Building these containers is like designing a Formula One car: everything must be optimised to protect any cargo, and that is especially the case for a vaccine for COVID-19. The use of advanced AI software is helping to achieve this.

By using this software, designers were able to enhance the container’s internal airflow in a pre-conditioning chamber and analyse the sub-model of the container insulation for temperature control. The design of the container was optimised to maintain a stable internal temperature despite what was happening externally. This modelling has meant that the containers can store up to five times more energy than traditional methods, helping to keep the container at a steady temperature.

A less sophisticated simulation tool simply would not have been able to cope with the complexity of the design and energy flows. The software was also able to model the IoT components of the container, allowing the manufacturer to accurately report its temperature and location in near real time. This helps pharmaceutical companies not only track the vaccines, but also deal with transport regulations quickly by using a comprehensive data log. This shows where the containers have been and how the internal temperature has changed throughout the journey.

The monitoring system also provides data on how quickly containers tend to pass through customs, identifying any unnecessarily slow parts of the route. This is vital in helping authorities and logistics firms to optimise their own transport networks and overcome local issues — or to help pharmaceutical companies ship to new areas for the first time with minimal delays or mistakes. In a world where delivering vaccines around the world could save thousands of lives, this data analysis is critical and the data logs provide logistics companies with crucial insights.

The combination of innovative software and advanced hardware is making the future distribution of any potential vaccine around 40 times safer than the previously Spring 2021 Volume 13 Issue 1

Logistics & Supply Chain Management accepted industry average. To highlight the seriousness of this, should a temperature excursion occur on a shipment, the entire shipment would need to be retested – which can take up to three weeks and cost around £50,000 per pallet. The ability of the hybrid container to incorporate the benefits of active and passive containers has been aided by advanced AI systems to help develop groundbreaking materials and designs, resulting in a solution to a problem that has plagued the pharmaceutical logistics industry for many years.

Prith Banerjee

Nico Ros

Prith Banerjee is the Chief Technology Officer of Ansys. He is responsible for leading the evolution of Ansys’ technology strategy and will champion the company’s next phase of innovation and growth. Previously, he was Senior Client Partner at Korn Ferry where he was responsible for IoT and Digital Transformation in the Global Industrial Practice. Prior to that, he held leadership positions at Schneider Electric, Accenture, ABB and HP. In 2000, he founded AccelChip, a developer of products for electronic design automation, which was acquired by Xilinx Inc. in 2006. During 2005–2011, he was Founder, Chairman and Chief Scientist of BINACHIP Inc., a developer of products in electronic design automation. He was listed in the FastCompany list of 100 top business leaders in 2009.

Nico Ros is a leading Swiss engineer and the co-founder and CTO of SkyCell.

He is the mastermind behind Smart Containers Group and its technology.

Nico has always been curious about the functioning mechanisms behind the objects we use in our daily lives and has a passion for developing new technologies. Nico is also managing partner at ZPF, an engineering company in Basel. He has constructed some of the most expensive buildings in Switzerland in collaboration with the famous architects Herzog & DeMeuronand and has won prestigious architectural prizes.

Nico’s key strength lies not only in his state of the art engineering know-how but also in his ability to design from the ideal point and work that into the current technology and regulatory frameworks.

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