IPI Spring 2020 by Senglobal

Volume 12 Issue 1

Peer Reviewed

Excessive Prices in the Pharma Sector The EU Antitrust Perspective Rethinking Inhaler Systems from a Patient Perspective The Increasing Challenge of Technology Diversity Cardiac Imaging in Clinical Development: The Benefits of Advanced Imaging Management Systems Generic Solid Oral Immediate Release Products in EU Regulatory Perspectives Dissolution Specification Sponsor Companies –

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Contents 06 Editor’s Letter REGULATORY & MARKETPLACE 10 Excessive Prices in The Pharma Sector: The EU Antitrust Perspective DIRECTORS: Martin Wright Mark A. Barker BUSINESS DEVELOPMENT: Keath Martinez keath@pharmapubs.com Thomas Kurse thomas@pharmapubs.com EDITORIAL: Virginia Toteva virginia@pharmapubs.com DESIGN DIRECTOR: Jana Sukenikova www.fanahshapeless.com FINANCE DEPARTMENT: Martin Wright martin@pharmapubs.com RESEARCH & CIRCULATION: Ana De Jesus ana@pharmapubs.com COVER IMAGE: iStockphoto © PUBLISHED BY: Pharma Publications 50 D, City Business Centre London, SE16 2XB United Kingdom Tel: +44 (0)20 7237 2036 Fax: +44 (0)01 480 247 5316 Email: info@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 2020. ISSN No.International Pharmaceutical Industry ISSN 1755-4578. The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright. 2020 PHARMA PUBLICATIONS / Volume 12 issue 1 – Spring – 2020

An undertaking is defined as dominant if it enjoys such a significant market position as to grant it the power to behave, to an appreciable extent, independently of competitors, customers and ultimately consumers. This dominance lays a special responsibility on the undertaking not to hinder competition in the market. Sara Lembo at BonelliErede examines how the Treaty on the Functioning of the European Union (TFEU) prohibits a dominant undertaking from directly or indirectly imposing unfair prices. 14 Driving R&D Towards 2030 – Waging War on Carbon The largest threat currently faced by humankind is the ever-rising CO2 levels in the air we breathe. In our lifetime, the CO2 level has increased by 33% from 300ppm to 415ppm. The limit for the indoor CO2 level that is without risk to humans is somewhere between 1000 and 2000ppm. Bill Treneman at UPC Cambridge showcases how we have perhaps only 200 years until human health is affected by the CO2 that we breathe in the air, if humans do nothing to change current trends. 18 The Future Market Dynamics and Opportunities in Immune Oncology IO has witnessed a long history of highs and lows. Although conventional cytokines and vaccine immunotherapies were approved for certain cancers, high toxicities, low efficacy and conflicting evidence limited their widespread adoption. Jaideep V. Thottassery and Nidhi Dhingra at SmartAnalyst reveal how the discovery of the first checkpoint protein CTLA4, and approval of ipilimumab, a CTLA4-blocking antibody for melanoma, lay down the foundation for modern-day IO. 22 Understanding the Health Dimensions of the Climate Crisis Climate change is perhaps the most complex issue facing modern society, affecting every aspect of human life. According to a Lancet report, spending on climate change adaption is falling way short of the $100 billion a year commitment made under the Paris Agreement. Rich Quelch at Origin determines that while current projections may look bleak, things can change for the better, with the climate crisis becoming minimised and even potentially reversed, if pharma and other large industries can collectively transform their practices today. DRUG DISCOVERY, DEVELOPMENT & DELIVERY 26 Challenges of Drug Development in Progressive Multiple Sclerosis Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterised with focal confluent lesions of primary demyelination followed by diffuse axonal damage and neurodegeneration in the

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 1

Contents entire CNS. Tomislav Babic at Worldwide Clinical Trials discusses how disease onset and clinical course are highly variable and mostly unpredictable. 30 Enabling Competitive Entry: The Role of Drug Delivery Device Design in the Biosimilars Market It is no mystery to the pharmaceutical and biotech industry that between 2018 and 2023, several original reference biologics will be coming off patent. This clearly opens a significant window of opportunity for biosimilar manufacturers seeking to compete with the original biologics. George I’ons at Owen Mumford specifically focuses this article on analysing the different factors that will influence the uptake of new biosimilars and their advancing market share against original biologics. (PULMONARY) DRUG DISCOVERY, DEVELOPMENT & DELIVERY 32 Rethinking Inhaler Systems from a Patient Perspective – The Increasing Challenge of Technology Diversity The inhalation of dry powders is one of the oldest forms of delivering active substances via the pulmonary route. Despite the progress in DPI drug delivery technology, drug administration with inhaler systems by patients remains a critical factor. Sven Stegemann at ACG and Graz University of Technology stipulates that unrecognised administration issues are considered to contribute to poor effectiveness and medication errors. 36 Five Questions You Should Ask when Developing an Inhalation Device: How to Develop the ‘Right’ Device Developing a medical device is no easy task and knowing where to start is the first hurdle. Spending time early on working out which is the right path will not only help avoid costly changes later in the programme when the design is set, it can also determine the success of the project. Charlotte Harris at Team Consulting, Cambridge, UK recommends taking time to explore and prioritise the opportunities and requirements as a group, with input from all relevant stakeholders, before deciding on project direction. 40 Manufacturing Dpis: An Engineering Perspective (A Case Study) IMA Active and Medochemie have joined forces in order to achieve optimal low-dose dry powder inhalers by combining the dosator technology and the direct net weight control both in a table-top device and in an industrial productionscale capsule filler. A study conducted by IMA that investigates optimal process parameters for micro-dose DPIs achieved by the dosator technology. Pietro Pirera at IMA Active describes how maintaining the free-flowing properties of the dispended powder within the capsule better ensures the release of powder from the capsule into the inhaler when the capsule is pierced.

resource-intensive. The common theme of challenges has been formulation device incompatibility, lack of in vitro bioequivalence and the expensive in vivo failures. This article by Linda Liao of Proveris Scientific offers an instrumental guide to developing nasal spray and pressurised metered dose inhaler (pMDI) products for both innovator and generic drug products, using a quality by design approach. CLINICAL & MEDICAL RESEARCH 50 Caregivers in Oncology: How to Address the Needs of these Hidden Heroes There’s an important person out there influencing your next oncology trial patient. We don’t often talk about this person within clinical research, much less plan for them. Yet, they will have an unprecedented impact on your patient’s understanding of the trial, their ability to make site visits, and their adherence to medications and protocol. Mindy Gruba at Signant Health reveals how this person is the patient’s caregiver, highlighting the importance of giving the caregiver the recognition they deserve. 52 Study Oversight Models & Implementation in Clinical Trials Study oversight is a broad topic. We have reviewed how site performance and clinical data controls can be implemented across various monitoring techniques as well as technologies which implement statistical algorithms to detect any data anomalies. Thomas Underwood at Quanticate shows how this goes beyond reviewing clinical data, as they also review various data sources and identify issues at site that may not have otherwise been known. 56 Why Connected Data is Crucial to Pharmaceutical Research Big data combined with advances in data science approaches have provided a valuable opportunity for the pharma industry to uncover previously unobtainable insight that has the potential to improve – and save – lives. Alicia Frame at Neo4j explores how classic analysis tools fall short of revealing the insights within life sciences data – so researchers need to look for new approaches, such as graph technology. 60 Taking Charge of the Clinical Trial Master File The clinical trial master file (TMF) is a bit of a misnomer, in that it is not really one file. It is the collection of essential documents which allows the conduct of a clinical trial to be reconstructed and evaluated. Ben Enejo & Ben van der Schaaf of Arthur D. Little clarify why maintaining a TMF is a complex endeavour, as clinical trials can take years, involving hundreds or thousands of patients over many sites in multiple countries. TECHNOLOGY

44 Proveris by Design: A Roadmap for In Vitro Characterisation of Combination Products

62 Cardiac Imaging in Clinical Development: The Benefits of Advanced Imaging Management Systems

Combination products are complex by definition, and the product development cycles can be both time- and

Individuals involved in drug development are faced with many different challenges along the process of seeking

2 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Contents regulatory approval. Imaging plays an important role in the assessment of the effectiveness and safety of new drugs or medical devices and, in this article, Dr. Joseph Pierro and David Raunig at ERT focus on the role of cardiac imaging in clinical trials, while acknowledging imaging’s role may also span non-clinical drug development. 66 The Electronic Laboratory Notebooks: Addressing Data Security and Privacy Concerns By reducing enterprise systems into three key services of data management, information security and data access, we can solve many of the current challenges faced in the life science industry. Jeff Carter at Arxspan discusses how collaborative innovation continues to take hold as the dominant research and development model, while the challenges of legacy systems will continue to create challenges to this new model. MANUFACTURING 72 Help Your Tablet Tooling to Pack a Punch with Essential Maintenance Measures Tablet compression tools are often viewed as consumable items; therefore, maintenance can be seen as unnecessary and time-consuming. This can be a costly mistake and can directly affect production. Keeping tooling in good working condition not only reduces tablet press downtime but also minimises compression problems. Alex Bunting at I Holland looks at research which shows that when tooling is combined with a management system to monitor all aspects of the punches and dies, high-quality tablets are produced quickly and efficiently. 76 Generic Solid Oral Immediate Release Products in EU – Regulatory Perspectives Dissolution Specification The development of a dissolution method with suitable specifications is a key part of any oral drug product control strategy. Dissolution testing is an in vitro technique of great importance in the formulation and development of pharmaceutical dosage forms, as it can be used as a substitute for in vivo studies under strictly defined and specified conditions. The main objective of the present study, according to C. Venkateswara Reddy et al. at JSS College of Pharmacy, is to know that the drug release rate is identical batch to batch. PACKAGING 84 User Testing: Critical for Truly Understanding Patient Needs Ophthalmic pathologies include eyesight-threatening conditions (diabetic retinopathy, glaucoma, cataract, age-related macular degeneration and retinal detachment) and, relatively speaking, less serious eye conditions (dry eye, red eye, etc.), all of which are treated by ocular injections, eyedrops or surgery. Eyedrops are primarily used for glaucoma, dry eye disease (DED), conjunctivitis and allergy. Fanny Sellier of Nemera explains why, for chronic diseases, when daily treatments are needed, preservative-free formulations are key to protecting the patient’s ocular surface, as preservatives can cause 4 INTERNATIONAL PHARMACEUTICAL INDUSTRY

allergic reactions and irritations, and can even damage patients’ eyes. LOGISTIC & SUPPLY CHAIN MANAGEMENT 86 Q&A with Brussels Airport, Changi Airport & Pharma.Aero Way back prior to 2016, Brussels Airport, Miami International Airport and Singapore Changi Airport came together with the joint ambition of fostering greater collaboration amongst IATA CEIV pharma airport communities, as well as between the communities and pharma manufacturers to enhance the reliability of pharma air transportation. This interview with IPI explores how Brussels Airport, Miami International Airport and Changi Airport Launched ‘Pharma.Aero’. 88 Automated Quality Systems in Supply Chains Save Lives Ensuring high product quality while simultaneously increasing efficiency along the supply chain is only possible if suppliers and logistics service providers consistently supply customers with high-quality materials. Precise control of the material is indispensable. David Cahn at Elemica states how this is especially true when it comes to handling pharmaceuticals and biotechnological goods that are intended to save lives. 92 New Tools and Models Designed to Optimise Costs and Protect the Environment Over the past five years, high-performance passive isothermal packaging based on materials such as VIP (vacuum insulation panel) or PCM (phase change material) has been introduced onto the market. They make it possible to maintain pharmaceutical products at negative temperatures, between +2°C and +8°C or between +15°C and +25°C for 5 days or more, depending on the outside temperature. Florence Lehec at EMBALL’ISO Group reveals that these "PREMIUM +" products offer very high levels of performance that make it possible to limit or even eradicate temperature excursions. 94 How Advancements in Logistics Technology will Play a Role in Combating COVID-19 Coronavirus continues to dominate headlines as it spreads around the world. At the time of writing, there have been over 92,000 reported cases worldwide resulting in the deaths of more than 3100 people. Richard Ettl at SkyCell states that the hardest hit countries are China, Iran, South Korea and Italy, demonstrating the global scale of the pandemic. 98 Real-time, IoT-driven Supply Chains are Driving the Industry Forward While complete eradication of temperature excursions within the pharmaceutical supply chain is unlikely, real-time, IoT-driven visibility is providing measurable benefits for waste reduction, sustainability savings, and operational improvements leading to substantial cost savings. Ada Palmadottir at Controlant looks at how trends begin to surface through data, with strategic decisions being based on facts, risks being identified and mitigated, and how this technology will strengthen the industry. Spring 2020 Volume 12 Issue 1

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Editor's Letter At the start of 2020, I am sure not many people would have predicted that our world would be on lock-down due to Covid-19. I am an eternal optimist and I am very sure something good will come out of this. Already, positive things are starting to show – the climate is fighting back with air quality better over Europe due to the decreased activity in the aviation industry. I do wonder if now could be a very good time to look at a plan B. The current crisis is unearthing serious supply chain issues, which is why there must be more stringent sustainability, especially when it comes to healthcare and enabling patients to get the best treatment available. Bill Treneman at UPC Cambridge explains how driving R&D towards 2020 and waging war on carbon, we have seen AstraZeneca want to become carbon-neutral by 2025 – is this possible?

Rich Quelch at Origin talks about understanding the health dimensions of the climate crisis as, according to a Lancet report, spending on climate change adaption is falling way short of the $100 billion a year commitment made under the Paris agreement. One area that is being highlighted during these times is people’s lungs. Today, around 235 million people are living with asthma: Sven Stegemann at ACG and Graz University of Technology highlights rethinking inhaler systems from a patient perspective – the increasing challenge of technology diversity. Charlotte Harris at Team Consulting, Cambridge, UK says that there are five questions you should ask when developing an inhalation device, to seek to develop the right device and ensure you have a product that is going to last the test of time. Also, at this time of highlighting the amazing support that caregivers give, it is fantastic to hear that more than

half a million volunteers signed up for the NHS to help the vulnerable. Mindy Gruba at Signant Health highlights the hidden heroes behind the patients who have cancer, and the importance of giving recognition they deserve for this role. I think it’s also important to highlight the advancements in logistics technology which will play a role in combating COVID-19. Already in the last week we have seen much higher demand for protective clothing for those in hospitals, and Richard Ettl at SkyCell talks more about this.

We are in an unprecedented time. We hope all our readers and clients are safe and healthy. All the things that were taken to be self-evident a couple of weeks ago are no longer so. That is how fast this epidemic is spreading. Investors fear the spread of the coronavirus will destroy economic growth and that government action may not be enough to stop the decline. In response, central banks in many countries, have slashed interest rates. That should, in theory, make borrowing

cheaper and encourage spending to boost the economy. Global markets did also recover some ground after the US Senate passed a $2 trillion (£1.7tn) coronavirus aid bill to help workers and businesses. But some analysts have warned that they could be volatile until the pandemic is contained.

Many lessons will be learned from this crisis, not the least of how companies and government can work together, progress with potential coronavirus vaccines and how we can be better prepared for future health crises. I am sure we will come out of this crisis and build a stronger and healthier economy.

The pharmaceutical industry is working at lightning speed on antibody hopeful. Gilead has an antiviral drug in late-stage development, and Moderna is set to begin testing the first novel coronavirus vaccine. Pfizer is working on potential antiviral therapies, and BioNTech on a potential mRNA coronavirus vaccine.

I really hope that everyone reading this will find some normality in dealing with the daily situation we find ourselves in, but I do know that we are part of an amazing sector, and we drive to make patients better. Lucy Robertshaw Director, Lucy J.Robertshow Consulting

In the meantime, IPI will continue to publish exceptional articles, and remain a major source of communication within the pharmaceutical industry.

Virginia Toteva Editorial Manager – IPI

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

and Executive Vice President, Vienna School of Clinical Research

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

Catherine Lund, Vice Chairman, OnQ Consulting

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

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

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

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

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

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

Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting

Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group

Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

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

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

Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

Stefan Astrom, Founder and CEO of Astrom Research International HB

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

Steve Heath, Head of EMEA - Medidata Solutions, Inc

Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

T S Jaishankar, Managing Director, QUEST Life Sciences

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

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With the number of COVID-19 cases rising globally, Bioquell (bioquell. com) – a leading manufacturer of highperformance bio-decontamination systems – is offering a proven solution to help eradicate coronavirus in a range of healthcare, life sciences and pharmaceutical environments, such as isolation rooms and public spaces. Utilising the company’s scientifically proven 35% Hydrogen Peroxide Vapour technology, Bioquell’s Rapid Biodecontamination Service (RBDS) is helping to provide microbiologically clean surfaces and spaces for patients and staff.

type 1; transmissible gastroenteritis coronavirus of pigs (TGEV: a severe acute respiratory syndrome coronavirus (SARS-CoV surrogate)); avian influenza virus (AIV); and swine influenza virus (SwIV). The findings showed that after exposure to Bioquell’s Hydrogen Peroxide Vapour, no viable viruses were identified. The technology also has been evaluated by the UK Government’s Biosafety Group at the Centre for Emergency Preparedness and Response, Porton Down, using the non-enveloped virus surrogate MS2 phage, with full inactivation achieved. Respiratory viruses can contaminate and survive for long periods on environmental surfaces. Effective disinfection is essential for stopping transmission from the environment. However, this is not always achieved by conventional cleaning and disinfection techniques. Bioquell’s Hydrogen Peroxide Vapour is a vapour-phase disinfection method that is virucidal on structurally distinct viruses dried on surfaces.

Surface contamination has been implicated in the transmission of certain viruses, including coronavirus, and surface de-contamination is an effective measure to interrupt the spread of these agents. A study on the virucidal efficacy of Bioquell’s Hydrogen Peroxide Vapour was published in the April 2014 issue of The Journal of Hospital Infection. The study evaluated the in-vitro efficacy of Bioquell Hydrogen Peroxide Vapour for the inactivation of a number of structurally distinct viruses that could impact the healthcare, veterinary and public sectors, including feline calicivirus (FCV); human adenovirus 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

It achieves a level of efficacy unmatched by standard cleaning practices and other disinfection technologies. It is uniform across the entire target area and not limited to line-of-sight or easy-to-reach spaces. Bioquell’s RBDS can be quickly called upon to eradicate coronavirus from a single area, several locations within a facility or an entire building. Using Bioquell’s 35% Hydrogen Peroxide Vapour solution (Bioquell HPV-AQ) can eliminate pathogens, providing a 6-log sporicidal kill. Through complete coverage of every exposed surface in an enclosed area, the process is residue-free, proven safe on sensitive electronics and shown to kill a wide range of microorganisms

including bacteria, viruses, fungi, spores and more. Bioquell’s RBDS offers the flexibility to retain or recover the microbial integrity of critical areas with every deployment including planning, co-ordination, setup, equipment, and cycle validation and verification. It provides a complete final report confirming a 6-log kill of the spaces and surfaces that have been treated with the use of biological and chemical indicators. For further information on Bioquell’s RBDS visit https://www.bioquell.com/ healthcare/systems-and-services/ rapid-bio-decontamination-servicerbds/?lang=en-uk REFERENCES 1.

S.M. Goyal, Y. Chander, S. Yezli , J.A. Otter. 2014. Evaluating the virucidal efficacy of hydrogen peroxide vapour. J. Hosp. Infec. Vol 86, 255-259. T. Pottage, C. Richardson, S. Parks, J.T. Walker, A.M. Bennett. 2009. Evaluation of hydrogen peroxide gaseous disinfection systems to decontaminate viruses. J. Hosp. Infect. doi:10. 1016/j. jhin.2009.08.020 Van Doremalen et al. 2020. Aerosol and surface stability of HCoV-19 (SARS-CoV2) compared to SARS-CoV-1. US Government work. medRxiv preprint doi: 10.1101/2020.03.09.20033217

Bioquell Hydrogen Peroxide Vapor is an EPA registered sterilant but is currently not listed on the EPA emerging viral pathogens list. Until Bioquell’s hydrogen peroxide sterilant is presented on this list, Bioquell is unable to make a specific claim against SARS-CoV-2 / COVID-19 in the United States. For further information on this position, please contact your Bioquell representative. Spring 2020 Volume 12 Issue 1

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Regulatory & Marketplace

Excessive Prices in the Pharma Sector: The EU Antitrust Perspective An undertaking is defined as dominant if it enjoys such a significant market position as to grant it the power to behave, to an appreciable extent, independently of competitors, customers and ultimately consumers. This dominance lays a special responsibility on the undertaking not to hinder competition in the market.1 Although a dominant market position2 is not unlawful per se, Art. 102 of the Treaty on the Functioning of the European Union (TFEU) – and equivalent national provisions – prohibits abuse of dominance aimed at excluding “as efficient” competitors from the market or at exploiting customers or consumers.

In particular, the article prohibits a dominant undertaking from directly or indirectly imposing unfair prices (or other unfair trading conditions). According to the Court of Justice of the European Union’s (CJEU) landmark judgment in the United Brands case,3 a price applied by a dominant undertaking is excessive (and thus unlawful) if it:1 has no reasonable relation to the economic value of the product or service; and2 is unfair in itself or when compared to competing products. Subsequent CJEU caselaw establishes that unfairness and excessiveness may be proven also through other means, such as by comparing the price applied by the dominant undertaking in different geographic markets or at different times. These assessment criteria may also be used cumulatively, as clarified by Advocate General Wahl in the AKKA/ LAA case.4 From a general standpoint, competition authorities rarely used to apply Art. 102 TFEU (or equivalent national provisions) to excessive pricing practices, mainly because of the complexity of the underlying economic analyses and because of the liberal policy argument to leave market forces to self-regulate prices. But in the last five years, the pharma sector has seen a sharp increase in investigations for excessive pricing. Indeed, since the European Commission’s 2009 enquiry, competition-law enforcement 10 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and market monitoring have been a high priority for both the European Commission and national competition authorities, with the ultimate aim being to protect patients’ access to affordable, innovative and essential medicines – also considering the significant constraints on public healthcare budgets. Needless to say, to carry out a proper assessment of particular conducts in the pharmvvca sector, competition authorities have to take into account all its features. Unlike for other sectors, it is essential to consider that the end customers (i.e., patients) generally:1do not decide what medicine to buy (their physicians do); and2 do not pay for it (the cost is usually charged to the national healthcare system or insurance companies, which thereby act as additional market players). To discuss how the prohibition of excessive prices is to be applied, it is key to consider the very rigid structure of the demand (especially for life-saving medicines), the high R&D investments necessary to launch new pharmaceutical products, and the functioning of the marketing authorisation regime and other protection mechanisms (such as orphan drug designations).5 Ultimately, competition law must not prevent pharma companies from recouping their R&D investment (also for research projects that do not lead to new medicines) and making a fair profit. In this respect, the risk of overdeterrence is significant and ultimately jeopardises patients’ access to care. Two landmark cases of excessive pricing in the pharmaceutical sector are undoubtedly represented by the Italian Aspen case6 (which was later followed by two investigations into similar conducts in Spain and before the European Commission, currently pending) and the Pfizer/Flinn case in the UK. More recently, several competition authorities across the EU are currently investigating Leadiant Biosciences for an alleged abuse of dominance through excessive pricing.5

The Aspen Case in Italy In 2016, the Italian competition authority (AGCM) imposed a EUR 5 million fine on Aspen. According to the AGCM, Aspen had pursued an exploitative strategy that consisted of: (1) acquiring the rights over five life-saving medicines that had been marketed at their original price for more than 40 years; (2) “delisting” those medicines so that Aspen could set prices even outside negotiations with authorities regulating the Italian reimbursement system; and (3) exploiting the lack of alternatives to threaten to withdraw those medicines from the Italian market. The national regulator (AIFA) was thereby forced to agree to excessive and unfair prices, which soared to between 300% and 1500% higher than the prices previously applied. To assess whether Aspen’s conduct constituted abuse for excessive pricing from an antitrust perspective, the AGCM applied two different tests: •

The first was based on an analysis of the margins that the five drugs had, as resulting from Aspen’s balance sheets. Basically, the AGCM found that the revenues of the five drugs already outweighed the costs directly connected to them, even before Aspen proposed the price increases. Given the absence of any increased costs for Aspen, the price increases were held to have contributed only to higher profits.

•

The second was the cost-plus method. In brief, the AGCM determined the costs directly connected to manufacturing and marketing each drug and then increased it to take into account a certain share of indirect costs that could be attributed to those drugs, and a percentage of fair remuneration for the company (namely, a 13% return on sales, ROS).

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Regulatory & Marketplace years before, and all the patents had ceased to protect the company from competition from new and generic drugs. Similarly, Aspen did not have to do any promotional activities because the drugs were already well-known in the market. The AGCM’s decision was upheld by the first-instance administrative court, which dismissed Aspen’s arguments on market definition and price fairness.8 The decision is under appeal before the Council of State (hearing scheduled for February). In summary, the Aspen case seems to suggest that the main focus of competition authorities when assessing whether a price is excessive is the correlation between the costs directly or indirectly relating to the pharma product and the sell-out price applied by a dominant undertaking. A significant difference between these two parameters is undoubtedly a reliable proxy for competition authorities when assessing excessi-veness and unfairness. The UK Pfizer/Flynn Case In a similar vein, in 2016 the UK Competition and Markets Authority

12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

(CMA) fined Pfizer and Flynn for having abused their dominant position by applying unfair prices for an anti-epilepsy drug. The CMA ruled that a price hike of between 2300% and 2600% was excessive, particularly when compared to the prices applied in other EU Member States. The CMA also applied the cost-plus method (with an expected ROS of 6%), which confirmed the assessments.

the UK Pharmaceutical Price Regulation Scheme. By contrast, the CAT ruled that the comparison with the ROS of Pfizer’s and Flynn’s competitors would have represented a reliable proxy for the normal competitive market conditions in the absence of any abuse.

However, the CMA decision was not upheld by the Competition Appeal Tribunal (CAT), which criticised and severely disapproved the type of test applied by the CMA to ascertain whether the prices applied were excessive and unfair. According to the CAT, the cost-plus approach might be insufficient to establish that a price is unfair if different assessment methods are available that lead to the opposite conclusion, and the main benchmark for assessing excessiveness should thus be the price that would prevail under “normal competitive conditions”. The CAT thus held that the significant differences in price regulations across the EU rendered both the following prices insufficient proxies: (1) the price applied in other Member States and (2) the price to be applied according to

In short, the Pfizer/Flynn case – albeit not exhaustive on the assessment of excessive pricing – seems to suggest that a pharma company that sets its prices in line with its competitors’ ROS might be presumed not to apply excessive prices from an antitrust perspective. In this situation, competition would be focused on the cost structure and the efficiency of pharma companies, partly due to how many R&D projects ultimately result in the manufacturing and marketing of a medicine.

An appeal against the CAT judgment is pending before the Court of Appeal (hearing scheduled for April).

The Leadiant Case Even more recently, several competition authorities across the EU (including the AGCM and the Dutch Authority for Consumers and Markets) have been investigating whether Leadiant Biosciences has engaged in abusive

Spring 2020 Volume 12 Issue 1

Regulatory & Marketplace conduct aimed at applying excessive prices for Chenodeoxycholic Acid Leadiant (an orphan drug authorised by the European Commission to treat cerebrotendinous xanthomatosis). According to publicly available information, competition authorities are investigating whether Leadiant abused its dominant market position by applying an excessively high price for such a generic and repurposed drug, especially compared to its reference medicine (which had been used off-label to treat the same ultra-rare disease until Leadiant withdrew it from the market). The AGCM is even alleging – somewhat similarly to the Aspen case – that Leadiant is exploiting its strong bargaining position with AIFA to obtain a higher reimbursement price. Although the Leadiant case is the first time competition authorities have focused on the pricing of orphan drugs, several elements suggest that competition authorities are not applying an innovative approach. Indeed, Leadiant is being investigated in relation to a medicine whose marketing authorisation seems to have been granted based on retrospective studies that were not even carried out by Leadiant. Therefore, a far lesser amount of R&D costs could be claimed to justify high prices. And, as mentioned, the medicine in question seems to be a repurposed drug (and thus a temporal comparison with the price applied for the drug’s previous version is possible).

allegations could also be raised in the future in relation to entirely innovative medicines initially marketed at high prices. In fact, competition authorities might struggle to make comparisons in those instances, in which case the underlying economic analysis would need to be based entirely on the direct/indirect costs of researching, manufacturing and marketing the innovative medicine. In any case, pharma companies need to remain highly vigilant. Significant R&D investment is still needed to launch innovative medicines (ultimately promoting competition) but only sound economic analysis based on the parameters outlined above could prevent the price of pharma products from being excessive and unfair. In any case, competition authorities should not prevent pharma companies from obtaining a fair return on this investment, particularly given the business risk. Antitrust enforcement against excessive pricing in the pharma sector should therefore be cautiously exercised, as overdeterrence might endanger innovation and, ultimately, be detrimental for patients.

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6. 7.

REFERENCES 1.

It remains to be seen whether the criticisms raised by national competition authorities will ultimately determine the imposition of fines for excessive prices or other infringements of antitrust law. In any event, the Leadiant case confirms antitrust authorities’ keen interest in the pharma sector, particularly in terms of protecting patients’ access to affordable care and innovative essential medicines. Conclusion In conclusion, the above three cases show that competition authorities are keen to investigate excessive pricing cases in relation to off-patent medicines. Indeed, the fact that these medicines have been available on the market for quite some time allows competition authorities to establish specific geographical or temporal benchmarks for excessiveness. It is unclear whether excessive pricing

The first step to assess whether a company enjoys a dominant position on a given market is to define the product and geographical boundaries of the “relevant market”, which encompasses all products and services that are substitutable on either the demand or the supply side. In the pharma sector, the relevant market is generally defined with reference to the third classification level of the Anatomical Therapeutic Classification (i.e., ATC3). In specific circumstances, also ATC4 and ATC5 may be used for reference. In the recent Avastin/Lucentis case (C-179/16), the CJEU held that different drugs capable of treating (including off-label) the same disease can belong to the same relevant market. From a geographical standpoint, markets in the pharma sector are national in scope, due to the differences in the regulatory framework and in the reimbursement/purchasing policies of the different countries. According to CJEU caselaw, an undertaking can be deemed to hold a dominant market position based on the specific circumstances of each case and especially if its market share is higher than 40%. If an undertaking has a market share of more than 50%, a rebuttable presumption of dominance applies.

CJEU, Case 27/76, United Brands Company and United Brands Continentaal BV v Commission of the European Communities, Judgment of the Court of 14 February 1978, ECLI:EU:C:1978:22. CJEU, Case C-177/16, Biedrība “Autortiesību un komunicēšanās konsultāciju aģentūra – Latvijas Autoru apvienība” Konkurences padome, Opinion of Advocate General Wahl delivered on 6 April 2017, ECLI:EU:C:2017:286. Competition authorities should also consider that, as is well known, the pharma sector is not entirely harmonised at EU level: for example, although marketing authorisations may be issued under the centralised procedure established by Regulation (EC) No. 726/2004, the pricing and reimbursement mechanisms are still regulated at national level. The mechanisms may therefore differ between Member States and are merely required to meet certain transparency criteria set out in Council Directive 89/105/EEC. See AGCM decision Decision No. 26185 of 29 September 2016, in Case A480 – INCREMENTO PREZZO FARMACI ASPEN. See, for example, the investigation opened by the AGCM in Case A524 – LEADIANT BIOSCENCES/FARMACO PER LA CURA DELLA XANTOMATOSI CEREBROTENDINEA and by the Dutch Authority for Consumers and Markets. For further cases of investigations into excessive pricing in the EU, see the CD Pharma case in Denmark and the investigations conducted in the UK against Actavis UK in relation to the pricing of Liothyronine and Hydrocortisone tablets. TAR Lazio, judgment no. 8945 of 26 July 2017, Aspen Pharma Trading Limited and Others v. AGCM.

Sara Lembo Sara Lembo is a partner of the EU law, competition and regulatory practice at BonelliErede and she is a member of the Healthcare and Life Sciences Focus Team. She gained significant experience in complex litigation having assisted leading multinational pharmaceutical companies before the Antitrust Authority in cartel and abuse of dominance cases, and in the subsequent judicial appeal phases and action for damages. She has also developed great experience in the implementation and management of antitrust compliance programmes. Email: sara.lembo@belex.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 13

Regulatory & Marketplace

Driving R&D Towards 2030 – Waging War on Carbon

The largest threat currently faced by humankind is the ever-rising CO2 levels in the air we breathe. In my lifetime, the CO2 level has increased by 33%, from 300ppm to 415ppm currently. The limit for the indoor CO2 level that is without risk to humans is somewhere between 1000 and 2000ppm. CO2 has been rising in recent years by 2.5ppm per year, but with the combination of population growth and energy consumption growth per person per year, it is predicted by some that a 5ppm CO2 increase per year is quite possible. Doing the maths, if the human race does nothing to change current trends, we have perhaps only 200 years until human health is affected by the CO2 that we breathe in the air. A rather scary thought.

For the last sixty years, since CO2 was measured directly by NOAA and others at different locations around the globe, the correlation between temperature rise and CO2 has been monitored. Pure scientists are fond of saying that ‘correlation of data is not proof of causation’ but they are in the minority. See the graph for yourself from a Nature article.

investment in wind and solar. This has driven the UK CO2 emission level down to 300gm per kWh, so clearly electric anything, including all electric vehicles, still are responsible for CO2 emissions.

Global warming is happening for certain (+1.1C 2019) and the most likely cause as agreed by 10,000s of scientists is human-generated CO2 from burning fossil fuels. In engineering terms, anything requiring an energy source to make it, or move it, light it, or heat it, or cool it, or pump it will be currently adding to those CO2 levels. The UK electricity supply is quoted as achieving 50% consumption from renewables last year, thanks to successive UK government

https://www.nature.com/articles/srep21691. Extract from ‘On the causal structure between CO2 and global temperature@ Adolf Stips et al., 22 February 2016. 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

It does not take a rocket scientist to work out that if we rapidly change to all electric home heating (UK new build home policy) and all electric vehicles (UK government incentive and guidelines) the UK electricity requirements will rapidly outpace our ability to increase renewable capacity to match demand. Therefore the emissions from electricity generation will rise again, as more fossil fuels are burned to make up the shortfall. Nuclear energy is a possibility, but it takes decades to build plant and get them running. To stop the atmospheric CO2 level spiralling forever upward, we need to address as a global nation two main issues below, neither of which is trivial: 1.

Population growth – 7.73 billion humans (UN estimate), projected to rise to 8.3 billion (7.4c% rise) by 2030. The population needs to be stabilised back to the 2.1 children per couple level required for zero growth. Family planning, education, reduced infant mortality all factor in this equation. Sources: UN, population matters etc.

Reduced carbon footprint per head. The average global annual emission per head is five tonnes CO2 – the UK sits at roughly seven tonnes per head (including air travel), the USA at 15 tonnes per head. See UN data 2018 published on Wikipedia.

In the drug delivery device industry, we can do little to address the first point (unless working on more reliable, low carbon, cheap contraception methods) except at our family level, but we can all make great progress in the latter. Spring 2020 Volume 12 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 15

Regulatory & Marketplace One hopes that plastic recycling will be improved, but only if it becomes commercially viable. Medical devices like inhalers have to be made from virgin medical grades of materials, with no regrind. If the regulatory authorities, like the FDA, moved to a more pragmatic position for non-human contact components, then the window would be open to use more recycled materials in devices, and so potentially reduce carbon.

Copyright GSK PLC ‘Product Carbon footprint certification summary report’ 26th March 2014 performed by the Carbon Trust. https://networks.sustainablehealthcare.org.uk/networks/sustainable-respiratory-care/ carbon-footprint-gsk-inhalers

Reducing the Carbon Footprint of the Devices that we Engineer This kind of ‘cradle to grave’ public carbon document produced for GSK will be the norm in a few years’ time, not the exception that it is today. UPC predicts that all products will be labelled, much as foodstuffs are for content today, showing whether they are carbon heavy or carbon light. For drug delivery devices, doctors will preferentially prescribe equivalent low-carbon products, and patients will ask for them. So How do you Make Low-carbon Products? The simple answer is make them as light as possible from materials with the lowest carbon footprint, usually measured in kg CO2 per kg material. Typical values are shown below, but please be advised these are only indicative, not for calculating formal carbon footprints from your product: • • • • •

Polypropylene mouldings inc sprue ~ 5kg CO2e per kg plastic POM/PBT mouldings inc sprue ~ 5kg CO2e per kg plastic ABS mouldings inc sprue ~ 9kg CO2e per kg plastic Virgin aluminium ~16.8kg CO2e per kg metal Virgin stainless steel 316 ~ 2.5kg CO2e per kg steel

It is quite difficult to decide on the best common way of treating CO2 in medical devices to provide a rating. Single-use medical disposables are 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

relatively easy, as all the CO2 involved in production will be disposed of by high-temperature incineration. The life cycle analysis (LCA) is not too daunting for the engineer. For treating a chronic disease where daily medication is prescribed, then I would suggest the fairest method is to look at CO2 per day and thus per year for that treatment. So, for instance, in the future there might be once a week depot drug by nasal, subcu, intramuscular or even lung delivery that although carbon-heavy, has a lower total CO2 footprint than say 28 (seven bidaily doses, requiring two puffs) or low-carbon daily tablets. Another very clear trend is to try and reduce the amount of plastic waste that humans produce every year. There is no evidence that there will be exceptions made for medical devices in the future. Every sector will be made to do its bit to reduce consumption – drug delivery devices clearly need to be made as light as possible. It is a shame but plastic recycling is not currently done at this time to any great extent. I know that PET bottles can be made into fleece material for making clothing – I bought a Patagonia product in the 1990s made of such material. PP, which is commonly used in medical devices, such as inhalers, is recyclable, but only about 1% of consumption is currently recycled. I believe that POM and PBT – common engineering grades – are also not recycled much at this time.

Biomaterials – not made of plastic and easily degradeable – are entering the R&D device arena. To my knowledge, there are no like-forlike swaps for, say, PP, yet. There are exciting opportunities in this area, but only if the materials are both low-carbon LCA and biodegradable or reusable in some way. Metered dose inhalers form the bulk of prescribed asthma and COPD treatments both in the UK and the USA. As most people know, they contain HFA propellants in each can, varying between six and 18 grams – including roughly 15% overage that remains in the canister at the end of use. The most common HFA used is 134a which has a GWP of 1300, which makes for a large multiple to convert HFA weight to CO2 equivalent (CO2e). The BBC in late 2019 reported on the NHS sustainability development unit’s desire to reduce the use of MDIs to lower NHS carbon emissions by a few percentage points. Patients would be switched to lower carbon multi-dose dry powder devices, but which contain more plastic and metals and are more difficult to recycle than MDIs. This NHS top-down forced switch on non-medical grounds is revolutionary in the field of medicine. It shows that people wish to and will act to reduce global medical CO2 now – and this trend will only accelerate over the next decade. Interestingly, low GWP HFA inhaler propellants like 152a and 1234 are emerging at the R&D stage that could provide the lowest carbon per dose product in tomorrow’s market. Congratulations go to Chiesi for taking the inhaler industry lead with 152a propellant in MDIs and taking Spring 2020 Volume 12 Issue 1

Regulatory & Marketplace responsibility for future green inhalers seriously. A typical drug delivery device LCA looks like this: First stage – energy, waste and emissions will be considered for the raw material production, then processing, assembly, testing and packaging. This first stage applies to plastics, metals, films and naturally the active pharmaceutical ingredients and excipients which in themselves can contain a surprisingly large percentage of the overall carbon footprint of an inhaler. Second stage – there is the carbon journey from factory to warehouse to pharmacy to surgery/hospital/ home – this is mostly product weight dependent. Third stage (usage) – for example, in an MDI containing HFA the throughlife emissions come next – typically less than 15% +/- 5% of the propellant fill weight. The fourth and final stage is recycling/reuse or disposal of the product. If materials can be recycled on an economic scale, there can be carbon negative offset in this final stage. New product designs can be designed and made for re-use, and this can drastically cut the carbon ticket price. Say a current single-use product can be used safely ten times, then the carbon footprint falls to 10% of the single-use product. For parenteral products such as syringes or injectors that can be biologically contaminated (blood and pathogens) during patient use, safe disposal involves high-temperature incineration which is carbon heavy, and I cannot see this requirement ever changing. Incineration can be made

more fuel-efficient, but that is out of the control of the inhaler industry and lies with combustion engineers and hospitals. There has been a growing number of active devices with electronics, batteries, connectivity to mobile computers etc., both in final stage R&D development and entering the market as treatment products in the last few years. It is probably fairly obvious that these complex devices are considerably more carbon heavy to produce than a passive simple device, and so contain more embedded carbon as it is known. To make these products work in the low-carbon future, they need to be long-lasting, perhaps up to 1000s of doses for chronic long-term treatments. In the mobile phone market today, the high-value products are simply memory reset in the secondhand store, resold, and so re-used a number of times before disposal. Electronic medical devices need to follow this multi-use trend, to reduce the product LCA and thus the patient annual treatment carbon footprint. So, to sum up the UPC inhaler device predictions for the 2030 market are: •

High weight, single-use devices will no longer be used.

•

High weight, monthly-use devices will be being switched out.

•

Lowest weight devices, with lowest LCA treatments will be preferentially prescribed, assuming clinical equivalence.

•

Carbon per product dose or carbon per treatment year manufacturer declaration

legislation will be in place in all territories. •

Life cycle product responsibility legislation for manufacturers is likely to be in place in some territories (cradle to grave responsibility).

•

Re-use of high-carbon electronic devices will be becoming a requirement, as well as re-use of single-use high weight products.

I am sure many drug companies will explore alternative routes to changing the core carbon activity in their legacy product manufacturing by carbon offset investments in, for example: • • •

Plant biota (forest growth, rewilding, peat bog) Renewable electricity investment (yet more windmills, photovoltaics and nuclear) Scaling up of carbon capture systems (currently proof of principle only)

I look forward to the change that the new carbon economy will have on medical devices and look forward to the expression of those new aims in new products. Engineers are always most productive when new rules change requirements and so drive better products. Exciting and challenging times.

Bill Treneman Bill Treneman started his professional engineering career in the automotive industry, is a published author of Working in the wild – Land Rover’s manual for Africa and has been working in medical engineering for nearly 30 years. Drug delivery is a particular focus for him, as it requires knowledge in chemistry, biology, physics and maths to engineer high-volume, high-reliability products. He is the founder and principal engineer of UPC Cambridge. Email: wrt@upccambridge.co.uk

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 17

Regulatory & Marketplace

The Future Market Dynamics and Opportunities in Immune-oncology IO is transformative Long term survival, tumour-agnostic effects and potential for cure in a fraction of patients is the key catalyst for the explosion of research and recent approvals in IO. What was the catalyst for increased focus on immuno-oncology (IO)?

IO has witnessed a long history of highs and lows. Although conventional cytokines and vaccine immunotherapies were approved for certain cancers, high toxicities, low efficacy and conflicting evidence limited their widespread adoption. Cancer immunotherapy research regained momentum with the finding that blocking inhibitory receptors on T cells can re-invigorate their antitumour function. This led to the discovery of the first checkpoint protein CTLA4, and approval of ipilimumab, a CTLA4-blocking antibody for melanoma, laying the foundation for modern-day IO. Subsequently, discovery of another checkpoint axis, PD-1/PD-L1, along with the finding that anti-PD-1 afforded higher response rates and survival than anti-CTLA4, and further that their combination resulted in even higher benefit, opened the floodgates of IO. Deep durable responses, including complete responses in a fraction of patients and improved long-term survival rates with these therapies compared with standard treatment options, then led to a series of approvals in multiple tumours, including melanoma, NSCLC, squamous cell carcinoma of head and neck (HNSCC), bladder cancer, renal cancer, triple negative breast cancer (TNBC), hepatocellular carcinoma (HCC), Hodgkin’s lymphoma and several others over the last four to five years. FDA approval of anti-PD-1 in microsatellite high (MSI–H) solid tumours also represents the first tissue-agnostic approval of an oncology drug based on a tumour biomarker. Benefits with checkpoint blockers have also been observed in high unmet need segments including patients with poor prognostic characteristics. 18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Their relative safety, lack of impairment of quality of life, combinability with diverse modalities and potential for cure opened the way for use of these agents in treatment-naïve and early-stage settings. This resulted in their use as backbone therapies across the patient continuum. CAR-Ts and T cell engaging approaches further continued the success story and reinforced IO as a fifth pillar of cancer treatment (after surgery, radiation, chemotherapy and other targeted agents). Are there any overarching themes emerging from the current MoAs being targeted?

Exploring IO Mechanisms beyond Anti PD-1/L1 Anti-PD-1/L1 redefined treatment in many indications; however, only a limited set of patients respond to these agents. This has led to a revolution in exploring other novel IO approaches that can raise the bar. Several new classes of agents targeting diverse novel immune mechanisms are being assessed, including co-stimulatory or co-inhibitory agents, cytokines, chemokines, oncolytic viruses, neoantigen vaccines, metabolic signalling inhibitors, bifunctional mAbs, fusion proteins, adoptive cell transfer therapies such as CAR-Ts and several others. Immune mechanisms which are examined range from stimulation of innate immunity, adaptive anti-tumour immunity, enhancement of T cell priming and antigen presentation, epigenetic modulation, mechanisms to overcome TME resistance and improve immune cell infiltration. Clinical experience suggests that single agent efficacy of these therapies will be important not only for their success as monotherapies but also as combinations. Only a few IO agents have been able to pass this benchmark so far. IO Combinations can Provide Benefit in IO Resistant/Refractory Segments Several novel IO agents and non-IO drugs are being combined with checkpoint inhibitors primarily to

improve rates, depth and durability of responses in low immuno-responsive tumours (e.g. microsatellite stable cancers, PD-L1 low expressors and tumours with low mutational burden). Combinations are also being evaluated with the hope that they will enhance infiltration of immune effector cells into tumour types generally considered to be ‘immune excluded’ or ‘immune deserts’ and turn them into ‘hot’ tumours. Moreover, combinations are also being tried with the goal of restoring responsiveness in tumours that have previously experienced checkpoint inhibitors and have since become refractory or resistant. Frenzied exploration of mechanisms that can raise the tail of the curve Mechanisms that can further enhance survival rates seen with anti-PD-1 and anti-CTLA-4 are being intensely investigated in clinic. Unprecedented Rise in IO Combination Trials Worldwide Combinations that can improve the therapeutic index of IOs and extend their applicability to low immuneresponsive tumours or IO experienced patients are being vigorously pursued. However, this has resulted in intense competition to enroll trial participants and increased times and costs for drug development in the IO arena.

Although optimal combinations are yet to be identified, a few have been approved, including the combined IO/IO regimen of PD-1 and CTLA-4 blockade mentioned above. While other novel IO/IO combinations are still exploratory, promising early results have been seen in trials of checkpoint inhibitors combined with TLR agonists, stimulatory cytokines and oncolytic viruses. This still needs to be validated in a broader spectrum of indications. On the other hand, combinations of checkpoint inhibitors with conventional chemotherapies and radiation have shown some benefit and also resulted in some approvals, however, benefit with chemotherapy combinations is inconsistent across tumours and is not evident in some tumours Spring 2020 Volume 12 Issue 1

Regulatory & Marketplace such as gastric cancer. Anti-PD-1/L1 agents with tyrosine kinase inhibitors (TKIs) have demonstrated meaningful efficacy in low immune-responsive tumours. Combination of anti-PD-1 Pembrolizumab with Lenvatinib was recently approved in endometrial cancer (September 2019). The potential of TKI combination strategies should be investigated further. One major challenge is the virtual explosion IO combination trials worldwide which has put severe constraints on resources. A recent analysis showed that there are 1716 open trials of anti PD-1/L1 antibodies attempting to enroll 380,900 patients. PD-1 Experienced Population Represents a Significant Unmet Need PD-1 pathway blockade provides benefit in only a subset of patients. A majority of patients either fail to respond to PD-1 pathway blockade or eventually progress. No effective therapies are available for a large population of patients progressing on anti PD-1/L1 therapy in tumours where anti-PD-1/L1 are the standard of care. Identification of mechanisms of resistance and ways to overcome it, characterisation of patterns of progression and defining “true progressors” has become a key pharma focus. Several IO and non IO strategies are in clinical evaluation to explore therapeutic potential in PD-1 progressors including monotherapy or IO combinations with other checkpoint inhibitors, T cell agonists, stimulatory and inhibitory cytokines, metabolic targets, TLR agonists, vaccines, oncolytic viruses, HDAC inhibitors, tyrosine kinase inhibitors, antibody drug conjugates and cellular therapies, besides conventional modalities. While most of these strategies have provided modest objective response rates below 30%, some approaches appear more promising than others, such as IO combinations with TLR agonist, multi TKI, and ADCs. The success of the ADC approach is reflected in the first FDA approval of Enfortumab Vedotin, a Nectin-4 ADC, in IO progressors for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have received prior treatment with a PD-1/PD-L1 inhibitor and platinumcontaining chemotherapy. Expanding Applicability of CAR-Ts to Solid Tumours A new IO modality called CAR-T – www.ipimediaworld.com

for chimeric antigen receptor T cell therapy – has been gaining a lot of buzz since the approval of two agents in this class in 2017 for blood cancers. While their utility in inducing life-saving remissions in refractory and relapsed lymphomas and leukaemias is a true breakthrough, one must acknowledge that they come with severe side-effects and a heavy price tag. A number of trials are now evaluating CAR-Ts against various targets in both haematological and solid tumours. Successful application of CAR-Ts in solid tumours hinges on improving CAR-T persistence, overcoming barriers in the microenvironment and manufacturing challenges. Intense innovation is being pursued in technical designs of CAR-Ts to engineer and develop improved versions that address the unmet needs in solid tumours notably “armoured” CARs, integration of safety switches and additional genes to reduce toxicities, improve tumour infiltration, CAR-T persistence and functionality, combat suppressive tumour microenvironment, and overcome T cell exhaustion.

address drug resistance/relapse or to confer enhanced features which can improve safety, specificity, pharmacokinetic or immune properties. On one hand, these developments have expanded the treatment choices; on the other hand, they have complicated the portfolio and drug development decisions for the innovator companies. What will the IO market look like in five years? What will be the key developments? How will these developments come about? Rapid Growth of the Global IO Market The global IO market will reach $100 billion by 2022. Investment in IO will rely heavily on innovative research, pinning down appropriate patient populations, and on partnerships by biotech and pharma companies

Development of tumour-agnostic/ modular platforms, off-the-shelf allogeneic CAR-Ts, use of iPSCs and better gene editing methodologies are other areas where many companies are concentrating their efforts to develop next-generation CAR-Ts. Innovative technologies brought to the clinic by companies such as Gracell Biotechnologies have considerably shortened the duration of the manufacturing from weeks to a day, thus significantly reducing vein-to vein time and accessibility. These next-generation engineered cellular therapies are expected to address the current challenges to make them widely available.

The global cancer immunotherapy market is set to reach about $30 billion in 2019 and will steadily rise to about $100 billion by 2022. This is expected to be driven largely by use of these agents in nine key tumour types (melanoma, NSCLC, urothelial, RCC, HNSCC, TNBC, gastric, esophageal and HCC). The four key players will include BMS, Roche, Merck and Astrazeneca. These players are investing heavily in both basic research and clinical trials which will contribute to market growth. Increasing innovation and approval of novel treatments in the Asia Pacific region will also contribute to market growth. A large share of this growth will be the result of key IO approvals in early disease, such as adjuvant and neoadjuvant settings. It is likely that these advances could result in cannibalisation of market share from the advanced disease settings but will pave the way for differentiated strategies that will work in those settings. Another constraint on market growth will be the high cost of these therapies.

Increasing Focus on Differentiated Modalities While discovery of new MoAs/targets still remains the heart of new drug development, an increasing thrust is being observed towards developing differentiated modalities/engineered bio-therapeutics in the form of bispecifics/multispecific fusion proteins or mAbs, immunomodulatory ADCs, engineered CAR-Ts and other immune cells, engineered oncolytic viruses either against multiple targets to

IO Biomarkers: Where do we Stand? The limited efficacy of IOs demonstrated in unselected populations thus far, coupled with several failures, indicates that appropriate predictive biomarkers that enrich for responders, will be crucial in order to enhance benefit rates and for developing tailored therapies. This recognition has led to the exploration of a range of immune markers predictive of IO monotherapy and combination response in pivotal and early-phase studies. Consequently, there has been INTERNATIONAL PHARMACEUTICAL INDUSTRY 19

Regulatory & Marketplace a rapid rise in the market for various IO assay reagents and technologies. According to some recent reports, the global IO assays market was ~ 2.9 billion USD in 2018 and is expected to exceed 6 billion USD by 2025, growing at a CAGR of around 12.9% between 2019 and 2025. There is also substantial interest in developing predictive biomarkers from liquid biopsies and other non-invasive methods, although identification of appropriate biomarkers is severely limited by (a) complexity of tumour, microenvironment and immune system interactions, (b) variability in assay development and interpretation, and (c) lack of validation in large prospective trials. The high cost of new technology and diagnostics required for many of these unique biomarkers will also be a challenge. What other key areas are clinical immuno-oncologists currently exploring?

Despite several successes, IOs still remain a difficult area to tackle. Clinical immuno-oncologists are challenged with several key questions on multiple fronts. Besides identifying promising next-gen drug candidates, predictive biomarkers of response, combinations that can improve the efficacy and/or immune sensitivity of the low responsive tumours, other areas of focus in IO are:

Trial Design, Endpoints and Regulatory Considerations FDA’s commitment to bring new lifesaving treatments into the market has contrasted with the recent failure of many such drugs that were conditionally approved on the basis of endpoints other than survival, which has raised several questions regarding appropriate trial designs. One issue being hotly debated is whether such failed IO drugs should be withdrawn or continued to be given to patients, considering their benefit in some patients. The guidelines for next-gen innovative therapies such as bispecific/multispecific molecules, fusion proteins and cellular therapy products are also rudimentary and will need to be clearly defined. Potential in Early-stage Disease, Treatment Sequencing, Duration and Impact on Later Line Therapy Immunotherapies are shifting to early-stage disease settings in many indications. Positioning in early disease, treatment-naïve settings and as maintenance will delay disease progression but will also modulate patient immune profiles, which will impact initiation and choice of next-line therapy. Tumour immune characteristics influence not only response to IOs but also efficacy of conventional therapies

and targeted agents given post IO which will complicate treatment sequencing decisions. Other challenging questions are optimal duration of IO treatment, continuation beyond progression and when to discontinue the treatment. Many trials are trying to address these issues. Value-based Frameworks for Immuneoncology Given the unique pattern of responses with immunotherapies, current value frameworks are inadequate to measure the magnitude of clinical benefit. It has also become essential to address the cost-effectiveness of these new and expensive therapies.

Jaideep V. Thottassery Jaideep V. Thottassery, Director, Life Sciences Consulting, Oncology at SmartAnalyst. With a PhD in biochemistry from the University of Missouri-Kansas City, Jaideep performed postdoctoral research at the University of Tennessee Health Sciences Center, and at St. Jude Children’s Research Hospital in Memphis. At SmartAnalyst, he provides technical expertise in executing oncology projects, including clinical development strategies, life cycle management, and asset and disease strategies. He has a focus on new cancer immunotherapies and targeted agents.

Nidhi Dhingra Nidhi Dhingra, Associate Director, Oncology at SmartAnalyst. Nidhi has over 12 years’ experience in pharmaceutical research/drug discovery and has worked at Dr Reddy’s Labs, MatrixMylan Laboratories and Panacea Biotec Ltd. At SmartAnalyst, she has led projects involving clinical trial profiling of key immunotherapy compounds in solid and haematological malignancies, as well as leading efforts on a proprietary IO database, the IO Navigator. Nidhi holds a PhD degree in molecular biology.

20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Spring 2020 Volume 12 Issue 1

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Regulatory & Marketplace

Understanding the Health Dimensions of the Climate Crisis Climate change is perhaps the most complex issue facing modern society, affecting every aspect of human life. According to a Lancet report, spending on climate change adaption is falling way short of the $100 billion a year commitment made under the Paris Agreement. And of this spending, less than four per cent is channelled into health, despite climate change threatening to undermine the last half-century’s advances.

While the health risks are increasingly being explored, there’s a much lower degree of understanding when compared to economic activities, infrastructure and ecosystems. This is fuelling under-preparedness when it comes to public health emergencies, with the effects becoming magnified in specific regions such as Africa, where more than half of nations fail to meet core requirements set by International Health Regulation. Current projections may look bleak, but if pharma and other large industries can collectively change their practices today, the climate crisis can be minimised and even potentially reversed. The Health Dimensions of Climate Change There are many health implications of climate change, and some are more understood than others. It’s true, there will be beneficial health impacts from milder winters which could help to reduce the

22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

winter-time peak in deaths. Hotter than average summers could also help to limit disease-transmitting mosquito populations, for example. However, scientists agree that most impacts will be adverse, with some declaring a public health emergency. Small changes in temperature and precipitation are already increasing the transmission of vector and water-borne diseases like malaria, dengue fever and cholera. We can also expect an increase in tick vectors such as Lyme disease, flea vectors which carry diseases such as the plague, and fly vectors which can transmit leishmaniasis. As accelerators of global warming, many air pollutants such as methane, black carbon and sulphate aerosols are contributing to what experts are calling “a silent public health emergency”, resulting in an increasing number of recorded respiratory illnesses and early deaths. Aeroallergens are also on the rise due to climatic change, such as mould spores indoors and pollen spores during spring and summer, which could mean respiratory conditions like asthma become more common. Extreme weather events, such as droughts, typhoons, hurricanes and snowstorms are also putting food supply at risk and increasing the prevalence of malnutrition and starvation, affecting people’s ability to fight off and recover from

a range of illnesses. The effects are already being felt across Asia, South America and Africa in regions which have historically suffered from low incomes, poor sanitation and food shortages. Even for those living in lessaffected areas, the uncertainty of the Earth’s future is likely to have an adverse effect on millions of people’s mental wellbeing. So much so, the term “eco-anxiety” has been coined by doctors to describe a new psychological disorder where people worry (to an extreme) about the climate crisis. In the words of the young climate change activist Greta Thunberg, “I don’t want your hope. I don’t want you to be hopeful. I want you to panic”. Pharma – Part of the Problem and the Solution Pharma, as one of the largest global industries, is both part of the problem and the solution when it comes to minimising the adverse effects of climate change. In fact, the pharmaceutical sector is far from green. A first-of-its-kind study by environmental engineers at The University of Ontario, found the pharmaceutical industry is significantly more emission-intensive (13 per cent more) than the automotive industry despite the sector being 28 per cent smaller. It’s not an overstatement to say that a level of opacity still exists

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Regulatory & Marketplace in big pharma. It isn’t uncommon for large multinational companies to group their environmental data across their product divisions – pharmaceutical, medical equipment and agricultural. This can make it difficult to see the collective impact of the pharmaceutical supply chain on the environment. However, there are many trailblazers in the industry who are leading the way in changing the status quo and creating a more sustainable pharma supply chain. There are multiple ways pharma can help reduce their carbon footprint and work towards an end goal of carbon neutrality. Any new pharma plants should incorporate green spaces and energy-saving technologies into site plans. From the installation of rainwater harvesting systems, solar panels, inverter-driven machinery and reactive lighting designed to maintain a consistent lux output whenever an area is occupied, to robotics which increase production yields and accuracy with reduced input. Pharmaceutical waste continues to be a huge problem, so to eliminate non-biodegradable and single-use plastics from the supply chain, more research is taking place around bio-based PET. It’s made from ethylene derived from sugarcane which has a negative carbon footprint, using CO2 and releasing oxygen when cultivated. Researchers are now testing pioneering technology which converts PET waste back into virgin-grade material to be used again. Cuttingedge manufacturing methods like 3D visualisation and printing are also helping to reduce waste by eliminating the need for multiple prototype designs. Environmental awareness is even starting to extend to the syringe market, perhaps the most complicated field of primary pharmaceutical packaging. Some syringes are now replacing glass with cyclic olefin polymer 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

(COP), which has allowed a number of pharma companies to abandon secondary packaging altogether as the design forms its own outer shell. The ability of packed syringes to clip into place also eradicates the need for packing materials like Styrofoam and cardboard. Working with a hybrid partner, pharma companies can design or redesign their product’s primary and secondary packaging to support compliance and make it easier (and cheaper) to transport, while simultaneously reducing the amount of materials used overall or facilitate a switch to more eco-friendly alternatives. A virtuous circle, if you will. These cost-saving and efficiency gains will help the industry fulfil its social responsibilities, including the need to both pioneer more sustainable manufacturing processes and produce more effective and safer medicines the entire world can afford. Is Pharma Ready for a World in Flux? Commercial benefits aside, there are huge social impacts and environmental benefits of creating a more efficient pharma supply chain and as the importance of these issues grow, these benefits will only increase. Now, more than ever, environmental management is key. A pharmaceutical supply chain that’s fit for purpose today and tomorrow is one that’s not just reactive, but proactive. It will anticipate and accommodate current and future

trends, driving forces and challenges presented by the climate crisis. Whether it be a fast-developing public health emergency caused by an extreme weather event in a specific region, or a slow but steady increase in respiratory diseases from worsening air population levels in urban populations, the pharma industry needs to have the agility to respond quickly and support the effective functioning of healthcare systems. The pharma and biotech industries are no stranger to the chaos caused by extreme weather on their research and manufacturing capabilities. In 2017, Pfizer’s manufacturing facilities in Puerto Rico were wiped out during a devastating hurricane season, resulting in a loss of an estimated $195 million in inventory. Investment in sites’ resilience is key to preparing for extreme weather in advance and patching vulnerabilities which could close plants, such as flood barricades, emergency power generators, and keeping critical digital infrastructure on higher floors. Governments and regulators may start to enact policies to force big pharma companies to geographically diversify the locations of their production facilities, particularly for products that are lifesaving and have no substitutes, as well as carry heavy inventory to protect against supply chain disruption. The issue of antimicrobial resistance (AMR) may too intensify as a result of Spring 2020 Volume 12 Issue 1

Regulatory & Marketplace climate change and the accelerated spread of bacterial diseases. If current trends continue, it’s believed by 2050 antibiotic resistance will cause more deaths per year than cancer, becoming the world’s biggest killer.

Teams on the ground need to be capable of creating any solution, to any problem, anytime, and anywhere. However, at the moment, it’s common for multiple teams to be managing multiple international supplier sites.

The consequences of AMR are far-reaching, reducing our ability to treat common infectious diseases resulting in prolonged illness, more complications and higher fatality rates; the accelerated spread of infections due to ineffective treatments; compromising advances in medicines because of the risk of infection; and placing increasing financial pressure on global healthcare systems.

Consolidating the supply chain under one roof brings a large range of benefits including, but not limited to: reduced risks and overheads, greater innovation, assurance of supply and compliance, tighter quality control and local availability via regional distribution sites on a global scale.

Developments in digital packaging technologies are helping pharmacists and doctors on the frontline monitor usage data and get a clearer picture of compliance trends. “Smart” blister packs are becoming more advanced, utilising built-in microchips to capture use-related data and remind patients when the next dose is due. The data collected from these packs can then be accessed by health professionals to give a clear picture of a patient’s medicine-taking behaviour at home. Over the next five years, the integration of more advanced digital features into the packaging and delivery systems of antibiotics will become the norm.

The promise of artificial intelligence (AI) in the pharma supply chain of the future is already being seen. For example, programmes can now independently monitor market signals and accurately predict risks related to medicine shortages; others are using machine learning to control and reduce pharmaceutical costs, using real-time signals to direct when to buy and recommend formulary strategies. AI can even pick up that a large number of people in a city are complaining of flu-like symptoms on social media and use this analysis to predict an imminent large-scale outbreak, giving local authorities and healthcare systems more time to react.

Keeping global supply chains moving in the aftermath of a large-scale climate event is also vital.

When it comes to transportation, AI is making it possible to predict and manage transportation capacity at a highly granular level, while virtually eliminating manual work and best-guess decisions, helping to keep the supply chain running.

To facilitate the new pharmaceutical landscape, a fresh and agile approach is needed, one which leans towards an all-in-one solution which isn’t restricted to one manufacturing location or field of expertise.

It Isn’t Too Late for Change There will certainly be taxing times ahead for the global pharmaceutical industry as the medicines they deliver become more complex and so too does the world we live in.

Patient safety has always been, and will always continue to be, the number one priority for the pharmaceutical industry. After all, as a sector its mission is to save and prolong life. But pharma’s ability to deliver on this promise is being put under threat by a changing climate. When we think about the future of the pharmaceutical industry – and the future of Planet Earth – we’re actually not talking about the future at all, but the here and now. The effects of the climate crisis are already being seen and felt by everyone. The supply chain is becoming a key battle ground where the war against climate change is being fought. At the heart of transforming the supply chain is the application of lean principles. This essentially means using less human effort, less space and less time to produce high-quality products. It also means working as efficiently and economically as possible while being highly responsive to demand. The most successful pharma companies of tomorrow will be those who invest in and build agile and efficient supply chains – both virtual and physical – today.

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. www.originltd.com

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Drug Discovery, Development & Delivery

Challenges of Drug Development in Progressive Multiple Sclerosis Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterised by focal confluent lesions of primary demyelination followed by diffuse axonal damage and neurodegeneration in the entire CNS. Disease onset and clinical course are highly variable and mostly unpredictable. In the majority of patients (about 80%) the disease starts in the third decade of life with a relapsing and remitting clinical course, characterised by episodes of acute exacerbation followed by complete or partial recovery. These relapses are believed to be the consequences of focal inflammatory demyelinating lesions, the histopathological hallmark of MS. On average, after 10–15 years the disease converts into a course of slow progression (secondary progressive multiple sclerosis – SPMS). It seems that time to progression is independent of the number of relapses experienced after the first two years of disease1.

Only about 15% of patients develop primary progressive multiple sclerosis (PPMS) characterised by continuous worsening without distinct relapses. The onset of PPMS is typically about 10–15 years later than relapsing remitting multiple sclerosis (RRMS) but at a similar age when the conversion to secondary progressive multiple sclerosis (SPMS) occurs2. It is not clear whether PPMS is a distinct disease entity or whether it just represents part of the variable clinical disease spectrum. If we assume MS as a primary inflammatory disease, in which demyelination and tissue injury is driven by immune-mediated mechanisms throughout all different stages and in all different courses, PPMS would be just a clinical variant of a common disease process3. However, if MS is a primary neurodegenerative disease, which is modified and amplified by the inflammatory process, PPMS could reflect the primary disease process of MS, and the other courses (RRMS and SPMS) are those modified by an inflammatory reaction4. Regardless of substantial difference between RRMS and progressive (secondary or primary) multiple sclerosis 26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

(PMS), evidence of subclinical disease activity defined by the presence of new focal contrast enhancing lesions at the brain MRI, typical for RRMS, can be present in patients with SPMS as well as PPMS. For this reason, it has been suggested to classify MS patients who have entered the progressive disease stage into those with or without evidence of disease activity and with or without disease progression5. The progressive phase of MS is characterised by diffuse white (WM) abnormalities, atrophy and cortical demyelination1. Clinical disease severity and the speed of disease progression are very variable between patients, but on average the speed of progression is similar between patients with PPMS and SPMS and is independent of the severity of previous relapses. The predicted average EDSS progression on ambulatory patients based on the linear mixed effects model in PPMS and SPMS are similar, at about 0.25 points per year6–7, although it depends on EDSS entry level8. Diagnosis of progressive MS is a clinical judgment, with no gold standard diagnostic test. It is based on patientreported clinical history and should be confirmed based on objective physical examination findings. Based on the 2017 McDonald diagnostic criteria, PPMS can be diagnosed in patients with a one-year history of disability progression, which can be retrospectively or prospectively determined, independent of clinical relapses, plus two of the following criteria: (1) One or more T2 lesions characteristic of MS in one or more typical brain regions (periventricular, cortical or juxtacortical, infratentorial); (2) two or more T2 lesions in the spinal cord, and; (3) the presence of CSF-specific oligoclonal bands. Providing a clinical definition of disease progression, might be difficult. Progression is characterised by a steady increase in neurological disability occurring independently of relapses. Diagnosis can be difficult to establish at disease onset (PPMS) and may go unrecognised by patients or physicians for some time. Exact date of progression onset is difficult to establish and is usually

estimated retrospectively, once duration of continuous neurological worsening can be calculated9. Symptoms often fluctuate (pseudo relapses), although superimposed typical relapses might occur. Careful and detailed history-taking is key in differentiating events suggestive of disease activity from worsening of previously experienced symptoms. PPMS is defined by a progressive course from onset and SPMS by a progressive course following an initial relapsing–remitting course. Possible Treatment Targets in PMS The absence of suitable animal models for PMS makes it difficult to ascertain the reliable selection of therapeutic approaches in humans. Moreover, in the light of uncompleted understanding of PMS pathophysiology, possible treatment strategy to ameliorate progression could generally include protection of cellular elements against degeneration, and/or promotion of repair (remyelinisation). Because microglial activation, including the frequent presence of microglial nodules in the brain is a prominent feature of PMS10, the use of drugs that enter the CNS and inhibit microglial activity might be one of the therapeutic options. Additionally, neuroprotective strategies to inhibit oxidative damage or induce antioxidative cellular defence mechanisms; mitochondrial protection strategy and/or strategy that targets different ion channels should be considered as potential treatments of PMS. A further potential approach to treatment of PMS is promotion of remyelination, as axons that are remyelinated in experimental models seem to be protected from degeneration, at least in the short term11. A number of approaches to support remyelination show promise in animal models and could be investigated in PMS. Biomarkers in PMS Biomarkers that are predictive of disability accumulation in PMS would be useful to monitor treatment effects. However, no biomarkers specific for Spring 2020 Volume 12 Issue 1

(Pulmonary) Drug Discovery, Development & Delivery PMS are currently available. As axonal degeneration is prominent in this form of disease, brain atrophy and proteins that are released from degenerating axons into the cerebrospinal fluid (CSF) are of potential utility. Brain atrophy accumulates in multiple sclerosis at a rate of 0.5–1% per year, two to three times more rapidly than in healthy subjects, and is generally thought to reflect neurodegeneration underlying relentless accumulation of disability in PMS12. Extensive demyelination of grey matter has been reported in patients with PMS and the cortex is thought to be a primary site of neurodegeneration13. Cortical atrophy is associated with both disability and cognitive function. Grey matter atrophy is more useful than white matter atrophy in the prediction of clinical disability and is, therefore, regarded as a good potential outcome for trials of PMS14. However, it is not totally established what measure of atrophy is most informative: whole-brain atrophy, white matter, or grey matter changes, or atrophy of specific regions (thalamus, corpus callosum, or cerebellum)15. To be a useful biomarker for Phase II studies, the change of brain volume should be detectable over a short period of time (within one year or less). Sample sizes needed to demonstrate 50% reduction with 90% power on whole-brain atrophy progression in subjects with RRMS have been estimated on 70 subjects per arm needed in a one-year trial16, which is quite close to data obtained from PMS subpopulation17. To improve the sensitivity to change of atrophy measures, it has been proposed to focus on specific brain areas like deep grey matter (DGM) which are including thalamus caudate, putamen and globus pallidus, or individual brain structures such as the cervical spinal cord and the cerebellum, rather than on the whole brain, which presents with more marked volume changes over time in the PMS population. The high-resolution, retrospective 3T MRI study over one year in patients with PMS showed a statistically significant change in raw volume in the caudate nucleus and in the raw total DGM, whereas clinical disability (EDSS score) did not significantly change during the one-year observational period18. It has been proposed that the raw DGM atrophy may prove efficient as www.ipimediaworld.com

a short-term outcome for proof-ofconcept therapeutic trials in PMS. A treatment trial for an intervention that would show a 50% reduction in DGM brain atrophy would require a sample size of 123 patients for a single-arm study (one-year run-in followed by one-year on-treatment). For a two-arm placebo-controlled one-year study, 242 patients would be required per arm18. However, if only raw caudate atrophy will be assessed, 183 patients per arm will be requested18. The recently reported study of thalamic atrophy in a mixed population of MS (RRMS, SPMS and Clinically Isolated Syndrome – CIS), showed the average thalamic volume reduction of 0.71% per year in MS subjects, versus 0.29% per year reduction in healthy controls19. For the maximal effect size (hypothetical treatment that could slow the rate of thalamic atrophy in MS to that of normal aging) in CIS and RRMS population with 80% power, 118 patients per arm will be needed19. In a cervical spinal cord study17, the sample size to show a 30% treatment effect using the cervical spinal cord was estimated at 157 subjects per treatment arm utilising PPMS patients, but 1538 subjects per arm if an SPMS-only study population were enrolled. These results suggest that the cervical cord area is more sensitive to change in PPMS than in SPMS. As for the cerebellum, the sample size estimation indicates feasible studies: the numbers of patients required to detect a 30% treatment difference has been estimated to be 81 per arm for cerebellar volume and 162 per arm for cerebellar cortex volume (90% power, type 1 error alpha = 0.05)20. Several new outcomes, including diffusion tensor imaging (DTI), magnetic transfer ratio (MTR) and diffusion weight MRI imaging, have been considered for clinical trials PMS. The diffusion weight imaging has been proposed for the assessment of caudate and brainstem integrity, while MTR has been proposed as a marker of brain myelin content, including in the cerebral cortex. Optical coherence tomography (OCT, a non-invasive, quantitative, and low-cost imaging technique of the retina) showed high correlation with whole brain and grey matter atrophy and physical disability in subjects with PMS. It can serve as an outcome measure of axonal loss in proof-of-concept clinical trials in PMS21.

CSF and serum biomarkers: The two most promising biomarker candidates for nervous system damage-related pathology in PMS are neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). Both of them can be detected in serum and they reflect their concentrations at cerebrospinal liquor (CSF). Higher serum concentrations of both GFAP and NfL were associated with higher EDSS, older age, longer disease duration, progressive disease course and MRI pathology22. GFAP, unlike NfL, is not increased in association with acute focal inflammation-related nervous system damage. Clinical Outcome Measures in PMS Clinical Trials EDSS: Almost all clinical studies of PMS have used Expanded Disability Status Scale (EDSS) assessment, as a primary clinical endpoint. Despite general acceptance of the EDSS, there are many limitations and caveats, which include high intra- and inter-observer variability particularly in the assessment of PMS, non-linearity (bimodal distribution) and lack of the assessment of several functional domains (cognition, upper arm function). Because of the unequal distribution between EDSS steps, a change will be dependent not only on actual disease progression, but also on EDSS entry level. Responsiveness to EDSS is limited (i.e. arm paresis at EDSS 4 will make a change in the score, but not at the EDSS 5.5 or 6). Because the EDSS is an ordinal scale, non-parametric statistics should be used in statistical analysis. This implies that significant differences between groups can be calculated, but the magnitude of differences cannot. In line with this, results should not be presented with means and standard deviation, but with median values and interquartile ranges23. Although it is a well-recognised scale for neurologists, the EDSS is severely restricted as an outcome measure for trials in PMS24. Indeed, in PMS patients, EDSS is insensitive to all but the most relevant changes in ambulation, which usually are difficult to observe in the majority of PMS patients included in clinical trials due to a plateau effect at the EDSS 6. This problem was recognised early in PMS trials, and many studies were designed to use not only INTERNATIONAL PHARMACEUTICAL INDUSTRY 27

Drug Discovery, Development & Delivery the EDSS (and ambulation scores) but also other functional outcomes, such as hand dexterity15. Using this approach, a study with oral methotrexate showed improvement in PMS subjects with no change at EDSS25. Multiple Sclerosis Functional Composite (MSFC) was developed as a complementary outcome to EDSS, adding its ability to quantitatively probe not only ambulation but also cognition and hand dexterity. The MSFC has been shown to be a more sensitive measure of treatment efficacy than the EDSS in PMS26, however, it is not widely accepted by regulatory agencies as a primary clinical outcome measure. The crucial issue with this method is the use of Z scores and the unknown clinical value of a change in the Z score with respect to a patient’s actual function in the three domains tested. Moreover, comparison between Z scores across studies is difficult. MSFC includes the floor and ceiling effect in the cognitive domain test – PASAT-3, which is why the Symbol Digit Modalities Test (SDMT) has been suggested as a replacement. Several authors are recommending the low-contrast letter acuity test as an additional, fourth domain, to add to the MSFC. Regardless of its disadvantages, the MSFC may be used as the primary endpoint in future clinical trials if its components are applied in a sensible way23. Patient-reported outcome measure (PROM) is defined as ‘any report of a patient’s health condition that comes directly from the patient, without

interpretation of the patient’s response by a clinician or anyone else’27. There is an increasing importance of PROM in PMS trials. There are several measures of health-related quality-of-life used in MS studies. PROMs that assess activities of daily living (ADL) are of particular value in PMS. They are able to demonstrate clinical relevance of MS-specific outcome measures. Unfortunately, there is no MS-specific ADL scale. The most frequently used global PROM in multiple sclerosis is the Multiple Sclerosis Impact Scale (MSIS) which has been correlated with clinical and imaging metrics specifically in progressive forms of the disease28. Limitations of PROMs include their unblinded nature and potential expectance bias. Also, questionnaires assessing quality of life are prone to being influenced by more than just disability23.

REFERENCES 1.

4. 5. 6.

10. 11.

Table 1. Outline of the study designs in progressive multiple sclerosis 28 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Kremenchutzky M et al. The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease. Brain 2006: 129:584–594. Antel J et al. Primary progressive multiple sclerosis: part of the MS disease spectrum or separate disease entity? Acta Neuropathol 2012:123:627–638 Hohlfeld R et al. The search for the target antigens of multiple sclerosis, part 1: autoreactive CD4+ T lymphocytes as pathogenic effectors and therapeutic targets. Lancet Neurol. 2016:15:198–209. Trapp BD, Nave KA. Multiple sclerosis: an immune or neurodegenerative disorder? Ann Rev Neurosci. 2008:31:247–2696. Lublin FD et al. Defining the clinical course of multiple sclerosis. The 2013 revision. Neurology 2014:83:1–9 Stellmann JP et al. Validating Predictors of Disease Progression in a Large Cohort of Primary-Progressive Multiple Sclerosis Based on a Systematic Literature Review. PLoS ONE 9(3): e92761. doi:10.1371/journal. pone.0092761 Neuhaus A et al. Comparing several simple models to predict the development of disability in individual multiple sclerosis patients from their disability history. J Neurol 2006:253: 58. Kragt JJ et al. Responsiveness and predictive value of EDSS and MSFC in primary progressive MS. Neurology 2008; 70: 1084–91. Rovaris M et al. Secondary progressive multiple sclerosis: current knowledge and future challenges. Lancet Neurol 2006; 5: 343–54. Prineas JW et al. Immunopathology of secondary-progressive multiple sclerosis. Ann. Neurol. 2001:50, 646–657. Irvine KA et al. Remyelination protects axons from demyelination-associated axon degeneration. Brain. 2008 131, 1464–1477. Spring 2020 Volume 12 Issue 1

(Pulmonary) Drug Discovery, Development & Delivery 12.

13. 14. 15. 16.

17.

18.

19.

De Stefano N et al. Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes. Neurology 2010;74:1868–76 Fisher E et al. Grey matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol 2008; 64:255–65. Shiee N et al. Revisiting brain atrophy and its relationship to disability in multiple sclerosis. PLoS One 2012; 7: e37049. Pardini M et al. Clinical trial design for progressive multiple sclerosis. MS Journal 2017:23:1642-48 Anderson VM et al. Detecting treatment effects on brain atrophy in relapsing remitting multiple sclerosis: Sample size estimates. J Neurol 2007; 254: 1588–1594. Cawley N, Tur C, Prados F et al. Spinal cord atrophy as a primary outcome measure in phase II trials of progressive multiple sclerosis. Mult Scler. Epub ahead of print 1 May 2017. DOI: 10.1177/1352458517709954. Kim G et al. Sample size requirements for one-year treatment effects using deep gray matter volume from 3T MRI in progressive forms of multiple sclerosis. International Journal of Neuroscience. 2017 Azavedo CJ et al. Thalamic Atrophy in MS: An MRI Marker of Neurodegeneration Throughout Disease. Ann Neurol

2018:83:223-234 20. Inglese M, Petracca M, Mormina E et al. Cerebellar volume as imaging outcome in progressive multiple sclerosis. PLoS ONE 2017; 12(4): e0176519. 21. Saidha S et al. Optical Coherence Tomography Reflects Brain Atrophy in Multiple Sclerosis: A Four Year Study. Ann. Neurol. 2015, 78, 801–813. 22. Hogel H et al. Serum glial fibrillary acidic protein correlates with multiple sclerosis disease severity. MSJ 2018 23. van Munster CEP et al. Outcome measures for clinical trials in multiple sclerosis. CNS Drugs (2017) 31:217–236 24. Ontaneda D et al. Clinical trials in progressive multiple sclerosis: Lessons learned and further perspectives. Lancet Neurol 2015:14:208-23 h 25. Goodkin DE et al. Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol 1995;37:30– 40. 26. Cohen JA et al. Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology 2002; 59(5):679– 687.: 27. Food and Drug Administration. Guidance for industry: patient-reported outcome measures: use in medical product development to support labeling claims. http://www.fdagov/downloads/drugs/

guidancecomplianceregulatory information/guidances/ucm 193282pdf. December 2009./ 28. Hayton T et al. Clinical and imaging correlates of the multiple sclerosis impact scale in secondary progressive multiple sclerosis. J Neurol 2012; 259: 237–45.

Tomislav Babic Dr. Babic is a board-certified neurologist and clinical pharmacologist, with particular interest in drug development for Alzheimer’s disease, Parkinson’s, and MS. He is the author of more than 60 peer-reviewed articles and books and has been integral to the development of many approved drugs for PD. His expertise has been widely noted in neurodegenerative disorders in both industry and academia for the past 25 years. Email: tomislav.babic@worldwide.com

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Drug Discovery, Development & Delivery

Enabling Competitive Entry: The Role of Drug Delivery Device Design in the Biosimilars Market It is no mystery to the pharmaceutical and biotech industry that between 2018 and 2023, a number of original reference biologics will be coming off patent. This clearly opens up a significant window of opportunity for biosimilar manufacturers seeking to compete with the original biologics. Success, however, and market share gain will depend on a number of factors, including ease of adoption. We have specifically focused this article on analysing the different factors that will influence the uptake of new biosimilars and their advancing market share against original biologics, and dwell on the importance of optimal device design for combination products in this process.

Available Market Opportunity The third and fourth waves of innovator biologic patents are set to expire in the next decade and the biotech industry is pursuing 106 biosimilars through clinical development for US and EU markets1. Currently, the EU has a greater number of approved biosimilars – 54 products2– than the United States (26 products3), yet expectations are that the number of biosimilars available today will represent just a paling fraction of what will be introduced in coming years4.

notes, “…biologics may increase drug costs. However, biologics offer demonstrated improvements in patient care that can reduce expensive interventions, thus lowering net healthcare costs.” In fact, greater availability of drugs and choice provided by the entry of new biosimilars contributes to improving market competition and has been seen to generate price discounts that cluster around the 30% mark in Europe, in spite of some outliers6. These estimates are confirmed in the US, where one particular biologic that came out of patent in 2015 reveals that 25% has already been discounted off the branded reference drug pricing, and that the market expects this discount to increase a little further before settling into sustainable competition7. In the longer term, discounting of course needs to stabilise at a level that enables a sustainable market – where competitive market cost savings are balanced by reasonable commercial incentive for pharmaceutical manufacturers to continue investing in new drug discovery, development and regulatory approval.

In just the period between 2018 and 2023, seventeen biologics will have come off patent in Europe, and fifteen in the US. Our cautious estimate on the market opportunity represented in Europe for biosimilar manufacturers is $3.12 billion per year based on current revenues. The equivalent market opportunity in the USA comes to $5.24 billion per year. This is in spite of conservative modelling factoring competitive discounts and is based on 50% market share.

Switching Pains The process of switching patients from original biologics to biosimilars is a tricky one, surrounded by a number of both clinical and regulatory issues8. An important element is, of course, the lack of real-world evidence on which to base the decision by regulators to designate biosimilars as interchangeable. Independent studies9 are beginning to add more significantly to the body of real-life clinical evidence that switching patients to biosimilars is effective and well-tolerated.

Competitive Pricing The development of new biosimilars is expected to bring a reduction in the cost of biologics, appealing to belt-tightening healthcare systems and to patients often suffering from rare or orphan diseases. Biosimilars thus provide the opportunity to treat more patients earlier on, potentially averting the need for more expensive treatments in the future. As one study5

On the other hand, healthcare regulators, managers and clinicians around the world are keen to harness the cost reductions and wider access to treatment that biosimilar competition would enable. In the UK, NHS England are now urging a more proactive and collaborative approach between commissioners, providers and patients to realise the potential savings from switching to biosimilar medicines10.

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Successful uptake of biosimilars, however, depends on a number of critical factors that need to be considered by pharmaceutical companies and drug delivery device manufacturers alike. These include confidence in the biosimilar by patients and physicians alike, a more competitive pricing, and patient confidence in the drug delivery device where self-administration is indicated. Smoother Switching: The Factors One of the critical enablers post clinical judgement for a smooth switch between original biologic and biosimilar being raised by numerous commentators is the drug delivery device design: a growing volume of evidence shows that the design of what typically is an auto-injector or prefilled syringe for subcutaneous injection plays a critical role in facilitating switching11. In particular, the influence of drug delivery ease is noted in a number of studies and the FDA has made it a requirement that human factor studies are conducted to both support the device design and demonstrate that user-associated risks have been understood and mitigated. Delivery of biologics is a particularly important element as larger molecule biological drugs tend to be more viscous, and also may present challenges with the volume of drug to be delivered as well as potential pain on administration, which may be frequent (weekly, for example). In addition to this, many healthcare systems are pushing towards self-administration within the home for chronic diseases to reduce the heavy burden on their systems and enable patients to access treatment without visiting a hospital. Patient usability therefore becomes of critical importance as it is both an important driver to encourage new users to adhere to their treatment plan, while existing users may also favour usability over habit, especially when suffering from degenerative diseases like Crohn's disease, ulcerative colitis, rheumatoid or osteoarthritis and many others. Combination Products New ‘combination products’ as designated by the FDA confirm the fact that the drug delivery device is an integral part of the Spring 2020 Volume 12 Issue 1

(Pulmonary) Drug Discovery, Development & Delivery therapy, with pharma companies seeking exclusive arrangements with device manufacturers to gain competitive edge in the switching/retention process12. The FDA Office of Combination Products was established in 2002 and since then, combination products have had to adhere to a specific regulatory compliance pathway for approval and marketing authorisation in the US market13. To date, no such equivalent process has been established in Europe and these products are still granted approval for marketing authorisation by the European Medicines Agency (EMA) via the medicines approval route. This may change in the future with EMA currently reviewing the process14. The Devil is in the (Design) Detail Analysis of both user and healthcare professional preferences15 highlights the preferred delivery device or device platform design features and the series of steps that need to be taken to evaluate them. In sum, these reports show that: Firstly, it is critical that the primary container is selected carefully. This initial evaluation should also take into account drug interaction and the impact of the container on drug stability, as well as its compatibility with the required manufacturing processes

involved. Secondly, it is critical that regulatory compliance factors are taken into account right at the initial stages of design selection, particularly given the FDA’s acknowledgement of the role of combination products and their specific set of compliance requirements. This phase will also require that design reviews are run and that human factor studies (as requested by the FDA) are undertaken. Device risk management considerations must be made in an organic and all-encompassing manner, and should include testing of development and qualification methods to provide accurate and realistic risk and confidence parameters. Design Selection: Process is Critical At this point, the selection of design and compliance features will have narrowed down to a restricted number of candidate devices that will need to be evaluated and tested further – on the following features as a minimum: robustness and usability based on target applications and patient population; assembly and manufacturing risk management; supply chain reliability; environmental/disposal risks and postshipping device performance. Procedures for design control should also be put into place with fully documented design history file and a transparent design review process. Methods of operational transfer when required and post-market

surveillance procedures also need to be considered. Finally, the review of design selection shows that manufacturability and control strategy risk evaluation are increasingly important in helping businesses select the right device, along with packaging and shipping considerations. Access to device vendor site documentation, design control, risk management, design verification and validation are also critical in the device assessment and selection process. Device handling patient/user safety considerations also play a key role, and ISO10993 accreditation for biocompatibility of materials for cytotoxicity, irritation and skin sensitisation needs to be taken into account. Conclusion It is clear that the delivery device design is going to play an increasingly important role in the future of competition within the biosimilars market. With our estimates showing that the likely available market for biosimilar manufacturers seeking to compete with original reference biologics coming off patent between 2018 and 2023 is estimated to be $3.12 billion per year in Europe and $5.24 billion per year in the USA, close attention needs to be paid to device design to grasp upcoming opportunities. Successful uptake of biosimilars in fact depends on several factors, spanning from clinical confidence to competitive pricing and usability of the drug delivery device.

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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Drug Discovery, (Pulmonary) Drug Development Discovery, Development & Delivery & Delivery

Rethinking Inhaler Systems from a Patient Perspective – the Increasing Challenge of Technology Diversity The inhalation of dry powders is one of the oldest forms of delivering active substances via the pulmonary route which had been described as early as ~1554 BC. However, the interest remained limited and seemed to become obsolete in the early 1950, when metered dose inhalers (MDIs) using chlorofluorocarbon (CFC) propellants revolutionised pulmonary drug delivery. Even with the introduction of the first capsule-based dry powder inhaler (DPI) product (Spinhaler) in 1970, it remained the only DPI product for many years until the Montreal protocol in 1987 and finally the Kyoto Protocol in 1997 led to a ban on CFC, triggering substantially the interest in DPI as an effective and environmentally-friendly alternative to MDI1. The following wave of research and development in the field of DPI formulation and devices led to numerous new products which came to the market during the past 20 years. While the patents started to expire in the last decade, a variety of generic versions and competition reached the markets just a few years ago. Despite the progress in DPI drug delivery technology, the drug administration with inhaler systems by patients remains a critical factor. Unrecognised administration issues are considered to contribute to poor effectiveness and medication errors. With the increasing number of older and multimorbid patients, as well as emerging regulations to strengthen patient-centric drug product development by focusing on acceptability, usability and real-world evidence, the patient-DPI product interface will become even more dominant.

The Main Patient Population According to the Global Asthma Report2, it is estimated that asthma affects as many as 339 million people worldwide. For chronic obstructive pulmonary disease (COPD), the Global Burden of Disease Study published by the WHO estimates the prevalence of COPD to affect 251 million people globally. Asthma and COPD cause a substantial burden of disease, including both premature death and reduced quality of life, in people of all ages in all parts of the world. Asthma symptoms most commonly develop for 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the first time in early childhood, might persist into adulthood, and predispose people to COPD. COPD generally develops later in life as a result of tobacco smoking and chronic exposure to air pollution. "The disease in itself because I panic, I'm afraid it’ll degenerate, it shows, I’m not clear, unable to focus, I’m desperately looking for my inhaler." Female COPD patient. Patients with asthma and COPD experience a number of fearful symptoms like dyspnea, cough, and sputum production, and wheezing, chest tightness, and chest congestion. The symptoms are experienced as life-threatening with anxiety and depression as well as breathlessness and a perceived continuous disease progression, with a decline in freedom and social participation3. In the situation of sudden breathlessness, panic dictates the behaviour with potentially increasing oxygen demand and very unthoughtful actions trying to overcome the situation. The inhaler will be the first anchor for the patient to get immediate relief and reemphasise the need for effective prevention in form of the long-acting inhalation products. Pressurised metered dose inhaler (pMDI) is still the preferred option for the delivery of short-acting drug (e.g. salmeterol) in an acute asthma or COPD attack, as pMDI delivers the drug in aerolised form independent of the patient inhalation capacity. For preventive treatment, long-acting inhaled glucocorticoids, ß-agonists, anticholinergics and other drugs are being used in combination on a regular basis. Such products are delivered in the form of breath-activated DPI systems. For special patient populations like paediatric patients, nebulisers are being used to administer the therapeutics with the help of care givers (e.g. parents) through an inhalation mask over a few minutes. In addition, spacers are being used for children to allow the inhalation of a single dose by multiple breath cycles. The preventive therapy is performed by the patient on a routine basis and relies on the patients to administer the DPI product “as intended”. Beside a clear understanding and recognition of the drug

product, minimum cognitive, physical, physiological and sensory capabilities are required by the patient and/or the care giver and/or the healthcare professional. Use of DPI System in Administration of the Therapy The use of an inhaler device does not differ from the typical use of any other tool or instrument that requires a certain number of operational steps. The first step in the interface with a device is the visual and tangible investigation in order to understand the object and functioning. This assessment is done based on prior experience with similar devices to reduce the level of cognitive demand. The intention is to identify a few dominant visual or sensory cues that fit into any known design model. The use then follows the previous manual proceedings and enables an effortless and intuitive user process. This intuitive user approach bears a high risk of errors or incorrect use that might remain undetected by the patient or lead to short-cuts by skipping steps which might not be seen as necessary for the administration. The issue does not only occur on the patient level, and also affects healthcare professionals or care givers not trained and educated on the devices4. Since awareness is growing on the patient as an important part of the intended drug administration process, regulatory sciences have moved towards more involvement of the patients into the device and drug product development process. Human factor design and usability engineering studies into the development of medical devices5 as well as to consider usability studies in special patient populations provide evidence that the targeted patient population is able to use the product as intended6. The Importance of Usability of DPI Products in the Targeted Populations According to the EMA, usability is defined as “The level to which a medicinal product can be handled in accordance with the product information in the different settings where it may be used, taking into account the variety of patient characteristics, the risk for medication Spring 2020 Volume 12 Issue 1

(Pulmonary) Drug Discovery, Development & Delivery and the rate of successful treatments dropped from 34% to just 20%14.

errors and the burden to the patient and caregiver quality of life.” This definition of usability is based on three major elements, which are the handling of the medicinal product according to operation procedures (therapeutic complexity), the environment in which the medicinal product is being used at patient level and the capabilities of the patient populations to handle and operate the medicinal product. For the treatment of respiratory diseases like asthma, COPD and cystic fibrosis, the medicinal product is a combination for the drug formulation and a device, by which the formulation is being administered. Usability of inhalation therapy is a complex interface including a combination of preparative steps and a coordinated inhalation step under the specific disease conditions. For inhalation therapy, it was found that the rate of correct use of inhalers by patients after at least one month of therapy was very low. The rate of correct usage of DPI was 58.9% whereby pMDI were only used by 31.1% of the patients correctly. Even after educational training on the correct use, the rate increased to 92.6% for DPI and 45.2% for pMDI7. The errors in inhaler use were attributed to the device in 50% of the cases, 31% were related to the inhalation technique and 19% were derived from device and inhalation technique7. A recent review on medication errors due to problems with the use of inhalers found a statistically significant relationship with patient characteristics such as multi- and co-morbidities, obesity, cardiovascular disease, cognitive impairment and neuropathy9. Inhalation errors are associated with worse disease outcomes whereby a www.ipimediaworld.com

reduction in errors over time had improved outcomes for all therapeutic endpoints. Reducing inhalation errors will lead to higher disease control and quality of life for the patients as well as a reduction in the rate of exacerbations, hospitalisations and degree of dyspnea10. The Effect of Learning on Inhaler Use The patients’ approach and use of medicinal products and devices is derived from prior learning, intuition and health beliefs. In case of issues with the usability, patients tend to develop their own coping strategies to overcome the issue by their own means and strategies. They generally do this with the best intent or under the impression that it is fully compliant with the instructions for use11. The patient information leaflet and instructions for use (IFU), provide patients with the proceedings to use and maintain the inhaler system correctly. Along with, eventually, some training and their own use experience, patients learn to administer the medication through the inhaler system. The routine developed with the use of an inhaler system is then transferred to other inhaler systems intuitively, which means that patients unconsciously apply prior knowledge to a new device that is expected to lead to effective interaction12. The intuitive use of patients has been recognised as a potential critical source of errors, when switching from an inhaler product to another, as such generic versions of existing products should not be considered interchangeable unless they are accompanied by intensive patient education programmes to modify the intuitiveness of the patient13. After switching patients from one device to another, the rate of unsuccessful treatments increased from 38% to 51%,

Meeting the Expectations of the Patients Patients with respiratory diseases are in general requested to manage their inhaler medication themselves. As medical laypersons, they do not feel confident enough with this situation15. Education and training play a crucial role in improving patients’ capability to administer the therapy as requested by the healthcare professionals16. The variety of different inhaler systems and their co-prescription unnecessarily increases the complexity for the patients, as well as the potential sources of errors due to confusion. From a patient perspective, a standard inhaler system would be desirable, which is easy to use, discreet, easy to carry, able to verify that the dose was delivered, providing assurance that sufficient doses remain, as well as being reusable to avoid unnecessary waste. One of the oldest and most commonly used inhalers is the capsule-based Breezhaler, which was optimised a few years ago17. In a recent study comparing the six most commonly used inhaler systems, this improved inhaler system was also found to be associated with the lowest error rate by the patients18 as well as favourable patient satisfaction19. Conclusion Drug administration through inhaler systems remains the most effective therapy to treat respiratory diseases. Compared to oral forms, the administration of inhaled therapeutics is even more dependent on the patients’ ability and technique to self-administer the drug product as intended in prevention as well as acute crisis. This requires that patients with a variety of different characteristics can interface with the device and inhaler product more or less intuitively in a correct manner. Intuitive or automatic use is associated with the lowest level of demand from a cognitive as well as handling point of view for the patient preventing errors due to higher complexity. Standardisation and simplicity of inhaler systems should have high priority in DPI product development due to its impact on efficacy and effectiveness. Simplicity of the device will also impact cost of goods and hence accessibility of the medicine in low income countries, as well as contribute to environmental protection by reduced resource utilisation and waste. INTERNATIONAL PHARMACEUTICAL INDUSTRY 33

Drug Discovery, (Pulmonary) Drug Development Discovery, Development & Delivery & Delivery

11.

12. 13.

14.

15.

16.

17.

18.

19.

As a male COPD patient summarised his expectation very clearly: "A ’good’ inhalation system for me is a system that is efficient, fast acting and easy to use, because when a crisis occurs a state of ‘panic’ can set in, and so there should be no additional stress with a system that is complicated, and finally it should be correctly dosed and well adapted to the degree of asthma and my pathology.”

5. 6. 7.

REFERENCES 1.

2. 3.

Stein & Thiel, 2017. The History of Therapeutic Aerosols: A Chronological Review. J Aerosol Med Pulm Drug Del 30;1:20-41 The Global Asthma Report 2018. Auckland, New Zealand: Global Asthma Network, 2018; http://globalasthmareport.org/ Sigurgeirsdottir et al., 2019. COPD patients’ experiences, self-reported needs, and needs-driven strategies to cope with self-management. Int J Chron Obstruct

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10.

Pulm Dis 14:1033–1043 Plaza et al., 2018. Errors in the Use of Inhalers by Health Care Professionals: A Systematic Review. J Allergy Clin Immunol Pract 6:987-95 FDA, 2016. Draft Guidance to Industry Applying Human Factors and Usability Engineering to Medical Devices EMA, 2017. Reflection Paper on the pharmaceutical development of medicines for use in older people Aydemir, 2015. Assessment of the factors affecting the failure to use inhaler devices before and after training. Respir Med 109, 451e458 Lindh et al., 2019. Errors in inhaler use related to devices and to inhalation technique among patients with chronic obstructive pulmonary disease in primary health care. Nurs Open 6:1519–1527 Usmani et al., 2018. Critical inhaler errors in asthma and COPD: a systematic review of impact on health outcomes. Respir Res 19:10 Kocks et al., 2018. Systematic review of association between critical errors in

inhalation and health outcomes in asthma and COPD. NPJ Primary Care Respir Med 28:43 Schenk et al., 2020. Patient behaviour in medication management: Findings from a patient usability study that may impact clinical outcomes. Br J Clin Pharmacol DOI: 10.1111/bcp.2019.9999.issue-9999 Blackler & Hurtienne, 2007. MMI Interaktive 13:36-54 Lavorini et al., 2013. Switching from branded to generic inhaled medications: potential impact on asthma and COPD. Exp Opin Drug Del 10;12:1597-1602 Thomas et al., 2009. Inhaled corticosteroids for asthma: impact of practice level device switching on asthma control. BMC Pulmonary Medicine 9:1 Wong et al., 2014. Unmet needs of patients with chronic obstructive pulmonary disease (COPD): a qualitative study on patients and doctors. BMC Family Practice 15:67 Wieshammer & Dreyhaupt, 2018. Dry Powder Inhalers: Which Factors Determine the Frequency of Handling Errors? Respiration 75:18–25 Zhou et al., 2013. Effect of Device Design on the Aerosolization of a Carrier-Based Dry Powder Inhaler—a Case Study on Aerolizer® Foradile®. AAPS J 15; 2: 511-22 Molimard et al., 2017. Chronic obstructive pulmonary disease exacerbation and inhaler device handling: real-life assessment of 2935 patients. Eur Respir J 49:1601794 Oliveira et al., 2018. Evaluation of the preference, satisfaction and correct use of Breezhaler® and Respimat® inhalers in patients with chronic obstructive pulmonary disease – INHALATOR study. Respir Med 144: 61–67

Sven Stegemann Sven Stegemann, Ph.D., ACG and Graz University of Technology. For 28 years Sven Stegemann, Head of Global Scientific Business Development at ACG, has advised and collaborated with major pharmaceutical companies on the design, development and manufacture of pharmaceutical products. During this time, he brought together several multidisciplinary working groups to address emerging scientific challenges and patient needs beyond the molecule. Since 2014 he has been professor for patient-centric drug products, to better address the needs of patients. Email: sven.stegemann@acg-world.com

Spring 2020 Volume 12 Issue 1

Smartphone app connectivity to allow real-time tracking and care management

Mechanical Dose Counter

Introducing the next generation MDI For more information contact H&T Presspart: www.presspart.com eMDI@presspart.com

H&T Presspart are pleased to introduce the first marketready, fully-embedded, intuitive and connected metered dose inhaler (eMDITM), designed to improve patients’ adherence to medication doses, encourages self-care, and helps health professionals maintain real-time monitoring. The eMDITM integrates seamlessly with BreatheSmartTM from Cohero Health, the only respiratory disease management platform that enables tracking of both controller and rescue medications, along with clinically accurate lung function measurement, in real-time.

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Drug Discovery, (Pulmonary) Drug Development Discovery, Development & Delivery & Delivery

Five Questions You Should Ask when Developing an Inhalation Device: How to Develop the ‘Right’ Device Developing a medical device is no easy task and knowing where to start is the first hurdle. At the start it’s not always clear what to do or what direction to take. This is called the “fuzzy front end” for good reason. The opportunities could seem endless, and there could be many different directions that the project could take – and it can be hard to know which is the ‘right’ one to pursue. Spending time early on working out which is the right path will not only help avoid costly changes later in the programme, when the design is set and you have made significant investment, it can also determine the success of the project. During these early phases, it’s important to not only make sense of what you know, but also to discover what you don’t – and we recommend taking time to explore and prioritise the opportunities and requirements as a group, with input from all relevant stakeholders, before making a decision on project direction. Ask the following five questions to better explore the key factors which may have an influence on your programme. The answers will ensure you and your team are making informed decisions as you progress through the early development stages and will set you on the path to a successful device that meets your commercial, user and technical requirements.

1. Is the whole team aligned on the objectives of the programme? It is really important to gain consensus and alignment on project goals right from the word ‘go’. This prevents surprises and disagreements later on in the programme and means everyone involved is on the same page from the start. That’s why kicking off the project with a strategic workshop attended by multiple stakeholders from across the business is so important. The workshop is firstly a forum for all interested parties to share their own individual views on the project. Some of the essential attendees will likely be located around the globe, but you can’t beat meeting face to face if possible. The ultimate aim of the workshop is to get all those busy people in a room together working as a team to agree objectives 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and develop and agree a shared vision for the project. This vision then becomes an anchor for the programme – a stake in the ground for what you are striving to achieve and something tangible you can keep referring to throughout the projects as scope creep inevitably happens.

During this workshop, participants share what they know already and identify what they don’t, both individually and as a group, and agree a plan for filling any gaps in knowledge. We have found that it isn’t always easy to get a group of stakeholders with potentially very different views to a) share what they really mean and b) agree on what they want to achieve. Therefore, we often recommend using tools to aid communication and discussion during this workshop. There are numerous tools available, but some examples we’ve used are; Lego Serious Play – where participants are encouraged to communicate by creating metaphors in Lego; or Hopes and Fears – where participants are individually asked to write down their hopes (e.g. what do they hope to achieve with the new inhalation device?) and their fears (e.g. what are the barriers they see ahead?). In both these tools, individuals are encouraged to have their say and the facilitated discussion around these will help to generate an understanding of the group’s shared views.

2. Do you want to develop your own inhalation device or license one that’s already available / in development? You may not be able to answer this question right from the start – the answer is likely to be heavily influenced by timelines, resources, in-house experience and other factors which may not be clear until you’ve explored the other four questions. Licensing an Existing Inhalation Device: If you already know your best option is to license a technology, you need to start the process of exploring what is available, either on the market or in development.

As a first step, device technology requirements should be defined and prioritised, and scoring and selection criteria agreed that will be used to select frontrunner device candidates. When defining requirements for an inhalation device, it’s just as important to define commercial requirements such as ‘time to clinic/market’ or ‘device to be marketed in regions x, y and z’ and user requirements such as ‘suitable for use by patients with ‘x’ condition’ or ‘suitable for use by paediatrics’ as it is to define the key technical performance characteristics such as ‘fine particle fraction of <x%’ or ‘must be digitally enabled’. The final list may be lengthy, and these should be prioritised, but by considering the Spring 2020 Volume 12 Issue 1

(Pulmonary) Drug Discovery, Development & Delivery needs of multiple stakeholders, you can be sure you haven’t missed out any key requirements which could influence the success of the project. A thorough exploration of the technology landscape is the next step. Searches should include already marketed inhalation devices that may be able to be licensed for a different respiratory condition, as well as devices that are still in development. There are many different types of inhalation device such as metered dose inhalers, dry powder inhalers (capsule-based, multi-dose etc.), soft mist inhalers and a variety of different types of nebuliser. So, if from your earlier requirements definition activities (and most likely driven by the potential drug formulation(s)), it is possible to focus the search on a subset of these, then this will reduce the effort needed for this stage.

for your specific application and help assess the impact of any modifications that may be needed. Developing a New Inhalation Device: You might have decided to develop a new inhalation device. Maybe you’ve done something similar before or have some proprietary technology that you want to use. However, before you start innovating, you need to identify and prioritise your ‘design challenges’ by exploring technical, commercial and user needs. These needs can be identified using some of the techniques outlined in this article, and by phrasing them in such a way that they become a question (e.g. ‘How might we ensure that the user can co-ordinate inhalation with activation of the device?’) they become a ‘design challenge’ that drives your innovation activities and helps to focus development effort.

prototypes can be tested by using foam board form, rapid 3D prototypes, a quick piece of breadboard circuitry, mock app screens or the lashing together of development boards. Doing it this way means you fail fast and early (if you’re going to) and the technical merit of ideas can be assessed without investing lots of time and money developing them. 3. Do you know your target users and understand their needs, behaviours and preferences? Applying a user-centred design approach will ensure you are developing a device which meets the needs and desires of the people who will ultimately be using it. Engaging patients, caregivers and HCPs in a programme of design research will provide rich insights. It will help you to understand existing behaviours and the challenges that end users face in managing their health. Some common research techniques include focus groups and in-depth interviews, as well as more ethnographic approaches such as contextual enquiry where we use cultural probes and visit participants in their home or clinic environments. Online approaches can be a good way to access more participants and include Skype interviews or online threaded communities where multiple patient groups can be asked to assess ideas via an app-based platform.

We recommend starting with finding device information that is available in the public domain. Often it can be harder to find detailed information about devices still in development, but contacting the suppliers or attending respiratory conferences where new devices are being showcased can often be good ways to find out more information.

Once you start generating ideas, a rapid iterative development cycle can be a good way to create multiple ideas and assess both their technical feasibility and likely user acceptance. Using a ‘design sprint’ process helps to keep things moving quickly and involves going from ‘nothing’ to a user-tested prototype in just a few weeks.

Once you have your inhalation device longlist, each device technology should be scored and assessed against the requirements and selection criteria defined by your stakeholder group. This allows a systematic comparison and assessment of the technologies and will help you to filter down to a shortlist. A more structured process of further technical and commercial assessment will follow, but this initial activity will identify the most suitable technologies

Following this process means ideas can be mocked up very quickly and functional elements of concept

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Once you have your initial ideas or a shortlist of possible device technologies, it is important to consider what you want to test with users and design stimulus material accordingly. There’s immense value in putting physical prototypes in the hands of users, but you need to ensure that each of your concepts are presented with equal fidelity so as not to bias the research. This can sometimes be difficult when testing ‘licensed’ solutions which may be at different levels of technical maturity. It

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Drug Discovery, (Pulmonary) Drug Development Discovery, Development & Delivery & Delivery

is often sensible to focus your study on the key attributes you want to test and if prototypes aren’t feasible, you can gain great value in showing sketches, PowerPoint animations, videos or mock screens to demonstrate the functions of a device and gather feedback. 4. Do you understand the business/ commercial/regulatory drivers and requirements? The commercial drivers and strategy for a device development will be unique to each company. For some it may be all about timelines and being the first to market. For others it may be about differentiation in a crowded market, or delivery of a new chemical entity, so it’s important to consider the business drivers and strategy as part of your development process. Identifying your likely competition, understanding what devices they are marketing/developing and how they position themselves in terms of features and unique selling points will help identify what you’ll be up against when you get your own device to market (even though in some cases that could be 5–10 years away). Other commercial drivers to consider include reimbursement strategy and market access, and a thorough understanding of the device classification and regulatory pathway 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to approval are also critical to success. In the later stages of development, you will need to assemble a device technical file for presentation and scrutiny by the relevant authorities, so getting this right is essential. Whatever the commercial strategy, it’s important that the wider team have at least some top-level knowledge of the key commercial drivers and timelines, and an understanding of how the whole programme fits together in terms of drug development, clinical trials, time to market and key decision points along the way. 5. Do you have the evidence and confidence you need to move forwards? As you progress through the early stages of device development it is important that you gather enough information and evidence to make an informed decision of how to move on to the next stage of the process. At each key decision point asking your team ‘have we explored all the opportunities?’, ‘have we got enough evidence to make an informed decision?’ and ‘do we feel confident in the decision we’re making on how to progress?’ will help to ensure that you stay on track. If the answer is no to any of those, then more work needs to be done before you’re ready to move on.

Conclusion Each device development is different – as is each company developing it. However, to ensure that you set off on the right track, it’s important to consider each of the five key questions above. Answering these will form the basis of the business case for your device and help to ensure that you are on the path to developing the ‘right’ device.

Charlotte Harris Charlotte is Head of Front End Innovation at Team – focused on helping clients set off on the right path in the early stages of product development. Her goal is to ensure that all opportunities are uncovered, considered early on and to prevent the wrong product to be developed too late in a costly development programme. Charlotte has over 20 years’ experience in the medical device industry and is an experienced project manager and facilitator. Alongside a wealth of experience in contextual/design research, she has many innovation tools under her belt to help navigate through the fuzzy front end of product development.

Spring 2020 Volume 12 Issue 1

Micronization for Inhaled Medication

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

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dec-group.net

Drug Discovery, (Pulmonary) Drug Development Discovery, Development & Delivery & Delivery

Manufacturing DPIs: An Engineering Perspective A Case Study IMA Active and Medochemie have joined forces in order to achieve optimal low-dose dry powder inhalers by combining the dosator technology and the direct net weight control both in a table-top device and in an industrial production-scale capsule filler.

When developing new pharmaceutical products in DPI form, industrial manufacturing aspects must be considered from the very beginning to shorten the scale-up and optimisation of the final manufacturing process, as well as to achieve a more efficient and cost-effective production. Precise microdosing, weight control and ease of device assembly are all issues that must be faced at an early stage. IMA draws on its extensive expertise to provide the most advanced solutions for DPI processing and assembly: direct weight control performed in line on each single capsule or device, both before and after filling; absence of mechanical powder compression for improved airway intake; accurate micro-dosing and automatic feedback and adjustment. This study investigates optimal process parameters for micro-dose DPIs achieved by dosator technology. The study proves that a major advantage of using this technology for processing DPIs is that the dosators can be accurately adjusted without any need to compress or aspirate the powder. Maintaining the free-flowing properties of the dispended powder within the capsule better ensures the release of powder from the capsule into the inhaler when the capsule is pierced, thereby better controlling both the emitted dose and the fine particle fraction of the dose discharged from the DPI. Introduction In 1948, the first commercial dry powder inhalation device was launched on the market. This first technology seems archaic by today’s standards: a deep inward breath would cause a ball to strike a cartridge containing powder and shake the powder into the airstream. 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Since then, changes in the drug delivery market and regulatory pressures have driven innovation of DPIs forward. It is estimated by the WHO that, worldwide, some 300 million people suffer from asthma and 240 million people suffer from chronic obstructive pulmonary disease (COPD). DPIs represent 50% of the total asthma/COPD market by value worldwide. The latest patient-focused studies using DPIs indicated that the expectations regarding this technology have evolved. Patients and pneumologists are now increasingly focusing on convenience and ease of use, favouring a compact design. Indeed, DPIs have shown great promise in their ability to deliver drugs reliably and effectively, and novel designs can ensure that future cost, compliance and safety challenges are overcome. Some of the performance characteristics essential to DPIs are related to dose delivery, fine particle fraction content and performance levels at varying airflows. These characteristics can differ from one powder formulation to another, and some fine tuning of either device or formulation or a combination of both may be necessary to achieve optimal performance. Micro-dosing DPIs takes this challenge to extremes. IMA Active and Medochemie have joined forces in order to achieve optimal

micro-dose dry powder inhalers by combining the dosator technology and the direct net weight control both in a table-top device and in an industrial production-scale capsule filler. Case Study: Investigating Optimal Process Parameters for Low-dose Dry Powder Inhalers Aim of the Study The aim of the study was to explore the best process parameters to achieve the 5.5 mg dose of a powder mix including a first lactose type as carrier and a second one (4% in concentration by weight) of micro-fine lactose as API simulator. The process was carried out as a first approach in a table-top capsule filling device (Minima, IMA) and then upscaled to an industrial production-scale capsule filling machine (Adapta with 100% gravimetric net weight control, IMA). Two types of lactose were compared from different suppliers. Materials Components of the tested formulations are described below: A) Blend of placebo powder composed of Inhalac 251 (Meggle, Germany) and 4% in concentration of Lactochem microfine lactose (DFE, Germany). B) Blend of placebo powder composed

Table 1: Technological characteristics of the two kinds of powder mixes: Inhalac 251 (Meggle, Germany) and Respitose (DFE, Germany) with 4% Lactochem microfine lactose each. Spring 2020 Volume 12 Issue 1

(Pulmonary) Drug Discovery, Development & Delivery of Respitose (DFE, Germany) and 4% in concentration of Lactochem microfine lactose (DFE, Germany). For the execution of the tests, HPMC capsules size 3 produced were used. Methods The Minima and Adapta capsule fillers are designed to process micro-dose dry powder inhalers. Minima is a table-top capsule filler designed to dose solid products in hard capsules. Extremely precise and with a single dosator, Minima can be equipped with the same dosing devices applied on IMA production machines. Minima comes factory-preset for use with dry powder inhalers, thus being an efficient system for inhalation product research, development, optimisation and protocol validation. The Adapta capsule filling machine covers medium and very high-speed production requirements and features exceptional design flexibility. Fitted with the 100% gravimetric net weight control, Adapta ensures maximum dosing precision and reliability even at very high speed.

On the Minima machine, the target dosages of 5.5 mg, 15 mg and 25 mg was achieved with both formulations. Each lot consists of 20 samples. Reliability and consistency were assessed by replicating the acquisitions three times for each lot. The second step of the study was to upscale the experience gained on the bench-top machine to the production equipment. Since the target dose was 5.5 mg, the main work was concentrated on this target with both preparations. 100,000 capsules were produced with Adapta with 100% gravimetric net weight control for each blend.

To determine the net weight of the samples dosed with Minima, the macro-analytical electronic scale Sartorius was used. Weighing range: 220 g, accuracy: 0.1 mg. To check the net weight of the samples dosed with the capsule filling machine, the total filling control system of Adapta was used. Experimental Part In Tables 2 and 3, the experiments of the Minima first screening are reported including machine setting, real weight achieved, tolerances, range between minimum and maximum sample

weight obtained and relative standard deviation. Table 4 summarises the final results of the Adapta with 100% gravimetric net weight control: the powder mixtures and machine settings are reported including real weight achieved and relative standard deviation for an easy evaluation. Graphs 1 and 2 below show the net weights of all 24 dosators of the Adapta with 100% gravimetric net weight control for both powder mixes.

Table 4: Powder mixtures Adapta with 100% gravimetric net weight control trials.

Graph 1: Inhalac 251 + 4% Lactochem microfine lactose, behavior of the 24 dosators on Adapta with 100% gravimetric net weight control.

Table 2: Inhalac 251 + 4% Lactochem microfine lactose, Minima trials.

Table 3: Respitose SV003 + 4% Lactochem microfine lactose, Minima trials. www.ipimediaworld.com

Minima detail of the dosator technology INTERNATIONAL PHARMACEUTICAL INDUSTRY 41

Drug Discovery, (Pulmonary) Drug Development Discovery, Development & Delivery & Delivery capsules produced. It was confirmed that for 5.5 mg dosing, the range between the minimum and maximum weight value in the table-top capsule filler was always lower than 1 mg. The results obtained once formulations were tested in the productionscale capsule filling machine were even better: for both formulations the relative standard deviation was confirmed below 3%.

Graph 2: Respitose SV003 + 4% Lactochem microfine lactose, behaviour of the 24 dosators on Adapta with 100% gravimetric net weight control.

Results The tests on Minima demonstrated that both formulations gave good results in terms of workability and tolerance obtained. No significant differences were observed by the operator. Both formulations demonstrated good behaviour even on the machine Adapta with 100% gravimetric net weight control: no seizing and no empty

Minima table – top capsule filler 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Discussion and Conclusion As proven by this study, a major advantage of using the dosator technology for processing low-dose dry powder inhalers is that the system can dose very small amounts of powders into capsule. This powder dosing technology does not require powder compaction to transfer the powder to the capsule. This ensures that the powder within the capsule is less likely to form aggregates and is maintained as a free-flowing powder. Maintaining the free-flowing properties of the dispended powder within the capsule

Adapta capsule filler with 100% gravimetric fill weight control Spring 2020 Volume 12 Issue 1

(Pulmonary) Drug Discovery, Development & Delivery

Adapta detail of 100% gravimetric fill weight control

better ensures the release of powder from the capsule into the inhaler when the capsule is pierced, thereby better controlling both the emitted dose and the fine particle fraction of the dose discharged from the DPI. REFERENCES 1.

2. 3.

Edwards D. Applications of capsule dosing techniques for use in dry powder inhalers, in “Therapeutic Delivery”, July 2010. Rogueda P. Take a deep breath. Inhalable drug delivery, in “World Pharmaceuticals”, April 2016. Williams G. The future of DPIs: Aligning Design with Market Demands, in “Drug Development & Delivery”, December 2012.

Pietro Pirera Product Manager at IMA Active. He is Product Manager for capsule filling since 2003. Graduated in Mechanical Engineering at the University of Bologna (Italy), he has been working in the field of solid dose processing and manufacturing for more than 20 years. He is expert in pharmaceutical engineering and processing of micro-dosing Dry Powder Inhalers. Adapta detail of dosator technology. www.ipimediaworld.com

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Drug Discovery, (Pulmonary) Drug Development Discovery, Development & Delivery & Delivery

Proveris by Design: A Roadmap for In Vitro Characterisation of Combination Products Combination products are complex by definition and the product development cycles can be both time- and resourceintensive. Recently, Novartis discontinued the generic Advair Diskus programme after investing $442M and years of efforts1. There are several other companies struggling with generic drug development for orally inhaled and nasal drug products (OINDPs). The common theme of challenges has been formulation device incompatibility, lack of in vitro bioequivalence, analytical methods that fail to replicate patient usage, lack of understanding of critical quality attributes (CQAs), and the expensive in vivo failures.

This article offers a stepwise guide to develop nasal spray and pressurised metered dose inhaler (pMDI) products for both innovator and generic drug products, using a quality by design approach. Also, novel characterisation tools are introduced which can be used to demonstrate better correlation to clinical performance. Pressurised metered dose inhalers (pMDIs) and nasal sprays are available in a range of device shapes, sizes, and actuation mechanisms.

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Part 1: Stepwise guide to development of nasal sprays and pMDIs – a Proveris by DesignTM approach The quality by design (QbD) approach was first endorsed by the United States Food and Drug Administration (USFDA) in a report titled, "Pharmaceutical Quality for the 21st Century: A Risk-Based Approach"2. The approach was characterised by a focus on science and quality risk management. Today, many companies

employ this approach in R&D to save time and money during product development and preparation of regulatory submissions. The results show an overall reduction in approval timeline and minimised queries from regulatory agencies, such as the USFDA. Moreover, the insight gained into product performance can be used long after product approval to investigate and resolve any out-of-specification (OOS) or out-of-trend (OOT) disruptions to manufacturing.

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(Pulmonary) Drug Discovery, Development & Delivery

Figure 1 a) Shot weight results for a nasal spray product with different stroke length settings; b) Example PG results for different velocity settings

As for any pharmaceutical product, it is important to perform in vitro tests with repeatable, reproducible and robust methods for smoother OINDP development. However, unlike other dosage forms (tablet or capsules), combination products are affected not only by the formulation, but also by the delivery system (device) and patient usage. Variations in analyst technique have long been a source of errors in accurately evaluating product performance. For OINDPs, actuation of the product by hand can contribute to variation in data. Due to this, automated actuation based on human realistic usage has been recommended for OINDP testing for decades. The purpose for this is to eliminate the variability of human usage and translate the complicated biomechanics of patient actuation into a controllable mechanism through multiple key parameters. Proveris Scientific’s Vereo® Automated Actuators allow control for up to six actuation parameters for nasal sprays and pMDIs and four additional parameters related to shaking for pMDI devices. To ensure

data integrity and accuracy, it is crucial that an identical actuation mechanism is implemented across all the in vitro testing, including fire-down during through-life tests. Several critical quality attributes have been identified to assess the performance of nasal sprays and pMDI products including shot weight, spray pattern (SP), plume geometry (PG), and droplet size distribution (DSD). It has been reported that for most nasal sprays, the stroke length is a major influencing factor for shot weight, and that the velocity/acceleration drives spray performance (including spray pattern, plume geometry, and droplet size distributions3. For pMDI products, the use of suspension formulations adds additional complexity to analytical testing and requires adequate shaking and minimum shake-to-fire delay in order to maintain the uniformity of the delivered dose4. Other important influencing factors on pMDI performance include product actuation force and hold time to ensure that the metering valve is open long enough to deliver a complete dose.

For example, Figure 1a shows that shot weight increases with the stroke length increase, until a stroke length threshold is reached to deliver the full dose. It is worth noting that the trend of curve (shot weight vs. stroke length) will vary by device types. Figure 1b shows example PG image at different actuation velocities: the PG image shows that at low velocity setting, the spray is not fully atomised; as the velocity increases, the plume gets wider, which usually results in smaller droplet size distributions.

Figure 2a describes the effect of shaking on the dose content for a suspension pMDI sample. With improper shaking, initial doses at beginning of life are up to six times the label claim, which drops to one-tenth of the label claim by the end of life stage. Conversely, proper shaking provides a consistent and complete dose. Proper shaking and shake-to-fire delay ensures uniform dose delivery throughout the life of a pMDI device. Figure 2b shows the plume geometry results with time-synchronised intensity graph to

Figure 2 a) Dose content and shot weight for a suspension pMDI product with improper and proper shaking; b) Example PG results for a fully and partially opened valve www.ipimediaworld.com

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Drug Discovery, (Pulmonary) Drug Development Discovery, Development & Delivery & Delivery demonstrate the differences between fully and partially opened valve: the fully opened valve delivered a continuous and relatively strong intensity PG, compared to discontinuous and weak intensity PG for the partially opened valve. With that said, the first step to establish in vitro methods is to record the range of human usage of OINDP products through a human actuation

Table 1 Influencing factors for nasal sprays and pMDI performance

Figure 3 The SP area results for four different formulation/actuator combinations

study. A controlled strategy in product development starts with defining the design space for different factors influencing product performance. This involves considering all the possible formulation and device factors, and to understand how the product

performs in the hands of a patient. Example factors are listed in Table 1. Each factor could contribute to a different performance aspect of the product, and certain factors have more of an impact than others. The goal of the first step is to determine

the human achievable range for the actuation (and shaking) parameters for all the device/formulation combinations within specific demographic groups. It is likely that the product performs differently within and outside this human achievable range. The second step is to test the range of design spaces and gain an understanding of the control space: which factors have the most impact on product performance? This step will immediately rule out some device/ formulation candidates due to poor performance or incompatibility. It is recommended to start with shot weight (nasal sprays) or valve delivery (pMDI) as a key in vitro test to determine the effect of different factors in the control space.

Figure 4. Performance sensitivity mapping with example discriminatory factors and outputs 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

For generic product development in general, it is important to begin your project with a thorough benchmarking of the reference product. Having a full understanding of the performance target and the variations across different devices and lots will help guide the initial design work for the generic device and formulation. For an innovator product, more emphasis should be put on the possible correlation to the in vivo Spring 2020 Volume 12 Issue 1

(Pulmonary) Drug Discovery, Development & Delivery

Figure 5. The apparatus of in vitro inhaled drug analysis (INVIDA) platform

performance, as well as aspects like product stability and consistency. It is likely that two or more factors will influence each other systematically. Figure 3 shows the spray pattern area results from four different formulation/device combinations (formulation/actuator A; formulation/ actuator B; water/actuator A; water/ actuator B). Spray pattern area results were found to be similar for both actuator types (A and B) and highly variable when tested with water as the formulation; spray pattern areas for formulation showed distinct differences between the two actuator types (A and B) and were significantly different from water. This stresses the combination effect of both device and formulation, and the importance of evaluating the device with actual formulation instead of water.

The final step is to identify the target operating space and control key influencing factors in a tight range during manufacturing and testing. The results seen in the second step, and insights gained regarding the key actuation parameters, key formulation elements, and key device components must be used to formulate a plan for closely monitoring these critical quality attributes (CQAs). The Proveris by DesignTM approach generates a sensitivity map based on design of experiments and evaluates these results. As exemplified in Figure 4, the possible discriminatory factors will be listed on the x axis, against the outputs (usually in vitro test results) on the y axis. The discriminatory strength will be analysed statistically and used to systematically determine the most influencing factors driving the output.

For other dosage forms, including side actuated nasal sprays, syringe type nasal sprays, unit dose nasal sprays (aqueous or powder formulation), unit dose oral sprays, breath actuated metered dose inhaler, soft mist inhaler (SMI), dry powder inhaler (DPI), as well as over-the-counter (OTC) aerosol sprays (e.g., topical/dermal spray), the designing approach and the final controlling strategy can vary, but the overall principles remain unchanged. Part 2: Using a Novel Human-Realistic Approach for In Vitro Characterisation to Better Predict In Vivo Performance of Inhaled Aerosols The issue of poor correlation between the current in vitro testing and the clinical performance (in vivo) is widely acknowledged in the industry, and the high failure rate for generic drug approval in the inhalation space testifies to this. In 2012, the USFDA started the Generic Drug User Fee Amendments (GDUFA) program, aimed at expediting the delivery of safe and effective generic drugs to the public and improving upon the predictability of the review process6. In the interim, numerous product-specific guidance documents have been released for orally-inhaled and nasal drug products (OINDPs). In May 2019, the FDA released a product specific guidance for beclomethasone dipropionate7 that introduced approaches using new, alternative in vitro characterisation studies that are more representative and/or predictive of the clinical effect at the local sites of action in the human respiratory

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Drug Discovery, (Pulmonary) Drug Development Discovery, Development & Delivery & Delivery tract. Characterisation of the emitted aerosol spray velocity profiles and evaporation rate were proposed as alternative tools for use in comparative clinical endpoint bioequivalence (BE) studies. Also, it was encouraged to apply human-realistic mouth/throat models as well as breathing profiles to existing in vitro testing. A method to measure plume front velocity based on the well-established Proveris SprayVIEW® technique (which produces calibrated, time-synchronised image sequences of the entire aerosol plume and duration) was proposed by Proveris scientists8. The study shows a straightforward data analysis method based on the current PG measurements to generate a plot of distance travelled by the aerosol plume front versus time and thereby calculate the velocity. This method has the sensitivity to distinguish plume front velocity differences between different types of products, propellants, and formulations. Moreover, an evaporation fraction approach was also developed based on the SprayVIEW® technique (to be published in the upcoming RDD 2020 conference). This method integrates the dynamic spray pattern (SP) data and correlates the cumulative image intensity results with the drug product mass (formulation + propellant). The technique then allows for a comparison of the drug product mass loss to the baseline in order to demonstrate the percentage loss of mass due to evaporation (evaporation fraction) at various distances from the mouthpiece edge. In addition, Proveris has developed a novel platform called INVIDA™ (in vitro inhaled drug analysis) with emphasis on quantifying the regional deposition of aerosol drug products within different regions of the human respiratory tract. The deposition of drug in the deep lung drives bioavailability and in vivo performance of inhaled therapies. Many computational fluid dynamic (CFD) models of the respiratory system show that achieving the desired regional deposition in the deep lung is more complicated than just the aerodynamic particle size distribution. The unique geometries involved (variations in diameter create 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

pressure drop changes), as well as the respiratory environment (high humidity, constant temperature, and mucus layer) play an important role and cannot be ignored. Moreover, the mucociliary escalator clearance mechanism can greatly influence regional deposition. The INVIDA platform includes a specially designed model of the upper respiratory tract which can be easily disassembled and assayed separately. The components are designed to mimic human respiratory physiology (mouth/throat, trachea, carina – left/ right lung imbalance, lower lung) as shown in Figure 5, and the filter designed for drug capture is inserted following tracheobronchial and carina simulated model to measure the amount of drug that reaches the lung. A breathing simulator is connected to the apparatus to simulate realistic breathing profiles (inhalation, hold, exhalation). Further, a temperature and humidity chamber is attached to the airstream in order to simulate the human respiratory environment; and the inner surfaces of the airway models are coated with appropriate coating solutions to mimic the viscosity of the mucus. The API concentration can be analysed in the four major respiratory sections to understand the deposition across different regions. Finally,

the mass balance of all the regions provides the total delivered dose from the device. The INVIDA platform enables applying various breathing profiles that represent different demographics and disease states. It can be programmed with device resistance to replicate specific devices as some devices can be more difficult to breathe through than others. For breath-actuated inhalers (DPI, breath-actuated pMDI, and SMI), the minimum airflow to actuate the device can be obtained. In addition to inhalation, hold and exhalation parameters are available to study the effect of the full breathing cycle on the drug delivery and efficiency. Conclusion The performance of OINDPs is affected by a combination of formulation, device, and patient usage. Utilising automated actuation that replicates human usage with high precision is key to reveal the true product quality throughout life stages, for both testing and fire-down. Shaking is critical to suspension products and should be controlled. The Proveris by Design approach closely follows the quality by design approach recommended by the FDA and can save both time and resources while accelerating the time to market of these products. Spring 2020 Volume 12 Issue 1

(Pulmonary) Drug Discovery, Development & Delivery Alternative in vitro approaches that are human-realistic can enable companies to make data-driven decisions and expedite product development and approval while saving time and resources. Proveris’s in vitro testing platform (INVIDA) is built to replicate human usage of the product (in terms of breathing profile, respiratory geometry and environment) while minimising the gap between in vitro and in vivo performance to predict true product performance.

REFERENCES 1.

https://www.fiercepharma.com/pharma/ after-years-development-and-fdarejection-novartis-calls-it-quits-advairgeneric-and-takes https://www.fda.gov/about-fda/centerdrug-evaluation-and-research-cder/ pharmaceutical-quality-21st-century-riskbased-approach-progress-report Guo, C. & Doub, W. H. (2006). The influence of actuation parameters on in vitro testing of nasal spray products. Journal of Pharmaceutical Sciences, 95, 2029–2040. https://doi.org/10.1002/jps.20678 Hatley, R. H. M., Parker, J., Pritchard, J. N. & von Hollen, D. (2017). Variability in

Delivered Dose from Pressurized MeteredDose Inhaler Formulations Due to a Delay Between Shake and Fire. Journal of Aerosol Medicine and Pulmonary Drug Delivery, 30(1), 71–79. https://doi. org/10.1089/jamp.2015.1284 Chauhan, H., Liu-Cordero, S. N., Liao, L. & Werbeck, J. (2018). Impact of Actuator Design on Multi-dose Nasal Spray Characteristics. In RDD 2018 (pp. 497–502). FDA: Generic Drug User Fee Amendments [https://www fda. gov/ industry/fda-user-fee-programs/ generic-drug-user-fee-amendments]. Accessed October 31, 2019 FDA Beclomethasone dipropionate Inhalation Aerosol Metered NDA 207921 PSG Page RC May 2019 Liao, L. L., Ramos, K. & Farina, D. (2019). A Novel Characterization of Emitted Aerosol Velocity Profiles from Metered Dose and Soft Mist Inhalers (pMDI and SMI). In DDL 2019 (Vol. 30, pp. 287–290). Edinburgh, UK: Aerosol Society.

Starting a new OINDP project can be intimidating. A partner with the right expertise and extensive experience in the field can significantly streamline the development effort. To learn how Proveris laboratories can be your partner from early development to commercial

scale testing, please visit https://www. proveris.com/why-proveris/

Linda Liao Linda Liao is a senior application scientist who has focused her career on spray characterization, particle size, and shape characterization, and fluid dynamics as it pertains to the development and release of orally inhaled and nasal drug products (OINDPs). She has a strong technical understanding of in vitro testing requirements as defined by global regulatory agencies and is experienced in method development and quality by design (QbD) methodologies. Linda has authored numerous publications and spoken globally on the use of spray characterization technologies. Linda holds an M.S. in Chemical Engineering from the University of Florida and a B.S. in Chemical Engineering and Technology from Central South University, P.R. China.

BACHEM GENERIC APIs Bachem is the leading independent supplier of active pharmaceutical ingredients (APIs) for the human and veterinary pharmaceutical market. • Bivalirudin • Carbidopa • Desmopressin Acetate • Etomidate • Exenatide Acetate • Glucagon • Goserelin Acetate • Lanreotide • Leuprolide Acetate • Octreotide Acetate • Propofol • (Arg8)-Vasopressin

MEET US AT

CPHI JAPAN, March 16 - 18, Tokyo CPHI CHINA, June 22 - 24, Shanghai www.ipimediaworld.com

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www.bachem.com

Clinical and Medical Research

Caregivers in Oncology: How to Address the Needs of These Hidden Heroes There’s an important person out there influencing your next oncology trial patient. We don’t often talk about this person within clinical research, much less plan for them. Yet, they will have an unprecedented impact on your patient’s understanding of the trial, their ability to make site visits, and their adherence to medications and protocol. This person is the patient’s caregiver. For those who may not know, The American Cancer Society defines a caregiver as “…The person who most often helps the person with cancer and is not paid to do so... Caregivers may be partners, family members, or close friends. Most often, they’re not trained for the caregiver job. Many times, they’re the lifeline of the person with cancer.”

Caregiver Burdens The phrase “they’re the lifeline of the person with cancer” is telling. When it comes to oncology trials, caregivers have historically shared much of the patient burden while also facing their own unique issues. In fact, caregivers often face the exact same burdens as patients, such as taking time off work, providing or finding transportation to patients, finding or providing childcare, ensuring medication adherence, and ensuring the patient progresses through the trial as needed. They may also take on basic duties that support the patient outside of the trial. These can range from household chores (cooking, cleaning, etc.), to monitoring general health and providing emotional and financial support. In addition, caregivers often find themselves providing their own level of healthcare to patients, helping with symptom management, treatment monitoring, and more. However, that’s not all. Caregivers are in a unique position with oncology patients, who may be suffering from side-effects from cancer treatment. Patients on chemotherapy often suffer from excessive fatigue, neuropathy, and “chemo brain” (difficulty in thinking or 50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

recalling information). Each of these conditions can create additional burdens for caregivers, depending on their severity, or can make an already difficult situation more dire. For instance, a patient suffering from chemo brain and excessive fatigue may rely more on their caregiver than usual for basic needs such as cooking and cleaning, in addition to trial needs such as medication adherence and remembering site visits. As a result of all this, caregivers often seek as much information about oncology, cancer treatments, and clinical trials as patients do. Thus, it’s important that clinical trials treat oncology patients as a unit, recognising the legitimate needs of both the patient and their caregiver(s). Put simply, caregivers are just as essential to an oncology trial as the patient themselves and can be one of the reasons some patients end their participation in the trials. Clinical Research vs. Standard of Care The first place that patient and caregiver needs can be addressed is in explaining the differences between a clinical trial and standard of care. It’s important that clinicians ensure that both the patient and their caregiver(s) understand that the primary intent of clinical trials is to answer questions about the treatment itself, rather than treat the patient themselves.

Patients and their caregivers may also be unfamiliar with their trial drug, whether or not it’s blinded, or how to get information surrounding the drug. It’s essential that clinicians ensure patients understand how the trial, its protocol, and the therapy will work. Sponsors, contract research organisations (CROs), and research facilities can help ease clinician’s duties in these regards by providing them with pre-made materials about the trial, with answers to common questions that patients or their caregivers may have. Here, clinicians must be careful. Many oncology patients may have existing care plans to address common oncological co-morbidities that require regular or emergency visits to healthcare facilities outside of clinical research. Thus, any changes to the trial may be hard on patients and their caregivers, especially if it causes the trial to compete against their existing care plan. It’s also paramount that patients and their caregivers understand the nuances and levels of consent. While some standard treatment options typically require consent, most patients and their caregivers will be unfamiliar with the level of consent required for a clinical trial, such as re-consenting for protocol changes, consenting for biosamples, or trial-specific procedures. This is especially significant, as the larger the perceived burden is on the

Adult children make up 8% of caregivers for patients with cancer -OR- Caregivers often seek as much information about oncology, cancer treatments, and clinical trials as patients do Spring 2020 Volume 12 Issue 1

Clinical and Medical Research patient and their caregiver, the more likely they may be to drop out.

placed not only on the patient, but their entire familial unit.

Another key conversation topic is the financial requirements of the trial. Those coming from the oncology standard of care world may understand that insurance covers their regular care, but may not understand that the clinical trial sponsor covers the medication, biopsies, lab treatment, etc. As mentioned before, the higher a burden that a patient and caregiver feel, the more likely they may be to drop from the trial. Therefore, it’s important to ensure they understand that these items are taken care of and won’t provide any additional financial burden.

Lastly, consider offering caregivers the same benefits that patients receive. For instance, if you reimburse patients for adherence to medication, visits, or for other reasons, consider offering the same incentives to caregivers. Or, consider offering caregivers the option to rely on an alternate means of transportation for a few site visits.

Opportunities to Address Caregiver Specific Needs As mentioned previously, a caregiver can be as essential to the trial as the patient themselves. Thus, providing them with specific information geared towards their experience will help not only the caregiver, but the patient and the trial as a whole. At the least, caregivers should receive the exact same trial information as the patient. Research from Dewalt (Dewalt, D.A. et al., 2010) shows that patients are likely to forget 40% to 80% of the medical information they receive. Of what is retained, only half is correct. Thus, the information given to patients and caregivers around the treatment, visit schedules, adherence, diaries, or other requirements should be uniform. This is to ensure that the caregiver can act as a backup to the patients’ knowledgebase if need be. This is especially true in patients who do receive chemotherapy or other impairing treatments as part of their standard of care, who likely need the extra support. In most cases, clinicians should provide caregivers with specific information that pertains to their unique needs and burdens. Clinicians should seek to provide additional information to caregivers that shows how to best care for their loved one, within the best of their ability. This means basic instructions on how to increase comfort when a patient is feeling unwell, how to monitor symptoms, and when to seek medical help. www.ipimediaworld.com

Caregivers must also be armed with information about how to best care for themselves during this difficult time -OR- Caregivers offer a unique perspective on the patients’ condition

As caregivers are most often assigned with logistical tasks, it’s also important to provide them with emergency contact numbers, a primary point of contact for any non-emergency questions, take home instructions for any devices, reporting, adherence, or other tasks. Caregivers must also be armed with information about how to best care for themselves during this difficult time. It is common for caregivers to devote more time to their patient, ensuring they have everything they need as they help them through this difficult time. However, this can often lead to diminished self-care. Here, it’s quintessential to let caregivers know that this is common, and to provide them with support services such as health navigator, support groups, or other local services. Within the last decade, several trials have made an effort to consult with clinicians and their patients prior to developing a trial’s protocol. They’ve done so in order to provide a trial protocol that would be best for patients, sites, and investigators all at once. In these instances, trial sponsors should also seek to consult with patients’ caregivers, who will best understand the impacts to their own lives and ability to care for their loved one. Surveys are another quick and easy way to see the impact that your trial has on your patients’ caregivers. Caregivers have a unique perspective on the patients’ condition and often provide useful information that patients are unwilling to provide or cannot see on their own. They’re also a great way to understand, quantify, and document the amount of extra burden that is

Changing the Conversation When it comes to oncology clinical trials, the industry must remember that our patients are often not tackling trials alone. In fact, there’s an important person out there with direct influence on your next oncology trial patient. We don’t often talk about this person – but it’s time we do.

Mindy Gruba Mindy Gruba is a Senior Product Manager at Signant Health, responsible for developing the product strategy and roadmap for TrialGuide, the company’s mobile solution for patient engagement in global clinical trials. Mindy has worked with top 20 pharmaceutical companies and CROs to develop gamification, patient education, virtual trial and mobile engagement strategies for vaccine, rare disease, and oncology studies, leveraging her 10+ years of experience in mobile technology, product development, and behaviour change communication. Prior to Signant Health, she worked at J&J’s Human Performance Institute and multiple health information technology start-ups, taking products from concept to market. Mindy has also spent time advancing her health research and communication strategies at the NIH, Peace Corps, and NASA’s Kennedy Space Center. Mindy holds an MPH from The George Washington University and a BS from the University of Wisconsin-La Crosse.

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Clinical and Medical Research

Study Oversight Models & Implementation in Clinical Trials With clinical studies becoming more complex, there is increasing demand for study oversight to ensure high-quality clinical data and efficient site performance. Drug developers want to ensure their clinical trial is a success and reduce the potential reasons for failure of a regulatory submission – and data integrity or poor site performance are common reasons for failure.

Traditionally clinical research associates (CRAs) are sent to sites to validate data and check site performance. This generates a large cost for CROs and pharmaceutical companies who are responsible for the monitoring of the trial, and the industry has seen new and novel ways to perform study oversight remotely with new technologies, as well as acceptance from regulatory bodies to reduce trial costs with the ICH GCP E6 (R2) addendum. The addendum allows for a degree of source data verification (SDV) to no longer have to be done on site, as well as to reduce SDV from 100% where risk permits1. Emerging technologies allow for the industry to move away from this traditional monitoring technique and use a remote monitoring approach performed from a central location where source data verification is performed remotely, known as rSDV. As well as the ability to remote monitor, instead of investigating every site in a trial, which can become inefficient when there are multiple sites in large studies, a triggered monitoring approach can be implemented and study oversight is conducted when a set KPI is missed. This is also known as risk-based monitoring (RBM) and key risk indicators (KRI) must be defined to trigger these KPIs, which are defined in the study design of the trial. One of the disadvantages of RBM is that if a KRI isn’t defined, then a potential issue at site can go undetected or unnoticed. Centralised Statistical Monitoring (CSM) This is where centralised statistical 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

monitoring comes into play and has emerged in light of the proliferation of monitoring techniques. CSM addresses the need to review the data received from trial sites for integrity issues resulting from potential errors, misconduct or fraud occurring at trial sites. CSM is an approach for identifying and managing issues affecting data integrity as quickly and efficiently as possible. It combines centralised monitoring with statistical monitoring. Centralised monitoring is when site data is evaluated for risks from a single off-site location, rather than reviewing risks directly on site at each investigative site. Statistical monitoring is the detection of data anomalies and data outliers with the use of complex statistical algorithms recommended by TransCelerate (and other statistical tests at the discretion of the CRO or pharma) to analyse data of various forms. This would include patient data but could also cover investigation-site data, laboratory data, and metadata. The statistical analyses’ findings inform various monitoring, escalation or communication actions in line with the communication plan and the trial master plan (TMP). It has been suggested that CSM should be performed at limited times during a trial and before any major analysis, such as interim or final analysis2. It is best to agree the schedule with the study team and some examples include every six weeks in line with traditional on-site monitoring or at recruitment intervals (such as 25, 50, 75 and 100% of target patients population being recruited), in alignment with independent data monitoring committee data cuts3. This permits the study team to properly investigate and resolve or mitigate identified issues without being swamped with frequent alerts. Improving Data Quality with Data Quality Oversight Data quality oversight (DQO) is the performance of running the statistical analytics within CSM and generating

reports to identify outliers and anomalies, and improve the quality and integrity of clinical trial data. Monitoring and clinical data management teams can then investigate and resolve potential issues. Performing DQO during study conduct and improving data integrity (the maintenance of, and the assurance of the accuracy and consistency of, data over its entire life-cycle), leads to improved data quality in the final submission data used to demonstrate an investigational new drug’s (IND’s) efficacy and safety. Large trials with multiple centres and manual on-site monitoring via investigators are more time-consuming from a cost and clinical research associate (CRA) perspective. Importantly, they are more inefficient in the detection of data issues. This is because traditional on-site monitoring does not permit the easy application of statistical methods to detect data anomalies in important variables. Investigators cannot perform data oversight as well as they could and are not detecting issues to improve data integrity as quickly as they could, meaning that with a 100% SDV approach, issues can exist for longer and go unnoticed. RBM allows a much easier integration of key risk indicators (KRIs) into protocols and monitoring plans and can significantly expand the kind of KRIs a sponsor is able to consider. Detecting data quality issues early is important so that corrective action can be taken during the conduct of the trial and helps prevent future issues4. KRIs and the monitoring techniques that a trial will perform must be clearly defined within a monitoring plan and the FDA have actively encouraged the RBM approach. The FDA states: “At the same time, increasing use of electronic systems and records and improvements in statistical assessments, present opportunities for alternative monitoring approaches (e.g., centralised monitoring) Spring 2020 Volume 12 Issue 1

Clinical and Medical Research

that can improve the quality and efficiency of sponsor oversight of clinical investigations. FDA encourages sponsors to develop monitoring plans that manage important risks to human subjects and data quality and address the challenges of oversight in part by taking advantage of the innovations in modern clinical trials. A risk-based approach to monitoring does not suggest any less vigilance in oversight of clinical investigations. Rather, it focuses sponsor oversight activities on preventing or mitigating important and likely risks to data quality and to processes critical to human subject protection and trial integrity.”5 With this level of endorsement, it is no surprise that the use of RBM has risen over recent years – research has shown that between 2009 and 2013, the adoption of RBM has risen from 33% to over 50% among industry stakeholders6, and a survey in 2018 shows continued www.ipimediaworld.com

growth with 64% sponsor adoption and 71% CRO adoption7. Outsourcing Models Influence on Study Oversight CROs have been a major force in the development of RBM and CSM solutions and, as such, are relied upon by many pharmaceutical companies. The demand for CRO-conducted clinical trials continues to rise – the market for CRO-conducted clinical development in 2015 was $25.7 billion and $34.5 billion in 2018, and is expected to reach $55.3 billion by the end of 20248. With increasing outsourcing and the growth of the CRO space, sponsors need to perform a degree of CRO oversight to make sure that their partners are performing and delivering the results they are looking for in line with ICH GCP guidelines. This is why the governance of any relationship is important, and setting

KPIs between the sponsor and vendor with regular reviews is encouraged. Governance is an important part of an FSP relationship and supports the improved study oversight between sponsor and CRO. Full Service Many pharmaceutical and biotechnology companies have looked to large, full-service CROs to support much of their required R&D services. In some cases, this has progressed to the point where a product is handed to the CRO and the pharmaceutical company has a completely hands-off approach to its development. The challenge to adopting such an approach is primarily the reliance on a very small number of CROs (sometimes only one) and that the expertise and capabilities in specific functional areas may not be as consistently INTERNATIONAL PHARMACEUTICAL INDUSTRY 53

Clinical and Medical Research strong across the CRO. Since over 90% of the time and budget relates to the clinical operations aspect, the primary selection of a full-service CRO is based around capabilities in clinical operations and a functional or centralised approach may therefore be preferred to provide greater flexibility and to minimise risk. The advantage of this model is that with a single service provider, study oversight is conducted by one party so efficiencies can be achieved when working with a single vendor, as they centralise data and follow their own processes. However, there are some disadvantages because a single service provider (primarily focused on monitoring) may not have as much focus in a specific functional area that a niche provider can offer. Also, they may be less accountable as they are not working with other vendors, so study oversight does not have that extra layer of review. A sponsor that is using a full service approach should be advised to conduct regular data fitness checks with DQO. Functional Service Provision Many companies, particularly larger pharmaceutical, biotechnology and medical device companies, decide to split the outsourcing of functions further or have a single provider across multiple functions. It is usual though for two to five vendors to be selected per function. The idea is that using niche vendors allows pharmaceutical companies to focus more on developing each relationship and in turn, CROs will prioritise partnerships where there is a higher volume of work. Whilst a small number of companies have formed exclusive partnerships, having more than one vendor enables some degree of competitiveness and prevents reliance on a single CRO. Functional partnerships are often preferable because it allows the use of vendor companies that have focused expertise in specific functions. There can also be competitive benefits to having multiple CROs involved in a single study or programme, rather than a single CRO across all functions. Having 54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Spring 2020 Volume 12 Issue 1

Clinical and Medical Research functional partners can still result in efficiencies across studies, that can then help to reduce the overall cost of the work, if programmes are outsourced intelligently. From an oversight perspective, study oversight reduces as performed by vendors, but the CRO oversight increases as there are multiple vendors to monitor and check against vendor performance KPIs. Conclusion Study oversight is a broad topic. We have reviewed how site performance and clinical data controls can be implemented across various monitoring techniques, as well as technologies which implement statistical algorithms to detect any data anomalies. These go beyond reviewing just clinical data as they also review various data sources and identify issues at site that may not have otherwise be known. Also, study oversight is a vital component in different outsourcing models and sponsor/vendor relationships. Not only is governance key in a functional outsourcing model with CRO oversight,

but also the study oversight is influenced by the outsourcing model and the number of vendors working on a study for sponsor companies. REFERENCES 1.

4. 5. 6. 7.

https://www.fda.gov/ downloads/drugs/ guidancecomplianceregulatory information/guidances/ucm269919. pdf http://www.phusewiki.org/docs/2016_ Deerfield_SDE/Centralized%20 Statistical%20Monitoring%20to%20 Detect%20Data%20Integrity%20 Issues%20-%20Alun%20Bedding.pdf Quanticate White Paper – The Importance of statistical monitoring in the new ICH E6 (R2) Guidelines https://www. quanticate.com/the-importance-ofstatistical-monitoring-in-the-newich-e6r2-guidelines http://journals.sagepub.com/doi/ https://www.fda.gov/downloads/ drugs/ http://www.appliedclinicaltrials online.com/current-status-riskbased-monitoring http://www.appliedclinicaltrialsonline. com/rbm-barriers-adoption

https://www.marketwatch.com/ press-release/contract-researchorganization-cro-market-2019industry-research-share-trendglobal-industry-size-price-futureanalysis-regional-outlook-to-2024research-report-2019-05-14

Thomas Underwood Thomas Underwood, marketing manager, Quanticate, has over 10 years’ experience within the life science industry at Quanticate. Originally working in operations in both clinical data management and programm ing, Thomas moved into the organisation’s commercial division and has been involved in leading Quanticate’s marketing for over nine years. Thomas has a postgraduate professional diploma with the Chartered Institute of Marketing (CIM) and also secured Chartered Marketer status in 2014.

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Clinical and Medical Research

Why Connected Data is Crucial to Pharmaceutical Research Classic analysis tools fall short of revealing the insights within life sciences data – so researchers need to look for new approaches, such as graph technology, says Neo4j’s Alicia Frame. Big data combined with advances in data science approaches have provided a valuable opportunity for the pharma industry to uncover previously unobtainable insight that has the potential to improve – and save – lives.

The technology that has traditionally been used to work with big data, RDBMS (relational database management systems), was never intended to be flexible or scalable and to detect connections and patterns within datasets. This has resulted in re-visiting the tools historically utilised, including SQL and relational database technology. Desktop spreadsheets and relational databases that have been a mainstay over the past 30 years have reached their limits. They simply cannot cope with vast amounts of data nor the complexity of the multiple sources of data we want to explore, significantly hampering research efficacy. Medical data is after all highly heterogeneous and complex in nature. It can run from molecular interactions to population-wide epidemiological studies to macro-scale disease network tracking all within the same body of research. This presents a formidable challenge, especially since the reality is that relationships in data hold the key to actual breakthroughs. In parallel, researchers working toward promising new medical treatments are also looking at huge amounts of data, often running into thousands of terabytes. Working out how multiple researchers can access and collaborate within a dataset is also a challenge. With data that often comes in an unstructured format and needs to be turned into a valuable research ingredient as quickly as possible – not just simply initially analysed and stored – we clearly need a dynamic and scalable way to leverage its potential. 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Enter the Graph Database The good news is that graph databases are a viable and powerful alternative. Unlike the relational database, which stores data in rows and columns, graph databases connect data points in unstructured big data, essentially joining the dots to create a picture of the relationships between them. These data patterns are difficult to detect using SQL-based RDBMS or other approaches, such as NoSQL and Hadoop. Graph technology was first used to improve the user experience by social web giants Google, LinkedIn and Facebook, to find relevant web pages, friends, or personal connections. Outside of big tech, graphs showed tremendous promise in investigative journalism and notably to expose complex financial structures in The Panama Papers. In the case of the Papers, a team of global researchers carried out their investigations with a gargantuan 2.6 terabyte data set that would have been an onerous task using traditional database technology. Connecting the Dots Highly-linked datasets are too difficult for SQL to easily parse due to their inherent design. Relational database models employ sets of tables and

columns, carrying out complex joins and self-joins to action queries when the data becomes increasingly inter-related. As human beings, we naturally perceive connections between data points visually, making graph representations much more in line with how our minds associate and organise information. The ‘rows and columns’ approach does not match our mental visualisation of a problem, technically defined as ‘objectrelational impedance mismatch’ – and more to the point, rows and columns don't match the real world, systems biology data that confront life sciences researchers on a daily basis. Trying to take a data model based on relationships and pushing it into the tabular framework of a relational database, ultimately creates a disconnect that costs valuable time, and can lead to missing useful patterns and leads. The deep data mining and pattern detection capabilities of graph technology provide a route to the insights sought in leading-edge pharmaceutical research. The unique selling point of graph database technology is its innate ability to discover relationships between data points and understanding, analysing and interpreting them at huge scale. Joining the dots represents an exciting advance

Spring 2020 Volume 12 Issue 1

Clinical and Medical Research for medical researchers, enabling them to uncover hidden patterns in their own research and that which precedes their own, such as new molecule research and big clinical trial work. Graph technology has the innate power to collaboratively filter data, making great use of the information gathered by multiple users. Collaborative filtering is a core technique used by recommendation engines, where information or patterns can be filtered via data sources, viewpoints, multiple agents and so forth. This approach allows research teams to work on lots of promising data in parallel, saving time and money. And they get to work on the right data, at the right level of granularity, without being disconnected from the global context. Navigating an Information Triangle As interrogating data and knowledge in life sciences requires the modelling of an incomplete model of how our bodies work, it is essential we find a better way to model that complexity to speed up research. As our knowledge pool expands, so these models change, and one senior scientist, Stephan Reiling at Novartis Institute for Biomedical Research, has stated that graph technology can be a new tool to help these investigations. Novartis has engineered a large graph database of diverse heterogeneous biological data, which his team is combining with medical information from NIH’s PubMed. PubMed contains about 25 million abstracts from some 5600 scientific journals. The team wanted to establish one central database to look at how it can use its vast scientific knowledge to develop the next generation of medicines. Novartis had also collected decades of data on how various compounds affect protein targets, such as enzymes, amounting to around one billion data points. That historical data is critical, but sparse compared with the amazing granularity of the data currently being amassed. The company faced the challenge of combining its historical data stores with this new data, while also needing a way to place this research within the larger context of ongoing medical research from around the world. For Novartis, ingesting and connecting data about diseases, genes and compounds, www.ipimediaworld.com

along with identifying the nature of the relationships between these elements, held the promise of accelerating drug discovery. The Novartis team wanted to link genes, diseases and compounds in a triangular pattern. “For successful drug discovery, you need to be able to navigate this triangle,” explains Reiling. The team decided to create a knowledge graph and devised a processing pipeline for ingesting the latest medical research. Novartis Has an Ongoing Effort to Collect and Curate Text mining is used at the beginning of the pipeline to extract relevant concepts and facts from PubMed. That data is then fed into the graph database, along with Novartis’s own historical and image data. The data pipeline populates the 15 kinds of nodes that were devised to represent the data. The next phase fills in the relationship information that links the nodes together. The team identified more than 90 different types of relationships. Novartis uses graph algorithms to traverse the graph and identify a desired triangular node pattern linking the three classes of data together. Graph analytics not only finds relevant nodes in the desired triangular relationship, but also uses calculations the team designed to gauge the associated strength between each node in each triangle. Using this capability, the team devised queries to find data linked by the desired node pattern, with a given association strength and arrange the triangles according to this metric.

When researchers query the knowledge graph, results show the strength of the correlation between elements. If a researcher already knows about a highly associated correlation, they might choose to investigate others which could take their work in new directions. Currently there are half a billion relationships in the database, with the hope to triple this number. Graphs have allowed Novartis to flexibly navigate all of these data sources which is a huge boon to its research. More than a Billion Articles Another example of graphs leading the way in life science research is Miroculus, which saw the promise of microRNAs for cancer detection. Their detection has traditionally required highly-skilled scientists, specialised machinery, and very complex protocols, and Miroculus saw the potential to alter the course of microRNA detection with graphs. Conducting a study to find a microRNA biomarker for stomach cancer meant keeping up with an explosion in related medical research. Typical research methods involved manually searching for articles, selecting a relevant article and attempting to retrieve and assimilate it. But with the increase in microRNA research, absorbing all the relevant information would take several lifetimes. Miroculus needed a way to accelerate that process and connect scientists directly to the most pertinent research, in order to isolate the microRNA biomarker for stomach cancer. INTERNATIONAL PHARMACEUTICAL INDUSTRY 57

Clinical and Medical Research In order to isolate the microRNA biomarker for stomach cancer, life science researchers are required to keep up with the latest publications connecting genes, diseases and microRNAs. “In order to make sense of all the newly available microRNA information, we stored this high volume of data in a searchable graph database,” said Antonio Molins, VP of Data Science at Miroculus. The Miroculus team gathered more than a billion articles in Hadoop. Next, they used natural language processing (NLP) to extract specific sentences with keywords for gene, disease and microRNA. Inferring the relationship between keywords required another step. The team developed an unsupervised machine learning model to classify relationships, which are then stored in the graph database. “We think it’s good to use the right tool for the right problem,” says Molins. “Graph databases are the right tool if you are focusing on relationships.” The team created an interactive visualisation searchable by microRNA, gene and disease. The user’s search criteria becomes the central node of the visualisation, with surrounding nodes connecting specific microRNAs. Selecting a particular node extracts research papers that relate them, with the specific sentence cited and a link to the publication. With the latest medical research available, Miroculus designed a study following FDA guidelines. The study – conducted in collaboration with the NIH, the National Cancer Institute and experts

in Chile – included 650 people eligible for an endoscopy to diagnose stomach cancer. Summing up, Novartis and Miroculus are just some of the many use cases illustrating graph technology’s innate ability to discover data relationships, which promises to feature strongly in the future of medical research. Everything is connected, but sometimes the connections don’t emerge unless we coax them – and graph

technology is a highly effective way to do just that.

Alicia Frame Alicia Frame is the Senior Data Scientist at Neo4j, where she works as part of the product management team to set the roadmap for the Graph Data Science library, and with customers and the community to show the power of graphs for improving machine learning workflows. Prior to working at Neo4j, her focus was on computational chemistry and predictive models for genetic target identification, working at companies like BenevolentAI, Corteva Agriscience, and the US Environmental Protection Agency. She holds a PhD in computational biology from the University of North Carolina at Chapel Hill. Email: alicia.frame@neo4j.com Web: https://neo4j.com/

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Spring 2020 Volume 12 Issue 1

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Clinical and Medical Research

Taking Charge of the Clinical Trial Master File

Six simple but effective steps to set the TMF in the right direction The clinical trial master file (TMF) is a bit of a misnomer, in that it is not really one file. It is “the collection of essential documents which allows the conduct of a clinical trial to be reconstructed and evaluated”. It is the story of how the trial was conducted and key decisions were made during its process. Considering that clinical trials can take years, involve hundreds or thousands of patients over many sites in multiple countries, are supported by a variety of external vendors, involve several different functions, and can run to many hundreds of thousands of “records”, it is clear that maintaining a TMF is a complex endeavour. Most companies struggle with it, and no one escapes an inspection by the health authority (be it the FDA, the MHRA or any of the others) without TMF-related inspection findings.

Many companies treat the TMF as a necessary evil – something that needs to be maintained but doesn’t add any value. This is an understandable mistake. However, in today’s world, pharmaceutical companies claim they are all about data, and the TMF represents a vast data set that deserves to be properly maintained and managed. Companies that do this will find that the value they can generate from high-quality data sets – some large companies run hundreds of clinical trials per year – will far outweigh the cost and headache of keeping on top of their TMFs. Of course, this will not happen by itself. The keyword is “control”, and companies will need to recognise that they are not in control of their TMFs before taking the steps necessary to make the TMF an asset. Your TMF Does Not Have to Put You at Risk of Critical Health Authority Inspection Findings From our analysis of clinical trial master file Health Authority (HA) inspection results, we have found common TMFrelated indications associated with poor inspection outcomes. If these indications are present, you will be at high risk of critical findings from HA 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

inspections. The indicators can be easily identified and, with the right focus, effectively managed. They are: Missing Records of Essential Documents These are expressed in many organisations as 1) relevant trial documents not in the TMF or other predefined and validated systems, 2) required correspondence or emails not filed, and 3) difficulty locating the documents in the TMF. Missing documentation makes it challenging to evaluate the integrity of the trial data or compliance with regulations. Our analysis indicates that “missing TMF records” is one of the most commonly observed critical findings from HA inspections. A Poorly Defined TMF A TMF structure which does not clearly and fully identify the documents to be filed in a central TMF system, versus those in ancillary systems, leads to significant challenges in confirming where the TMF records are held during GCP audits or inspections. In some cases, when the TMF is robustly defined, the structure of the electronic filing folders might not be aligned with the TMF index, and this leads to a misaligned and consequently out-ofcontrol TMF. Records Filed in the Wrong Location Even with a clearly defined TMF index, lack of understanding of the required documents or how they are to be filed in the TMF is another commonly observed indicator. This mostly peoplerelated issue can be expressed as 1) product-level documents filed in study-level folders, 2) documents filed inconsistently or named incorrectly, and 3) documents duplicated and filed in multiple systems. With the advanced technology solutions in the market today, wrongly filed documents can easily be identified. Untimely Filing of Essential TMF Documents The common use of the TMF as a late-stage document repository, rather

than an “active contemporaneous system”, often leads to a rush to file large quantities of TMF records just after HA inspection notification. Untimely submissions, which HA inspectors can easily identify from data audit trails, lead to out-of-date TMFs and non-compliance with clearly defined contemporaneous requirements – which is another frequent reason for critical HA inspection findings. Poor-Quality Oversight of the TMF Poor oversight of the internal or third-party vendor TMF is another common reason for an out-of-control TMF. This is often expressed as poorly defined quality-control processes, lack of adherence to the TMF review process or frequency as defined by the standard operating procedures, vague scope of the sponsor’s versus the contracting vendor’s TMF quality responsibilities, system functionality limitations, or inability to collect and utilise quality metrics to enable preventative action planning. Commercial clinical trial sponsors often use multiple third-party vendors in trial management, and the inability to align TMF documents across these organisations and take control of quality oversight remains a stumbling block. These commonly observed issues are particularly exacerbated during mergers and acquisitions, as the various parties involved apply a different understanding of the TMF and the associated standards, processes, systems and naming conventions. Taking Charge of Your TMF We have identified six simple but effective steps that can be used to take charge of the TMF and avoid hefty penalties for poor TMF management. These are: 1. Define At an enterprise level, the clinical trial organisation needs to define and agree on a common understanding and use of the TMF – as either a document repository or a knowledge management system. If Spring 2020 Volume 12 Issue 1

Clinical and Medical Research the TMF is to be used as a document repository, the expectation needs to be clearly set that it is the storage location for contemporaneous filing of all TMF documents. Engagement with the filed document/data will not be required for knowledge capture – just for storage and archiving purposes. Increasingly, companies are setting the purpose of their TMFs as active knowledge management systems that are used not only for storage and archiving, but also for knowledge and insight mining in managing trials. Deciding which of the two approaches will be used is crucial, as switching between both options leads to confusion. 2. Identify At a study or product level, it is critical to define the required TMF record types based on the regulatory requirements that are relevant to reconstructing the conduct of the trial. The Drug Information Association’s (DIA’s) TMF Reference Model, which is widely accepted by the life science industry and regulatory experts, provides comprehensive information about essential TMF record types (artifacts). Although most record types (79 per cent of the 249 named artifacts) in the model are “core” and must be submitted in the TMF if produced during a trial, a significant amount are “recommended”, and submission is not compulsory. Defining and justifying the “core” and “recommended” document types to file in the TMF (before initiating a study) enables an efficient start to TMF record management. 3. Reveal TMFs are complex and require timely information from multiple stakeholders. Key to the successful set-up, maintenance and close-out of a TMF is the disclosure of the operational details required to collect the right information at the right time. This involves disclosing the roles (not just

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functions) that will be responsible for contributing the predefined record and data types, expected frequency of filing the documents, document contributor quality checks to ensure correctness and completeness, systems to be used and associated system access, issue escalation pathways, etc. Having this information agreed, and preferably signed off, before a trial starts provides the clarity that is often missing in TMF management. The DIA’s TMF plan provides a robust template for organising the TMF. 4. Evaluate A TMF is not a static system, and as such, the set-up defined at the start of the trial is bound to change throughout the life of the trial as study information, roles and systems change. It is simply not effective just to have one version of the TMF plan with pointers to ancillary systems throughout the life cycle of the trial; the plan needs to be contemporaneous with the TMF to maintain control. Updates to pointers should be put through the change-control process for an efficient and systematic approach to managing changes. 5. Check Study teams understand and appreciate the importance of data integrity; the FDA guideline of “Attributable, Legible, Contemporaneous, Original and Accurate” (ALCOA) data is widely understood. However, given the high volume of TMF records generated during a trial, it is impossible to check every document. Quality checks are easier if carried out frequently – preferably every three to six months. A risk-based approach could also be applied tohaving to do 100 per cent review of every record. 6. Train Maintaining a compliant TMF requires routine training, refreshers, and reminders, as TMF obligations are not always at the top of study teams’ agendas. Given the recent success in company-wide understanding of adverse-event reporting – which is well established in most companies today compared to 15 years ago – the TMF could follow a similar path to achieve the same level of success; i.e., the importance of a compliant TMF culture will need to be promoted company-wide, with regular, detailed

training for roles involved. Companies that educate associates regularly, with senior management endorsement of the importance of the TMF, are much more likely to establish TMF mastery. Turning the TMF into an Asset Ensuring compliance, avoiding inspection findings, and staying away from the last-minute dash, as well as the required heroics to be ready for inspections, are all very good reasons for a company to get control and stay on top of its TMF. With that in mind, there is a much bigger prize at stake. Biopharmaceutical companies are realising more and more that they are, in fact, data-driven organisations. It is a bit of a headscratcher that a trial master file, which is effectively the complete record of a clinical trial, is not seen as a valuable data set. Combine that with the fact that there is one for every clinical trial, and one gets a sense of the scope and richness of these data sets – all the more so when there is a significant number of them.

Ben Enejo Ben Enejo is a Senior Consultant with Arthur D. Little and UK Head of the Life Sciences practice. His expertise is in major business transformation initiatives, particularly across global pharmaceutical and device companies. Ben holds a B.Sc. in physiology and pharmacology, an MSc in molecular medicine, and an MBA. Email: enejo.ben@adlittle.com

Ben van der Schaaf Ben van der Schaaf is a Partner with Arthur D. Little in New York. He advises biopharmaceutical companies on complex operational matters of strategic importance, including digital and operational transformation and transactions and alliance management support. Email: vanderschaaf.ben@adlittle.com

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Technology

Cardiac Imaging in Clinical Development: The Benefits of Advanced Imaging Management Systems Individuals involved in drug development are faced with many different challenges along the process of seeking regulatory approval. Imaging plays an important role in the assessment of the effectiveness and safety of new drugs or medical devices, and this article will focus on the role of cardiac imaging in clinical trials while acknowledging imaging’s role may also span non-clinical drug development.

Successful drugs have a well understood and positive risk-benefit profile in terms of safety and efficacy. Cardiac safety adverse events, such as ventricular fibrillation, ventricular tachycardia or Torsades de Pointes, are a major point of emphasis in drug development1. As such, the US Food & Drug Administration (FDA) requires cardiac safety monitoring during the clinical development of new medical treatments2. Cardiac imaging is often used to meet this important safety requirement, and also has an obvious role in evaluating the efficacy of cardiovascular drugs during clinical development.

Yet, the imaging required to monitor for cardiotoxicities during clinical development can, at times, be treated as a perfunctory task. The fact is, for cardiac safety and efficacy trials, as in all multi-centred trials involving imaging: it matters how images are taken, how they are analysed, and how the process is monitored. The quality and capabilities of the imaging management system – the process and tools used to collect, share, interpret, and store images – has an appreciable impact on patient safety as well as trial costs and timelines. Importantly, clinical teams must understand the regulatory requirements or guidances available and apply the correct approaches to collecting the relevant clinical study information. “Ensuring that imaging is managed expertly – including the use of the latest technology and careful oversight – has a broad implication for patient safety as well as trial cost and timing.” – Joseph Pierro, M.D.

Cardiac Imaging: Essential in Clinical Trials Imaging is commonly used as a biomarker for safety in clinical development and in many trials is the primary efficacy endpoint. Echocardiography is widely used to assess symptomatic and asymptomatic cardiac dysfunction and to grade the severity of the condition; the results are surrogate markers for cardiac safety or efficacy. The rapid development and availability of modern imaging technology being deployed in clinical trials allows for the identification of potential pathological changes earlier (e.g., decline in left ventricular ejection fraction (LVEF) or end systolic volume, acute myocarditis, and valve leaflet thickening). Given the complexity of imaging services being required in today’s trial designs, study sponsors reach to the expertise provided by imaging core to fill internal team knowledge gaps. Such assessments are performed in order to (Figure 1):

The cardiovascular system can be assessed through a wide variety of imaging modalities which provide objective and reproducible methods to evaluate the clinical effectiveness of the study drug, i.e., impact of therapy on the disease state or heart function. These techniques include non-invasive and invasive techniques, such as: • • •

Ultrasound (echocardiography, intravascular ultrasound or IVUS) Multiplanar anatomic, functional (e.g. stress testing techniques) Quantitative imaging techniques including angiography, CT, MRI, molecular medicine SPECT and PET imaging

Experienced clinical development teams understand and apply the evolving body of clinical research and therapeutic-level recommendations to clinical trial protocols in order to monitor for these cardiac conditions. 62 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 1: Modern imaging technology allows for the identification of potential pathological changes earlier in clinical trials Spring 2020 Volume 12 Issue 1

Technology • • •

• • •

Make go/no-go decisions for continued drug development Understand baseline and post-treatment risk-benefit determination Assist in identifying high-risk subgroups within the population (for example risk stratification of subjects with low ejection fraction, low or ventricular volume or coronary artery calcification score) Screen subjects for protocol eligibility Detect disease progression or lack of treatment efficacy Monitor patients for treatmentemergent changes which may indicate treatment effect or necessitate the need for dose adjustment or treatment discontinuation.

The study team will recommend the monitoring frequency based on an understanding of the drug’s mechanism of action, the intended patient population(s), the therapeutic or toxicity profile, and a review of prior clinical and non-clinical data. As mentioned earlier, regulatory precedents in terms of prior approvals of similar drugs, i.e. a similar therapeutic class, as well as relevant guidance documents should be incorporated into the planning processes to meet FDA’s increasing expectations that imaging be performed in a robust manner. Early detection and diagnosis of the lack of cardiac efficacy or potential cardiotoxicity is, of course, important, as the goal in the latter example is to be able to medically intervene, prevent delayed effects, and improve outcomes for the patients when appropriate. And, should the investigational product need to be re-engineered in the lab, it is better to determine this as early as possible in the development path. Increasingly, echocardiography is the primary assessment tool for cardiac safety assessments, given its advantages of wide availability, lower cost, and the improved detection three-dimensional methods afford. Imaging: A Critical Factor in Patient Care and Data Integrity Several factors can impact the quality of data produced through echocardiography, as with other imaging modalities. www.ipimediaworld.com

First, the imaging technologist is the person acquiring the images and the individual’s skill, experience, and knowledge can influence the quality of the image. Second, there can be variations in how the image is acquired, such as the display, resolution, and scanner parameters that are related to the equipment itself. And third, how individual readers interpret the images can – and does – vary.3 This point is important when considering the inclusion of sitedetermined image interpretations. Numerous studies have reported on the diagnostic or interpretative differences between site physician readings and those performed by a centralised imaging core lab, where higher levels of process standardisation and adjudicated imaging reports (i.e. 2 + 1 reader model) may be provided to the sponsor.4,5 Studies conducted since 1947 have measured diagnostic discordance in the 25 per cent to 40 per cent range and the clinical team should understand or consult with available imaging or statistical experts regarding the potential impact that this level of discordance may have on study power and endpoints.4,6,7 In fact, FDA’s guidance document (2018) recommends that sponsors use multiple independent reviewers to evaluate each subject to control for errors, variability, and read quality, stating “We anticipate that a centralised image interpretation process may provide more verifiable and uniform reader training as well as ongoing management of reader performance, helping to ensure quality control of the images and their interpretation and to decrease variability in image interpretations, leading to a more precise estimate of treatment effect.”8 Additionally, wide variability in both quantitative and qualitative echocardiography assessments is recognised in recent expert society guidance publications offered by both The European Society of Cardiology (ESC) and The American Society of Echocardiography (ASE). Errors and inconsistencies can have a direct impact on patient care, as well as

on the chance of regulatory approval for the investigational product. Thus, there’s a need for a comprehensive approach to ensuring that image acquisition techniques are standardised, that images are appropriately collected to the highest quality standard across multiple sites, and that the images are evaluated consistently to support study protocol endpoints. That’s why imaging documentation, imaging management systems and active reader management practices are critical. Further emphasising the above point, the recent ASE Echocardiography Report recommends the use of a centralised echo-reading laboratory in multicentre clinical trials.9 Imaging Management Technology: Added Transparency, Reduced Risk Today’s imaging technology platforms can help reduce the chance of human error, speed the assessment process, increase objectivity and consistency, and improve patient safety. A single system is used to collect the source data (which is input directly by the clinical trial site staff), manage image analysis, report on the results, and archive records. Because the data are always contained in the same system, there are no delays or errors caused by transferring it between different platforms to perform various operational tasks. This, in fact, eliminates virtually 100 per cent of transcription errors. Furthermore, a consistent process is applied using standardised procedures in a common viewing platform. The best systems available provide: •

Real-time Safety and or Efficacy Monitoring. Imaging results are collected at the clinical site and are immediately available at the clinical institution, so safety and efficacy signals can be identified at once for clinical decision-making. They are also immediately available to ensure images are performed according to professional standards/guidelines and are available to the independent or blinded readers (BICR) so that they can make their independent assessments. The results can also be shared with other stakeholders such as sponsors, cardiac advisory boards, and data and safety monitoring committees. INTERNATIONAL PHARMACEUTICAL INDUSTRY 63

Technology •

•

Visibility to all Study Data in Near Real Time. Trial managers and medical directors have total visibility to all study imaging data, throughout the imaging life cycle. They can: • View reader assessments • Monitor intra-/inter-reader variability • Measure the degree of discordance between site-based and blinded, central readers • Track the number of cases requiring adjudication • Monitor for selection bias in adjudicated cases Such insight into reader workloads and performance makes it possible to quickly address issues around reader drift, variability, and bias, thus minimising their impact. If, for example, it becomes clear from the metrics that a reader’s approach has changed, re-training can be provided so that the reader’s performance is consistent with others in the reader pool. Automated Workflows. The system delivers reminders and gives users automatic prompts so that images pass through the agreed-upon workflow from reader to reader to adjudicator as efficiently as possible. The process is not dependent upon a project manager to keep it on track. Software-guided & AI-Assisted Reads. Image analysis software can direct a reader through the analysis of each imaging time point and even pre-process and segment anatomical structures of interest in lockstep with the study’s imaging charter and image evaluation protocol (IEP). This minimises protocol deviations and ensures that each reader’s unique bias does not creep into the analysis process by focusing the reader on targeted endpoints whose workflows are outlined in the trial-specific IEP. Artificial intelligence (AI) can be used to augment human assessment. Using AI in this way can reduce read times by as much as 50 per cent and the need for adjudication by 20 per cent. It

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would, in the process, increase speed and reduce costs. Ensure image acquisition techniques are standardised, that images are appropriately collected to the highest quality standard across multiple sites, and that the images are evaluated consistently to support study protocol endpoints. Active Reader Management: Added Efficiency and Effectiveness An imaging core lab will be concerned with all of the controllable factors that impact data quality, from data collection to image review and data analysis. The best practices of an imaging core lab include: • Ensuring that the imaging endpoints support the protocol • Selecting a limited number of independent readers based on their training and experience • Managing the image assessment – starting with standardising the imaging protocol, training on the system and reading endpoints or study criteria • Monitoring reader performance periodically during the study to lower variability and adjudication rates (readers are asked to re-read cases to identify performance drift) • Reporting on imaging status and reader performance with recommendations for discussion with the sponsor and intervention(s) if needed The lab’s ability to monitor reader performance and oversee imaging progress is dependent upon the capabilities of the imaging management software. Achieving Success: Tips for Sponsors Ensuring the validity of cardiac imaging data points is difficult, and the challenge must be addressed early in trial planning to both protect patients and the integrity of the trial itself. Sponsors should: •

• •

Look to both positive and negative results in early trials to determine the potential predictive value of cardiac endpoints. Identify patients likely to benefit from drug treatment or are at risk for cardiotoxicity and determine the risk-benefit balance, for example,

balance survival benefits with reduced cardiac risk relative to a patient’s quality of life. (There is a higher tolerance for adverse events in oncologic treatments, and the benefit/risk balancing point is different than in other disease states.) •

Clearly define the protocolrequired cardiac assessments and measurement parameters to be obtained during the echocardiogram or other imaging modalities. This will help the clinical team understand the patients’ clinical course and inform decisions on treatment adjustments that may be needed to maintain or restore normal cardiac function. The protocol should include details on the number of imaging findings required, together with information based on statistical analysis to assist investigators in managing patients.

•

Establish a baseline of cardiac performance prior to treatment, perform serial assessments during the trial, and conduct a follow-up assessment post-therapy.

•

Pay particular attention to the technologies and processes used to ensure accuracy in how images are taken and interpreted (See Box: Questions to Ask Your Imaging Partner). Questions to Ask your Imaging Partner in Cardiac Imaging Trials • • • • • • • • • •

Which system is used to collect imaging endpoints? How quickly is data available? How easy is the analysis? How precise are the assessments? What is the expected rate of reader discordance? What is the optimal number of independent readers for the trial? What has the adjudication rate been on similar trials? What process is used to monitor the timeliness and accuracy of reads? What process/technology is in place for creating an audit trail and ensuring compliance? What systems and training are in place to ensure that sites know how to follow the imaging protocol? What process or standards are used for the image archive process?

Spring 2020 Volume 12 Issue 1

Technology Conclusion Ensuring that imaging in cardiac safety and efficacy trials is managed expertly and with the benefit of the latest technology and careful oversight has broad implications for patient safety as well as trial cost, timing and trial success. Overall error rates can be reduced by as much as 20 per cent, read times can be reduced by up to 50 per cent, and adjudication rates can be cut by 20 per cent. REFERENCES 1.

Klepper Michael J, Cobert Barton, Drug Safety Data: How to analyze, summarize, and interpret to determine risk, first edition, 2011 Guidance for Industry, Cellular Therapy for Cardiac Disease. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research, Center for Devices and Radiological Health, October 2010

3. 4.

6. 7.

Colin G Miller, Joel Krasnow, Lawrence H Schwartz, Medical Imaging in Clinical Trials, Springer,2014 Birkelo CC and others. Tuberculosis case finding; a comparison of the effectiveness of various roentgenographic and photofluorographic methods, J. Amer. Med. Assoc. 1331:359-66, 1947. Abujudeh, HH et al. Abdominal and pelvic computed tomography (CT) interpretation: discrepancy rates among experienced radiologists; Eur Radiol (2010) 20: 1952–1957 Pinto A et al. “The concept of error and malpractice in radiology,” Seminars in Ultrasound, CT, and MRI, 2012, Elsevier Ford R and PD Mozley (2008) "Report of Task Force II: Best Practices in the Use of Medical Imaging Techniques in Clinical Trials." Drug Information Journal 42(5): 515-523. FDA guidance 2018. United States Food and Drug Administration Guidance for Industry: Standards for Clinical Trials Imaging Endpoints. FDA Rockville, MD. American Society of Echocardiography Recommendations for Use of Echocardiography in Clinical Trials A Report from the

American Society of Echocardiography’s Guidelines and Standards Committee and The Task Force on Echocardiography in Clinical Trials, Writing Committee: John S Gottdiener, MD (Chair), James Bednarz, BS, RDCS, Richard Devereux, MD, Julius Gardin, MD, Allan Klein, MD, Warren J Manning, MD, Annitta Morehead, BA, RDCS, Dalane Kitzman, MD, Jae Oh, MD, Miguel Quinones, MD, Nelson B Schiller, MD, James H Stein, MD, and Neil J Weissman, MD; J Am Soc Echocardiogr 2004;17:1086-1119

Joseph Pierro Dr. Joseph Pierro, MD Medical Director, Imaging, has over 30 years of expertise in the field of radiology and over 20 years of clinical trial research & development experience, which includes global senior level positions held within the pharmaceutical industry and as a medical reviewer at the FDA Center for Drug Evaluation and Research. In his current role, Dr. Pierro provides scientific, clinical and radiologic imaging guidance that enables biopharmaceutical companies to successfully implement ERT’s advanced imaging solution during the clinical development of new medical products.

David Raunig David has Raunig, PhD, Senior Principal Imaging Statistician, ERT. 20+ years of experience integrating current medical, scientific and statistical techniques into the collection and analysis of imaging data during the development of new medical products. As Sr. Principal Imaging Statistician, David is responsible for driving the quality of ERT’s imaging solution by integrating regulations, operations and statistics into the conduct of clinical trials. Previously, David held senior leadership positions with global pharmaceutical and clinical research organizations, including Bristol Myer-Squib, Icon Medical Imaging, and Pfizer.

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Technology

Electronic Laboratory Notebooks: Addressing Data Security and Privacy Concerns From 21 CFR Part 11 to GDPR: Evolving Standards for Managing Data With the introduction of 21 CFR Part 11 in 1997, research laboratories and their software providers have been under an increasing burden to provide proof that data captured electronically is managed in an immutable fashion. Records must provide a complete pedigree from the original state through each edit, including who made the changes, what the changes were, and the date of each change. As GDPR impacts laboratorybased software, this audit trail must be preserved while maintaining compliance with a complex set of new data privacy requirements. These two contrasting requirements are also challenged by the changing landscape of drug discovery and development. The concept of a single company managing the complete life cycle of new drug development has been replaced with an ecosystem of partner networks that change as drugs move through the development pipeline. The ability to share data and collaborate in real time creates new challenges in information security, data integrity and identity management. This change in paradigm is magnified by the changing demographics of scientists within the lab. With each passing year, scientists are expecting their user experience within these complex enterprise tools to be comparable with the experience they get using consumer applications like Facebook or banking applications on their mobile platforms.

It is important for software providers to manage each of these challenges and provide innovative solutions to maintain market position, or open new lines of business, in this new reality. Each aspect of data management must be individually considered to ensure each aspect involved in a data management platform. These “separations of concern” include data capture and preservation, security, privacy and user experience while considering both regulatory compliance and product usability. Separations of Concern to Meet Regulatory and Business Requirements Designing an enterprise data system in a highly regulated market requires satisfying several sets of regulatory and IT requirements, including: 66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Technology • • • •

Relevant regulatory requirements such as 21 CFR Part 11 and GDPR Information security, including data at rest and data in motion User authorisation; ensuring that this secure data is accessible to those who need access to it Data retention

Meeting the requirements above can make it challenging to address the concerns of the user community, who are generally voicing requirements such as: •

• • • • • •

Ease of use, both in terms of a modern and intuitive user interface and efficient support of common end user workflows Easy access to the system from any location for partners, CROs and employees Fast, easy-to-use search providing up-to-date search results Ability to configure and automatically run reports / searches Access to robust system administration and configuration tools Overall system performance API access providing data accessibility

These needs require separating enterprise systems into different functional areas: Data management, information security and data access. Data management refers to the entire data life cycle from data collection and retention to infrastructure and data redundancy. Information security is responsible for all user authorisation (but not necessarily user authentication) and should be as granular as possible. Ideally, information security services provide field level and user/group level information on whether a specific piece of data can be viewed, edited, or added. Data access encompasses all access to any data within the system, including vendor-provided applications, internal applications, end user scripts and queries, APIs, etc. Systems should provide robust APIs for data management, information security and data access. Allowing them to operate as independent services across the enterprise ensures broad access but only in cases where that access is authorised. It also allows a wide range of workflows and end user tools to be layered on top of these core www.ipimediaworld.com

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• • •

conclusions collected from end users Document and specification management systems Inventory systems – Location and container management for materials, reagents, etc. Registration systems – The management of intellectual property data

SDMS systems require the ability to automate data capture from scientific instrumentation. This could be a single record of a series of files and folders that provide a complete record unit. These systems should operate in an automated fashion, sweeping a network looking for new or modified data. Once found, this data is moved into the system with the appropriate metadata. The system must ensure that this process does not alter the original data in any fashion. The data also must be able to be accessed using the instrument manufacturer’s software with no loss of data fidelity. This capture and management of instrument files is in sharp contrast with specification management, registration, LIMS and inventory systems. These systems are configured to manage highly structured data sets that can be predefined before rollout. The forms utilised by the systems allow data verification by type and value to ensure quality of the asset they are tracking, as well as validity of the data entered. ELNs require management of structured and unstructured data. These systems are expected to provide both field-based data capture and the ability to manage all types of unstructured data from any number of sources, including MS Office, images, PDFs, chemical and biological drawing tools as well as results loaded from instruments.

services, while enforcing compliance with key regulatory and business requirements. The Spectrum of Data in Life Sciences Current data management solutions in the life sciences vary greatly in terms of the types of data they are designed to manage: 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

• •

•

Scientific data management system (SDMS) – Management of raw instrument data Laboratory information management system (LIMS) – Management of sample data with processed instrument results Electronic laboratory notebooks – Experiment data, observations and

While each system captures and manages data for different business purposes, they must manage the entire life cycle of the data from creation to destruction with a full audit trail record. They all must provide means for different access controls to the data from create and manipulate to read only and approve; each data system has similar but distinct requirements to meet these challenges. Spring 2020 Volume 12 Issue 1

Technology Data security issues exist across the entirety of the life cycle of data created in the laboratory. Customers must consider how conceptual, experimental and raw instrument data is secured in a manner that ensures no loss in fidelity or control through this process. Each of these systems provide challenges throughout the process. Customers must ensure that raw data captured from their systems is stored as a complete unit, with all the parameters required to reproduce both the raw data and the results generated from these systems. Each change to the data must be preserved in an audit trail. The configuration of an SDMS system to do this must not allow alteration of data external to the system. Controlling both the network access and the data access is paramount to managing data security. This capture and management of instrument files is in sharp contrast with specification management, registration, LIMS and inventory systems. These systems must allow customers the ability to set permission levels for all potential roles from read only to administration across all potential areas like project or product. By securing the data by individual, role and project, only the right individuals have the right access to the data. ELNs require management of structured and unstructured data. These systems are expected to provide both field-based data capture and the ability to manage all types of unstructured data from any number of sources. Decisions on what data should be placed in which solution must be made to ensure both data security and collaboration. Controlling data capture and access secures the data and provides controls on how internal and external collaboration teams can manipulate information. All systems from SDMS to ELN also need to ensure data security against external malicious access. Each system must provide controls against data breach, both on the front and back end of a solution. While providers can ensure their solution prevents attack, controlling a customer’s environment is impossible, potentially leaving systems www.ipimediaworld.com

open to infiltration or down time if a company suffers a malware or other attack. Solutions will Inevitably be Cloud-based Cloud-based solutions eliminate many data security issues associated with on-premise systems, such as many sources of malicious attack. Abstracting these systems benefits customers in two ways: 1.

Data captured can be stored in different cloud systems. Moving the data from multiple solutions on a centralised system to federated cloud storage significantly reduces the ability to understand context and meaning of any single data source. Infected systems can be isolated and corrected without impacting the hosted solutions. This greatly reduces downtime associated with malware attacks within a network. Any system outside the affected network can be provided access as required.

Data management in the cloud provides a cost-effective, real-time scaling of enterprise systems when properly designed and deployed. Internally deployed systems require both hardware and software platforms that require maintenance for continued performance at scale. These systems must be “specified” at deployment and updated as software and hardware updates are made. Redundant systems must be maintained (development, test and build) to ensure that any changes made to either the infrastructure or software solution does not impact the validity of the data stored within the system. Data storage must be managed to allow for new data stores to be purchased and implemented, introducing increased requirements of oversight. As new capabilities are released by software providers, these systems must undergo formal testing on test and production environments to ensure both that the system is working properly as specified by the software provider and that the new capabilities are impacting existing capabilities within the system or with any other system that interacts with. These requirements lead to long planning and validation

timelines for both initial release and all future feature updates. These systems also exist within a company firewall. This provides challenges in two key areas of system design outlined above: 1. 2.

Data access: How can external collaborators add data in a secure, auditable manner? Information security: How can the data be managed to ensure security?

Properly architected SaaS systems scale on demand eliminating infrastructure-related issues. These systems also abstract software infrastructure including operating systems and database solutions, allowing support of these systems to be focused on meeting end-users’ needs. Upgrades and feature enhancements are also isolated to allow customers to prepare for new capabilities, but these systems do not co-exist with any other solution limiting impact of an upgrade on other systems. Finally, most cloud-based systems provide restful APIs eliminating issues associated with integration continuity as versions of either platform are changed. Information security and data access are also significantly improved in the cloud. External collaborators can be granted appropriate access to add or receive data, without penetration into a company firewall. Access from internal contributors is provided by roles and privilege, allowing users to see all data required to perform their function, but not access controlled data. This eliminates data from leaving the organisation through copying, USB drives, etc. Data Access Modern life science organisations operate in a new, collaborative innovation model that requires data to be captured and shared across multiple contributing companies providing their specific expertise to a project, but also requires solutions that understand what data should be sharable among collaborators and what data should only been seen by either the originator or the sponsor organisation. This burden is typically managed manually by each contributor manually INTERNATIONAL PHARMACEUTICAL INDUSTRY 69

Technology

creating files with the appropriate information. These files can then be placed for file level access, control and security. Data reduction, transformation and loading becomes increasing complex and new file types and formats are added to a system. These files also provide an all or nothing approach to information security. The file can either be accessed or not. Information Security New, properly architected solutions must allow for both a high degree of

collaboration and discrete controls on data access. These systems should allow for configuration of access, quality, type and state of data and then these elements should be positioned within a scientific process. These discrete fields would then be available only to authorised users at the current state of a process. This allows for just-in-time data security. By providing both data typing and limits, new systems should also provide just-in-time data quality allowing for real-time correction of data regardless of the user’s location. This eliminates delays from data receipt to data available in highly federated and collaborative operations. Summary By reducing enterprise systems into three key services of data management, information security and data access, we can solve many of the current challenges faced in the life science industry. As

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collaborative innovation continues to take hold as the dominant research and development model, the challenges of legacy systems will continue to create challenges to this new model.

Jeff Carter As COO, Jeff oversees commercial and operational functions at Arxspan. He has nearly twenty years of experience in scientific informatics and cloud computing, including more than ten years of software development experience. Prior to joining Arxspan, Jeff held various technical and commercial positions at CambridgeSoft, a provider of chemical informatics software products and Amazon.com. Jeff has a B.S. in Chemistry from the University of Massachusetts at Amherst.

Spring 2020 Volume 12 Issue 1

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Manufacturing

Help Your Tablet Tooling to Pack a Punch with Essential Maintenance Measures Ensuring tablet punches and dies are kept in optimum condition to produce high-quality tablets is critical for productivity and overall equipment efficiency (OEE). The reality is, however, that tablet compression tools are often viewed as consumable items, therefore maintenance can be seen as unnecessary and time-consuming. This can be a costly mistake and directly affect production. Keeping tooling in good working condition not only reduces tablet press downtime, but also minimises compression problems. When combined with a management system to monitor all aspects of the punches and dies, high-quality tablets are produced quickly and efficiently.

Consequences of Poor Maintenance Practices There are many problems which are a result of badly maintained tooling from poor handling through to insignificant monitoring. One of the most common is sticking and picking. When in an optimum condition, the surfaces of a tablet punch face are usually polished to a high mirror finish (the exception to this are textured finishes designed to alleviate specific sticking issues). This

Implementing an effective E-leaning programme can be an invaluable initiative to improve productivity.

finish can deteriorate over a period of time due to the continuous compaction of granules. This deterioration can lead to tabletting defects like sticking which occurs from the adhesion of the granule to the worn uneven finish. This degradation in the tool’s surface can be identified during proper assessment and rectified by cleaning granule from the surface and through polishing. When required light polishing using an automated polishing system

To achieve optimum lifetime and performance from tablet tooling use a planned 7 step maintenance process. 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

is recommended, this should enable a smooth and efficient surface to be maintained, thus aiding the reduction of sticking and picking issues. Get a Handle on it Damage through handling is another familiar problem when it comes to tooling defects. Approximately 80% of damage to punches and dies is caused accidentally when handling the punches through the production and tool care processes. This ‘accidental’ damage can lead to significant production failings. It is important to understand the delicate nature of the tooling and treat it with respect.

80% of damage to punches and dies is caused accidentally when handling the tooling. Ensure they are handled correctly to prevent damage. Spring 2020 Volume 12 Issue 1

Manufacturing

Measurement is an essential step after any repair to tooling.

There are several stages of the tablet manufacturing process where damage can take place, including unpacking the tooling, loading and unloading the tools in or out of the tablet press, during tool cleaning and maintenance procedures as well as through storage and transportation. If damage occurs, it can lead to the production of poor-quality tablets, and even further damage to both the tooling and the tablet press. It is, therefore, important to implement and operate good tool care, maintenance, storage and handling procedures.

tested maintenance procedure to ensure tablet tooling is a kept in a workable condition. The most effective process should include the seven steps of clean, assess, repair, measure, polish, lubricate and store. These are designed to provide a consistent approach to tooling maintenance and aid production at all times. The steps should become a standard operating procedure (SOP) within tablet production and used consistently to ensure punches and dies are clean, undamaged, within specification and ready for use at all times.

Reducing Ringing Die bore wear or ringing is another defect which can lead to problems such as tablet capping where the tablet separates horizontally from the main body, forming a cap. This can also cause tablet ejection issues, resulting in reduced tablet output. Ringing is caused by abrasive wear and deformation from continuous forces acting on the face of the die bore. This type of wear can be reduced by utilising the zones in the die bore where the tablet is compacted or by the selection of a harder more wear resistant die material. However, unless maintenance procedures are put in place where wear can be monitored and identified through early diagnosis and assessment measures, the negative effect on tablet output will increase.

Cleaning is Essential The first and most critical stage in the seven-step maintenance process is to clean the tooling. Punch and die cleaning is essential for the removal of residue and to avoid product contamination. It also reduces potential production issues such as sticking. Cleaning also allows for an accurate assessment of tooling condition during further processes within any maintenance schedule. If the procedure is not carried out effectively, it will have a negative impact on the subsequent steps in the maintenance process. For example, if punches are not adequately clean, visual assessment of the punch tips and die bores for signs of wear, damage or corrosion will be difficult. This can then lead to problems like die bore ringing.

Implementing Structured Maintenance Procedures To alleviate these production problems, it is important to adopt a tried and www.ipimediaworld.com

Cleaning also helps to highlight damage to the delicate punch tip edges, which are seen in the form of nicks and bruises which can cause burrs and occasionally chipping. These defects can eventually lead to more

serious failures such as punch tip breakage. When tooling is removed from the tablet press, it must be thoroughly cleaned to remove any oil or product residue, particularly from difficult-toreach areas such as embossing and keyways. One of the most reliable cleaning methods to remove all deposits from the tablet tooling is through ultrasonic cleaning. Ultrasonic baths allow for consistent cleaning results, reduced processing and operator time and reduced risk of tablet contamination. Importantly, ultrasonic cleaning allows for the whole punch to be cleaned, including in and around the embossing. It is essential, however, that the process does not cause corrosion of the tooling material, therefore a corrosion inhibitor should be used during the process. Assess Your Tooling Step 2 and the next process in any well-planned maintenance procedure is to assess the tooling. Punches and dies should be visually inspected to establish if the tablet production process is running well and to identify whether any tooling maintenance is required. Assessment can be carried out visually using an eye glass or a high-magnification camera/lens. Close up inspection of the punch tips and cups, die bores, embossing and land will help to identify defects and wear. One typical problem that can be identified through this step is head wear. This is when areas of a punch that are in contact with other parts of the tablet press and are subjected to INTERNATIONAL PHARMACEUTICAL INDUSTRY 73

Manufacturing high-speed frictional and compaction forces resulting in excessive wear. It can derive from a number of causes, but more commonly it is due to punch tightness and/or poor lubrication. It is important to remember that identifying damage off the tablet press is by far a more efficient method when it comes to time and capital than running tablet production with faulty tooling, hence, step 2 – assess is crucial. Repair Damage Step 3 is the repair stage. This allows the user to rectify minor damage to the tooling. Light surface wear, corrosion and minor damage can be repaired and re-worked to a useable condition. Minor damage and corrosion can be repaired using a motorised chuck with double-ended polishing motors used in conjunction with abrasive polishing accessories. In all cases, it is important to remember that repair to punches and dies should only be carried out when necessary and only by trained and experienced maintenance technicians in order to ensure that the tooling does not exceed tolerance limits. It is also worth noting that repair should not be carried out on any coated tooling as this may remove the coating from the punch. It’s All in the Measurement Step 4 – measure – is essential after any repair. Critical tooling dimensions must be maintained within an acceptable

working tolerance range to ensure accuracy and quality throughout the manufacturing process. The equipment for measuring tablet tooling can range from simple handheld micrometers, vernier callipers and height gauges, to semi-automatic, computerised digital gauging systems. The use of digital measurement systems allows for dimensions to be taken consistently, reducing the risk of manual data entry errors. Even if a repair has not been necessary, measuring should be carried out at regular intervals, to check for natural wear during the compaction process. The essential measurement is the critical working length of the punch, as this controls tablet thickness, weight and ultimately dosage. Importantly, as the punches are already clean and assessed, outside influences to measurement such as oil or compacted granule will not interfere with measurement data. The Benefits of Polishing A good cleaning regime goes hand in hand with a good polishing regime. It is cleaning and polishing that delivers the most noticeable benefit in production, reducing tablet press downtime and helping to increase productivity. Step 5, polish, is extremely important and should not be underestimated. Automated polishing is crucial to ensure punches are evenly polished to a consistent finish. This stage

also helps to produce the optimum and consistent tooling condition. By following this step, costly tablet press downtime caused through poorly maintained tool surfaces will be reduced. Polishing can be achieved through manual or automated methods but due to the controlled and repeatable process, adoption of an automated polishing regime would always be preferable as all punches are polished to a uniform finish. Manual polishing can be unevenly abrasive and extra care must be taken not to deform the tip profile and embossing, causing a deviation from the tablet specification. Extensive polishing of die bores is not recommended as this can easily alter the size and geometry of the bore, leading to ejection problems and incorrect tablet size, weight and dosage. Only light polishing or cleaning should be undertaken, and the end result should be a mirror finish and smooth tooling surface. Protect and Preserve Step 6 is lubrication, a necessity as it serves to protect, preserve and support continuous press tooling operations. A non-toxic, FDA compliant oil or grease is recommended for this step, and a product that offers machine component protection and lubrication performance with a wide temperature range, to ensure it can be used in all equipment.

Polishing using an automated polishing system is recommended to enable a smooth and efficient surface to be maintained. 74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Manufacturing It is important to maintain longevity and extract the maximum life from tablet tooling. Following a consistent seven-step process will aid in this ideal to ensure punches and dies are always ready for production, with the assurance that they are clean, undamaged and within specification. Manage Your Tools Effectively We now know why the application of a planned seven-step maintenance procedure is important for productivity and OEE, but how do we know it is being adhered to? To establish compliant, efficient and accurate maintenance of punches and dies, it is important to implement an in-depth computer-based monitoring system. This should work seamlessly alongside your planned seven-step maintenance process. Polishing using an automated polishing system is recommended to enable a smooth and efficient surface to be maintained.

Store Securely Last but not least is step 7, store. Tooling storage and transportation should be specifically designed and developed with high security and safety handling considerations a priority, as this reduces the probability of damage and deterioration. There are many methods for storing punches and dies, from specially designed plastic storage boxes to custom designed and built storage cabinets, all of which provide high levels of protection. The tooling itself must be separated to ensure it avoids contacts with other punches and so that the tooling condition does not deteriorate during storage. Due to the nature and weight of tablet tooling, storage should also ensure safe handling for operators, and so tools should only be moved when necessary. Apply the Seven Steps to Your Production Application of the seven-step process will have a direct impact on the reduction of many common tablet and tooling problems, resulting in a betterquality end product and direct time and cost savings for the tablet manufacturer. www.ipimediaworld.com

Within pharmaceutical manufacturing, the importance of knowing where tools are, and what condition they are in, should be a priority. Without this information, either unnecessary tooling replacements are made, reducing productivity, or punches are deployed when they should be in maintenance or replaced. This then leads to problems with the end tablet when it is found that the tooling being used does not meet the highly demanding process of tablet manufacture. Rejected tablets, wasted formulation and press downtime is the usual result. A tool management system will help to assess and monitor the life of the tools, prioritising maintenance activity by creating an ‘action’ list. Any tool problems like wear to punch heads can be detected before they impact on production. A tool management system is not just important for maintenance history, it is also essential in satisfying regulatory procedures and complying with legal requirements in tablet production. It can consistently record a completely 21 CFR part 11 compliant audit trail of all production and maintenance. The data can also provide information to effectively measure areas of performance by way of showing what and how many products have been produced and a summary of any production issues experienced. Overall, it ensures that tooling is never a cause for delay in the production schedule.

Training – the Icing on the Cake When it comes to tablet tool maintenance, it is all very well implementing a seven-step process and tool management system, but unless all those involved in the tablet production are singing from the same hymn book, these processes may not work as effectively as they could. Online training may be the answer. Implementing an effective e-leaning programme can be an invaluable initiative to improve productivity and ultimately the quality of the end product in pharmaceutical manufacture. Investment in tool management software and maintenance processes can be compromised without trained and knowledgeable staff in place. The workforce must know how to undertake tooling care maintenance efficiently and the processes involved in managing the procedures. Make Tool Maintenance Routine Adopting a simple structured tooling maintenance process is essential to obtain the maximum life from punches and dies. Its success comes down to three main elements: 1 – the implementation of a seven-step maintenance process, 2 – a management system to monitor all tools and finally, 3 – focused training so all operators and managers work to the same standards and procedures. Applying these recommended ‘best practices’ will extend the tool’s usable life significantly, resulting in increased productivity and tablet quality.

Alex Bunting Alex manages the marketing team at I Holland, is a graduate of English and member of the Institute of Digital Marketing. He joined I Holland in April 2008 having spent the previous years working in Environmental Science. Alex was instrumental in the design of the 2010 edition of the widely adopted Eurostandard, educational animations and hosts I Holland’s extensive webinar program.

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Generic Solid Oral Immediate Release Products in the EU – Regulatory Perspectives of Dissolution Specification Abstract Development of a dissolution method with suitable specifications is a key part of any oral drug product control strategy. Dissolution testing is an in vitro technique of great importance in the formulation and development of pharmaceutical dosage forms, as it can be used as a substitute for in vivo studies under strictly defined and specified conditions. The main objective of the present study is to know that the drug release rate is identical batch to batch, and the same as those batches proven to be bioavailable and clinically effective. Results from IVIVC studies have been used to select the appropriate excipients and optimise the manufacturing process for quality control purposes and for characterising the release patterns of newly formulated IR products relative to the references. To facilitate generic drug manufacturers in the arranging of dissolution limits for IR solid oral dosage form for in vitro purposes, the European agency had revealed some guidelines through a reflection paper on August 17, 2017. The limits relate to solid immediate release drug products with systemic action, characterised as having at least 75% dissolution within 45 minutes. The principle is to derive the specification of the drug product on the basis of the quality characteristics of the biobatch. Key words: EMA, dissolution specifications, in vivo behaviour, batch–to-batch consistency

50 years, the apparatus of dissolution has needed non-stop upgrading and changes in order to supply favourable conditions with more variety of products for testing performance. Anyway, on new tablets and capsules, almost ninetynine per cent of dissolution testing was performed. These are evolved for instantaneous launch (IR) dosage forms and are supposed to offer:

below flow chart explains the procedure in steps worried when a normal tablet or capsule shape dissolves. The dissolution procedure may be categorised into three levels: pill erosion/breakdown into granule particles, granule breakdown into initial drug particles, and active pharmaceutical ingredient dissolution. Potential CQAs, potential critical process parameters (CPPs), and potential crucial material attributes (CMAs) are indexed to every three-level procedure.

Trendy suggestions for testing of dissolution method. Various routes for arranging dissolution limits relevant to the biopharmaceutical traits of a drug substance. Methods used statistically for CDP; and The method which helps to check testing of the dissolution method is enough to release a waiver for an in vivo BE study.

In early drug product improvement, wherein exceptional preparations and techniques are taken, modifications of each volume and method will affect each of these dissolution methods variously. Experimentation inclusive breakdown of drug particles, essential active pharmaceutical ingredients dissolution, and granule dissolution will assist in the knowledge of the relevant contribution of every step to the entire dissolution rate.

Discussion To know the complete dissolution method of a finished product, and also to know which components of the preparation and manufacturing process have the greatest effect on in vitro launch charge, are essential in evolving a dissolution method. The

As a part of choosing a quality control dissolution approach to the product, one frequently suffered with the value of challenging and evaluating the discriminatory power of the process. In order to come up with this, it is easy to perhaps know the effect of the aforementioned critical

1. 2.

3. 4.

Dissolution Academic Definition The solid substance, when placed in a solvent, dissolves and forms a solution; this entire process is called dissolution. Pharmaceutical Definition To know the amount of drug substance released from the dosage form, a test called dissolution is used in the entire life cycle of a pharmaceutical drug product. The ultimate test which is used to distinguish the performance characteristics for a solid dosage form is the dissolution test. As dissolution tests have become the unique and more commonly used test for the past 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Single Use Transfer Solutions Providing purity & performance for your products

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Manufacturing process parameters and/or critical material attributes in clinical studies or he may agree to strict limits and mitigate capability biopharmaceutical risk by arranging strict controls during manufacturing. Development of Immediate Release Solid Oral Dosage Form: Method of Dissolution and Exploring Factors

In fasting conditions, the gastric emptying time, i.e. mean T50%, is within fifteen to twenty minutes. According to this data, the final conclusion is that a drug with eighty-five per cent dissolution within fifteen minutes under low dissolution test conditions in 0.1N HCl shows the characters of solution and commonly it shouldn’t have problems like bioavailability. In the case

Biopharmaceutics Classification System: Depending on the solubility and permeability of the drug, the BCS has suggested the below four cases: • • • •

Case 1: High Solubility – High Permeability Drugs Case 2: Low Solubility – High Permeability Drugs Case 3: High Solubility – Low Permeability Drugs Case 4: Low Solubility – Low Permeability Drugs

The biopharmaceutical classification system is used as base for the purpose of arranging dissolution specification limits for in vitro purpose and in the same way it helps as a base for knowing the chances of IVIVC successful dissolution. The dissolution of a drug is known by converting a solid substance into a solution, maximum drug of one unit dose with 1.0 and 8.0 pH in 250ml of buffer solution. If the dose volume or the solubility composition of a particular solution is ≤ 250 ml, then the drug substance is taken as more soluble. If the increase of absorption was > 90% in the lack of known instability in the GI tract or if the permeability is known experimentally then the drugs are commonly highly permeable. In some cases the rate limiting step for absorption of the drug is GI, i.e. the biopharmaceutical classification system for two cases. Dissolution up to 85% in 0.1N HCl within fifteen minutes will guarantee dissolution cannot limit drug bioavailability. 78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

of slow dissolution when compared to GI emptying time, multiple time points of dissolution profile are suggested in various media. In the same way the case 2 expectations will be like a rate-limiting step in absorption of the drug, and in vivo and in vitro correlation will be the drug dissolution. In this group for the drug product, various media dissolution profiles are suggested. In case 4 of the BCS, the rate-controlling step is the permeability and restricted in vivo – in vitro correlation might be possible, depending on comparable rates in dissolution and intestinal transit. In case 4, the drug causes major problem for oral drug delivery. 1. Methods of Dissolution Test Dissolution Technique Development: This process is meant for use as a regular control test. A look at instant release drug products must be strong, reproducible and discriminatory so that you can guarantee a regular product is great and to find out quality attributes of a product, which, if changed, might also affect the in vivo performance. To make improvements in this sort of dissolution method, subsequent elements are specifically to be considered: 1.

The physico-chemical qualities of the active substance depend entirely on the dissolution medium (volume, composition) which is going to be selected and the drug products mean dose range and the method to be examined. Sink conditions may or may not be followed.

In common, primarily pH should be maintained within the physiological pH range and an aqueous medium should be used. The surfactants are not used. If used to attain good enough release of active substances which are low soluble, the known surfactants should be used. The concentration of the surfactant must be maintained very low and it was checked by relevant solubility and dissolution statistics and associated scientific discussion. Dissolution equipment has to be selected by an applicant according to his own needs and should be known about exactly. The starting stage of the dissolution method was done with the paddle apparatus and the speed limit should be adjusted to 50rpm, and in the same way the basket apparatus should start with a speed limit of 100rpm. The known various mesh sizes or different speed limits are used in the method. The higher rotations per minute was known by seeing high changes in the outcome results at low speed rates due to hydrodynamic effects, or possibly because of other factors. Already it was identified that techniques with more rotating limits may be low discriminatory. A rise in rotating limits at the expense of discriminatory power just to minimise the changes of outcome results or to finish the entire dissolution process in less time ought to be averted. A rise in the stirring speed may be accepted in case of over-discriminatory conditions near to in vivo performance. Anyway, in all cases of dissolution profiles, raising the rotation limits ought to bring enough discriminatory power to the finished product QC.

When the dissolution process is developed, the inputs of process parameters to the various outcomes must be investigated and minimised. Suitable Conditions and Discriminatory Power: QC Test Conditions Selection: To permit increased outcomes of BE study from biobatch to commercial batch, it is essential to have an exact amount of active substance released at a given time point. Test conditions ought to allow discrimination among batches prepared by various CPP and/ Spring 2020 Volume 12 Issue 1

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Manufacturing or CMA which might also have an effect on the bioavailability. The other batches which are not bioequivalent have been perfected. The dissolution outcomes, beneath various conditions at some point of development, need to be compared with pharmacokinetic data prepared to pick the most appropriate testing conditions in regular testing. The low in vivo data which is obtained for most generic applications was not possible to know mathematical correlations, but all the related in vivo information has to be considered in deciding on the appropriate in vitro dissolution conditions. Discriminatory Power Demonstration: Appropriateness of test conditions to a common batch test ought to explain utilizing batches with various quality attributes. To accomplish this, batches with correct variations compared with the applied drug product ought to be prepared. Such variations might be relevant to the quantitative formulation and material specifications, and additionally utilise somewhat altered process parameters. Present information which is available on both BCS and the drug product should be considered when selecting the quality attributes to slight variations. For example, for a drug product in which the in vivo absorption is known to have restricted the solubility/intrinsic dissolution of the active substance, for example BCS II and IV, reasonable quality attributes might be the molecule size of an active substance or different attributes that would affect the in vivo dissolution. For drug product in which in vivo absorption is thought to be restricted with gastric discharging or intestinal permeability, for example, BCS I or III class active substance by fast / extremely quick dissolution appropriate quality attributes might be factors in the formulation, as well as preparation methods that will affect the breaking down of the drug product and essentially influence the in vitro dissolution rate. Modifications to the drug composition to make a "bad batch" ought to be enclosed by released qualitative batch formula, and the extent of engaged 80 INTERNATIONAL PHARMACEUTICAL INDUSTRY

excipients might be a variant. Total release with one or more than one excipient from formulation (for example binder, disintegrant) is not supported. The conditions for the testing of the dissolution method ought to have the option to distinguish these modifications by setting appropriate specifications. Ideally, the test for the in vitro dissolution method ought to expect the in vivo result; however, occasionally the tests for in vitro dissolution are not expected due to over-discrimination. This is additionally accepted due to dissolution profiles being changed, leading to in vivo equivalence being accepted. As a rule, in vivo information to the batches with various quality attributes is not present. The conditions setting for the dissolution test are totally based on their ability to identify variations within batches with various quality attributes, and as given modifications are not known to be in vivo related, it is impossible to claim that these conditions for the dissolution test are in vivo discriminative. The finished products, which are BCS class I or III active substances by more excessive solubility towards a physiological pH range and by fast or faster dissolution, may now be impossible to identify any variations with dissolution behaviour after relative modifications by appropriate formulation, material specifications and/or preparation parameters have been made. Within those situations, techniques can be taken as good enough without any more clarifications, or get changed by means of a dissolution test. Batch by Various In Vivo Behaviour Inside Pharmaceutical Improvement: In some situations where more batches of finished product have been tested in in vivo development, leading to batches by suitable pharmacokinetic parameters and those which are not by proper pharmacokinetic parameters, the dissolution takes a look at conditions which must be selected which permit discrimination between applicable and non-ideal batches via putting in place an appropriate specification. The first choice should be given to in vivo discrimination when compared with other influencing factors to the selected method.

Batches with Suited In Vivo Behaviour Present in Pharmaceutical Improvement: Approaching Side-batch Batches showing various in vitro dissolution profiles originated from described manufacturing methods through the way of process parameters below the limit of maximum changes predicted by process validation studies, which are known as “side-batches”. This method profile of side-batch might be helpful in setting appropriate dissolution specified, while BE with the brand product was explained. In case the batches with an intense variety of in vitro dissolution profiles (i.e., fast & slow) are shown to be BE to the reference product, then future dissolution profile batches inside this range are also estimated to be the same. Test Conditions Selection vs In Vivo Trend: For MAA of a test product, BE study between representative batches of test product series versus reference product available on the market must do. Approval standards for BE arrange for the pharmacokinetic parameters area under the curve and Cmax. The latter is warning of rotation speed in vivo in case of a similar area under the curve, and Cmax suggests quicker in vivo dissolution. Corresponding to a bioequivalence, have a look at an assessment of dissolution profiles (n=twelve) of generic and brand batches used in BE study which is necessary for the use of planned test situations of the test drug product. For the examination of in vivo data of the bioequivalence study, it is helpful to know the discriminatory power of the dissolution test. Because of acceptance criteria for BE, the point known for Cmax + the respective 90% confidence interval of the test product should be in limit, i.e. eighty per cent and one-twenty-five per cent (according to the Guideline on Investigation of BE) of the Cmax of the branded product. By following the equivalence rules (contrary to a superiority test, with the goal of discovering statistical significant variations) minor variations not including clinical relevance will accept these criteria as long as confidence intervals are fulfilled by ninety per cent. For these types of cases, the comparison of in vivo and in vitro results Spring 2020 Volume 12 Issue 1

Manufacturing must be done for rank order. If a test product with large Cmax indicates faster in vitro dissolution than the branded product, for suitability of selected test situations, this may be used as an indicator. The more the difference and the less the changes in in vivo point estimates, the greater the option that this variation may also be opposite to in vitro. If possible, in case of a reverse rank order, i.e. a test product with appreciably more Cmax suggests less in vitro dissolution behaviour or vice versa, test situations need to be similarly optimised additionally to replicate the in vivo trend. Batches Without In Vivo Behaviour Incorporated in Pharmaceutical Improvement In some cases, the requirement for BE study was waived depending totally on satisfying criteria, referred to as a biopharmaceutical classification system-based biowaiver. In that case, there was no batch utilised in BA/BE studies or in clinical testing (biobatch) and by analogy, the batch, which has been proven to be the same as the brand product primarily depends on reasonable in vitro dissolution data in a batch of not less than three various pH media taken to be tested.

product administered to the patient, the entire commercial batches ought to display related behaviour in comparison to the biobatch. The dissolution profile of biobatch, using test conditions supplying discriminatory power, has to be used to set an appropriate arrangement. Relative dissolution of two batches might be expected in case of variations of <10% of the label claim of their mean consequences. Therefore, Q value was recommended to be set on the basis of biobatch dissolution result (mean price of 12 units) minus 10%. The recognition criterion, Q value is normally set in the range 75-85% (5% intervals) to illustrate discriminatory and satisfactory dissolution. A maximum value >85% is not related. Usually the time points 15, 30 or 45 mins would be sufficient, but different time points may be used if justified. It does not always take into consideration the relevance of selecting a time factor before 15 minutes. Way to Read the Suggestions in the Annex: The suggestions in the Annex are intended as guidance in arranging the

dissolution specification. Discriminatory power was strongly related to the point of time and the Q value selected. If point of time / Q value differs from that proposed in the flow chart, this may lead to discriminatory power which is also satisfactory. •

•

In case the dissolution process of biobatch is >=ninety-five per cent in fifteen minutes, the limit can be set to Q value equal to eighty-five per cent after fifteen minutes. In case the dissolution process of biobatch is much <ninety-five per cent, but >= eighty-five per cent in fifteen minutes, the limits (Q value) can be arranged to seventy-five per cent, eighty per cent or eighty-five per cent which value is near to Q and equal to biobatch end result of ten per cent at fifteen minutes. In case the dissolution process of biobatch is >= eighty-five per cent a half-hour later, the limits (Q value) might be arranged to seventy-five per cent, eighty per cent or eightyfive per cent, which value is near to Q and equal to biobatch outcomes, i.e. ten per cent in half an hour.

2. Specifications Setting for Dissolution If the dissolution conditions for testing are chosen, an appropriate dissolution specification should be arranged to obtain the perfect dissolution outcomes. The limit for the dissolution arrangement is described via the Q value, called mean value, at a known point in time, which allows bias among batches which are acceptable and non-acceptable. Batch results displaying compliance by means of stage S1, S2 and S3 are acceptable. The specification ought to be set in one of these ways so that in routine manufacture and testing, it would be predicted that compliance with S2 was attained. Prior to setting Q value, the time ranges are permitted with discrimination needing to be considered from the dissolution profile of the biobatch. Sampling time points need to be enough to attain a significant dissolution profile. To make sure that the results of the BE study may be extrapolated to the drug www.ipimediaworld.com

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Manufacturing •

In case the dissolution process of biobatch is >= eighty-five per cent only 30 mins later, the limits can be arranged to seventy-five per cent, eighty per cent or eighty-five per cent forty-five minutes later.

In case dissolution of biobatch is much <or = 85% after 45 mins, not less than 75% at 45 mins ought to be specified if possible. Otherwise, if dissolution specification (Q) is much < 75% after forty-five minutes, the dissolution specification must be primarily based on > 1 time point. Suggestions in Case of Biopharmaceutical Classification System Biowaiver If there was no biobatch, the limit for the specification with standard Q value within fifteen minutes or half an hour should be released. The given value of Q has to be minimum eighty per cent using conditions of a discriminatory test, regardless of the outcomes of test batch dissolution found in a study which was helpful for the biopharmaceutical classification system biowaiver. The dissolution test conditions within the specification

ought to be selected as mainly discriminatory among those used in the CDP. Conclusion Dissolution specification settings by giving similar choices for in vitro purposes of generic drug products with the aim of IR traits. It can be concluded that developing the specification limits of finished products is based on the quality characteristics of biobatch. Relative standards can be taken into consideration in deriving the specification limits for brand products.

8. 9.

CHMP/QWP/428693/2013) ICH guideline Q8 (R2) on pharmaceutical development (EMACHMPICH/ 167068/2004) Note for Guidance Specifications: Test Procedures and Acceptance Criteria for new Drug Substances and new Drug Products – Chemical Substances (CPMP/ICH/367/96) VICH GL52 on Bioequivalence: blood level bioequivalence study (EMA/ CVMP/VICH/751935/2013 – Corr.1) VICH GL39 Test procedures and acceptance criteria for new veterinary drug substances and new medicinal products: chemical substances

REFERENCES 1. 2. 3. 4. 5.

European Pharmacopoeia (Ph. Eur.), 9th edition 5.17.1, Recommendations on Dissolution Testing Guideline on the Investigation of Bioequivalence (CPMP/EWP/ QWP/1401/98 Rev. 1/ Corr **) Guideline on the conduct of bioequivalence studies for veterinary medicinal products (EMA/CVMP/016/00-Rev.2) European Pharmacopoeia (Ph. Eur.) 9th edition, 2.9.3, Dissolution Test for Solid Dosage Forms Guideline on quality of oral modified release products (EMA/

C. Venkateswara Reddy C. Venkateswara Reddy is pursuing a Masters in Pharmaceutical Regulatory Affairs, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India Email: reddypharmacy7@gmail.com

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

Mahalakshmy R. Mahalakshmy. R is a PhD Research Scholar in Department of Pharmaceutics in JSS College of Pharmacy JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India. Email: rmlphd2015@gmail.com

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Manufacturing

Scalable Assembly Solutions by Mikron – Fully Integrated and Truly Global A Case Study With the demand for more stringent standards, larger varieties, smaller volumes and ever shorter product lifecycles, the requirements for automation solutions have risen sharply in manufacturing industries. In order to best meet customer needs, Mikron has specialised in flexible, modular assembly solutions that are easy to evolve during the different stages of a product lifecycle: from the development phase through to fully automated, maximum-performance production.

Demands on manufacturers in industries such as medical, pharmaceutical, automotive, consumer goods and electronics are especially high. In an extremely competitive market, pressure on costs is rising and the lead time for new products is getting ever shorter. An assembly solution often has to be ready before all the details of the new product are even known. In many cases, assembly solutions also need to be frequently switched to another variant. So it’s no wonder that demand for innovative, cost-optimised solutions has risen dramatically over the past few years. The future belongs to flexible automation systems that can be expanded and enhanced easily and cost-effectively – from the development phase through to fully automatic production. From the First Prototypes up to Fully Automatic Production Lines “Providers of automation solutions should be involved from the very beginning of product development” points out Rolf Rihs, President of the Mikron Automation division. “As a fully integrated project

Figure 2: High performance automatic assembly and test systems

partner, we often learn all about the process at the same time as the customer. We thus always have a sound grasp of the risks involved,” says Rolf Rihs, “and through constant communication, we are able to anticipate future changes. From the design for assembly to the proof of principle, from the validation process through to the pilot line and to the highest performance production.” “A major factor in our success is that we have a close partnership with our customers in order to understand their needs, allowing us to react immediately. That’s why the flexibility of our automation systems is so important,” says Rolf Rihs, President of the Mikron Automation division. “As a truly global company, Mikron is ready to go to its customers wherever they are. This means that the customer can start its production in very small batches anywhere in Europe – for example – and finish it in very high volumes somewhere in America or in Asia.” Mikron’s customers can count on a knowledgeable, experienced and trustworthy partner. Always and everywhere. Thanks to its multi-cell configurations of its automation systems and the integration of manual workplaces,

Figure 3: Low-speed assembly sequence

Mikron offers almost unlimited layout options. Throughout the whole process, it is easy to redeploy and reconfigure whenever necessary. This considerably increases cost-efficiency and greatly shortens delivery times. What’s more, process validation can be transferred from one automation level to the next. Minimum Risk with Flexible Production Starts The key word in the brave new world of flexible automation systems is ‘scalability’. “For customers, the new approach means minimum risk and a faster and more flexible production start – in several stages if required.” For many years, Mikron Automation has enjoyed an excellent international reputation as a partner for high-performance automation solutions in the large-scale manufacture of precision products. “For many, however, the fact that Mikron Automation is also one of the leading providers of scalable and flexible automation systems is a huge bonus,” adds Rolf Rihs. Mikron is thus strengthening its position as a first-choice long-term partner.

Jean-François Bauer

Figure 1: Mikron Scalable solution from the first idea to the highest performance solutions. www.ipimediaworld.com

Figure 4: Manual process station

Jean-Francois Bauer joined Mikron Automation, Switzerland, in 1998 as Head of Marketing & Business Development. With 30 years of experience in the industrial automation environment, he has covered many aspects of company organisation, including production, purchasing, sales, product management and marketing.

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Packaging

User Testing: Critical for Truly Understanding Patient Needs Ophthalmic pathologies include eyesightthreatening conditions (diabetic retinopathy, glaucoma, cataract, age-related macular degeneration and retinal detachment) and, relatively speaking, less serious eye conditions (dry eye, red eye, etc), all of which are treated by ocular injections, eyedrops or surgery. Eyedrops 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.1

Thus, preservative-free formulations are needed for glaucoma and DED. At present, two options are available for dispensing preservative-free ophthalmic formulations: unit-dose systems or preservative-free, multidose systems. Unit doses are generally considered to be not patient-friendly, and are often costly and bulky, making them unsuitable for home use for chronic conditions.2 Therefore, in order to improve patient compliance and limit waste, the preferable solution is to use preservativefree formulations with the convenience of a multidose bottle. Two main types of preservative-free, multidose (PFMD) systems exist today: Pump systems – These use either an airless container or a filter technology to allow air to enter back into the bottle. The advantage of pump systems is that the dose is controlled and consistent; however, priming is needed before delivering the first dose. Squeeze bottles – These dispense drops using either a non-return valve or a filtering system. Most of them also rely on an air filtering system to stop bacteria entering the bottle when it is open to the air. There is no priming with squeeze bottles, but the dose is less controlled. Eyedropper performance is mainly evaluated by in vitro tests, such as the dose variability against shelf life, the sterility of the content and the delivered drop. Despite these important 84 INTERNATIONAL PHARMACEUTICAL INDUSTRY

in vitro tests, the usability aspects of the drug delivery system are not fully considered. Therefore, also conducting a user test evaluation is key because, even if it is successful according to the in vitro tests, an eyedropper may not necessarily be appreciated by patients due to poor usability. Consequently, a device with good in vitro test performance could be clinically inefficient. In this article, we report on three user tests that have been conducted to evaluate the level of difference in terms of usability characteristics and user preferences for different PFMD systems.

drop onto the safety glasses. 97% of users named Novelia® as their first-choice container over the 3K® system, with only one participant in favour of 3K®. Comparative User Study 2: Novelia® Bottle & OSD A second randomised study was performed by the independent user studies consultancy GfK (Suresnes, France).4 This study comprised 90 patients (40 in Europe and 50 in the US). 75% of them were over 60 years old. 40% of the participants had glaucoma, 40% were regular users of eyedrops (primarily for DED) and 20% were occasional users (for example for conjunctivitis). The interviews happened at the respondents’ homes or in GfK’s offices, where patients instilled eyedrops (using safety glasses) with different eyedroppers and rated these systems on nine attributes from 1 (very poor) to 5 (very good). Both ophthalmic systems were PFMD bottles: The Ophthalmic Squeeze Dispenser (OSD) from Aptar Pharma (Radofzell, Germany) and Novelia® from Nemera. Based on the results, Novelia® was found to display superior usability characteristics, with the exception of the grip of the bottle, where both devices were considered to be the same (Figure 2). First, the screw cap on Novelia® proved intuitive, as it is a similar mechanism to that found on regular, preservativecontaining three-piece eyedroppers, whereas the OSD cap opening was not perceived as obvious or easy. Patients

Comparative User Study 1: Novelia® Bottle & 3K® A randomised study was conducted at the end of 2017 at the Department of Ophthalmology, Kuopio University Hospital (Kuopio, Finland), interviewing 30 patients over 50 years old with either glaucoma or ocular hypertension, with a majority of female participants (77%).3 The patients used safety glasses and instilled eyedrops from two different PFMD systems: the Novelia® bottle from Nemera and the 3K®-System pump from Ursatec (St Wendel, Germany). The participants were asked to rate several parameters from -5 (extremely difficult) to +5 (extremely easy): Opening of the container • Squeeze force needed for drop administration • Targeting the eye • Drop control • Removal of the residual drop • General usability of the container. In addition, the users were also asked about their preference between the two eyedrop containers. According to the results, Novelia® outperformed 3K® in the tasks of opening, squeezing, targeting the eye and removing the residual drop, as well as having better general usability (Figure 1). 100% of users were able to open the Novelia® bottle and deliver a singular drop onto the protective glasses. Five Figure 1: The difference between scores given by 30 patients participants did not succeed with glaucoma or ocular hypertension for Novelia® and ® ® ® in opening the 3K® system and 3K -System bottles (Novelia –3K ). Adapted from Figure 1 of the study “Preferences and ease of use of preservative-free IOPseven out of the remaining 25 lowering eyedrop containers: A comparison of two multidose were not able to instil a singular bottles” with the permission of Clinical Investigation journal.

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Packaging Cap opening • Ease of first-time use • One drop at a time • Targeting the eye • Hermetic sealing • On-the-go use • Ease of treatment adherence. Overall, the 3K®-system was rated at 3.4/5 (average/ good) and Novelia at 4.2/5 (good). Patients reported that Novelia® was easy to use and ideal for an Figure 2: Mean scores across different parameters given by 90 patients ® on-the-go use. Novelia® with glaucoma, dry eye or conjunctivitis using Novelia and OSD also outperformed 3K® by are not used to snap-on caps with 0.6 or 0.7 points on cap opening, hermetic their current bottles, and so found sealing and eye targeting. Both systems opening the OSD confusing. Additionally, performed equally (3.7/5) on one drop at some patients found it too loose after a time. 75% of users preferred Novelia® repeated use, meaning it ceased to seal over 3K® for these reasons. Another hermetically and could come off when interesting finding was that regular and carried in a purse or bag. The robustness occasional users don’t have the same of the Novelia® screw cap made patients preferences for eyedrop containers feel more comfortable when carrying it in and value them differently. On the one a bag as it felt more secure. The biggest hand, both systems were appreciated difference between both systems was similarly by occasional users: four of eight seen when the bottle was nearly empty occasional users preferred Novelia® and at the end of use, at which point the the same number preferred 3K®. On the participants found squeezing the OSD other hand, regular users demonstrated a bottle harder than the Novelia® one. very strong preference for Novelia®, with Additionally, participants appreciated the 11 of 12 regular users preferring Novelia®. Novelia® blue tip as it helped them target This would suggest that chronic users are their eyes. Overall, 68 out of 90 users more sensitive to easy-to-use features. (76%) preferred Novelia® over the OSD. Conclusion The three studies demonstrated a Comparative User Study 3: Novelia® significant difference between PFMD Bottle & 3K® The third randomised study sponsored by systems in terms of usability, which can Nemera was conducted early in 2018 in have an impact on patient adherence Marketing Espace’s office (Lyon, France).5 and treatment efficacy. The studies Out of the 20 users interviewed, 60% were conducted in hospitals, patients’ were regular users of eyedrops (including homes and offices. Participants had seven with glaucoma) and 40% were glaucoma, ocular hypertension, DED, occasional users. The participants were conjunctivitis and allergies. The studies asked to administer drops onto protective did, however, have some limitations due glasses with the same two PFMD to the low number of participants and containers as the first study: Novelia® two of them being sponsored by Nemera. and the 3K®-system. They also selected However, they all point towards a patient their preferred system overall and rated preference for the same PFMD system, them from 1 (very poor) to 5 (very good) Novelia®, highlighting the difference between the ophthalmic systems tested. on several individual parameters: The third study highlighted a difference in patient preference according to the frequency with which they use the eyedropper. Notably, patients with chronic diseases, such as glaucoma and DED, show a strong preference for a product that is easy to Figure 3: User preference segmented by user type (regular/occasional) use daily and easy to carry. and treatment type (medical with prescription/comfort) on 20 patients. Glaucoma patients are often www.ipimediaworld.com

elderly people and have difficulties using eyedroppers, but still need to administer eyedrops every day, sometimes twice daily. Nearly nine out of 10 glaucoma patients are unable to instil eyedrops correctly,6 and therefore an easy-to-use system that is appreciated by patients could contribute to improving their compliance to a treatment. In conclusion, drug delivery systems should be assessed not only in terms of in vitro performance (drop consistency, leachable, etc) but also in terms of patient usability. REFERENCES 1. 2.

“Report of the International Dry Eye Workshop”. Ocul Surf, 2007, Vol 5(2), pp 65–204. HertelF, PfeifferN, “Einzeldosisapplikationen in der Glaukomtherapie. Vergleich der Kosten mit Mehrdosis”. Ophthalmologe, 1994, Vol 91(5), pp 602–605. Kaarniranta K, Ropo A, “Preferences and ease of use of preservative-free IOPlowering eyedrop containers: A comparison of two multi-dose bottles”. Clin Invest, 2018, Vol 8(1), pp 29–33. “User study performed for Nemera by GfK to understand the Novelia® market opportunities versus competitors (Aptar OSD system)”. GfK report, Paris, France, 2015. “User study sponsored by Nemera and conducted by Marketing Espace to understand the advantages and disadvantages of an ophthalmic pump (3K®-System pump) versus the Novelia® system”. Marketing Espace report, Lyon, France, 2018. Gupta R et al. “Evaluating eyedrop instillation technique in glaucoma patients”. J Glaucoma, 2012, Vol 21(3), pp 189–192.

Fanny Sellier Fanny Sellier is responsible for ophthalmic products at Nemera, including the preservative-free technology, Novelia®. She joined the company in 2011. A graduate from the ISEG business school in Strasbourg and the IUT de Chimie (chemical sciences) in Besançon, France, Ms Sellier worked for seven years for Rhodia (now Solvay) in the US in marketing, Lean enterprise and business development. She was then with BASF in a marketing position managing products for the home care industry.

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Q&A with Brussels Airport, Changi Airport & Pharma. Aero 1. Brussels Airport, Miami International Airport and Changi Airport launched ‘Pharma.Aero’. Can you tell IPI more about how this collaboration came about? Way back prior to 2016, Brussels Airport, Miami International Airport and Singapore Changi Airport came together with the joint ambition to foster greater collaboration amongst IATA CEIV Pharma airport communities, as well as between the communities and pharma manufacturers to enhance the reliability of pharma air transportation. To the above end, the founding members concluded the need to create a neutral platform for the air pharma supply chain. This approach proved to be successful as since Pharma.Aero’s formation, many pharma shippers and operators have joined the alliance and work closely together in different projects. 2. It is clear to see that Pharma.Aero have taken the initiative to improve pharma handling and quality in the air cargo industry worldwide. What is Pharma.Aero’s next plan of action? Pharma.Aero aims to establish thought leadership within the organisation and become a global reference for creating transparency and reliability in the air pharma supply chain. This is achieved by bringing together pharmaceutical shippers and supply chain players to collaborate through projects, as well as the publication of technical/white papers. 3. With the increasing demand for reliable end-to-end air transport for pharmaceutical cargo, what steps will you take to focus on pharmaceutical shippers and all industry stakeholders who embrace the IATA CEIV programme? Without any doubt, IATA CEIV Pharma is the backbone of our organisation. Pharma.Aero enhances collaboration between all stakeholders in the market. Close collaboration amongst members and with other international industry platforms such as IATA and TIACA will further emphasise the needs for and promote high and harmonised standards when it comes to airfreighting pharma. 86 INTERNATIONAL PHARMACEUTICAL INDUSTRY

4. Pharma.Aero have recently signed global animal health giant Zoetis as a new Strategic Pharma Shipper Member. Can you tell IPI how collaborating with Zoetis can strengthen your pre-existing partnerships with airlines and airports like Brussels Airport? It is undoubtedly the case that a pharma shipper with global leadership such as Zoetis within the life science industry (in this case animal health) is of high value to Pharma.Aero. Zoetis’ membership underlines the importance of collaboration with global pharmaceutical shippers. It is only strong collaboration with pharma shippers that helps improve pharma air supply chain standards. “Zoetis are delighted to join Pharma. Aero. The integrity of our physical supply chain plays an important role in how we transport our products,” says Rita O’Sullivan, Zoetis’ Head of Global Transportation. “Of specific interest to Zoetis is how we can partner with airlines, GSAs and freight forwarders to continually enhance and improve the cold chain service offerings, which are critical to the animal health sector.” Nathan De Valck, chairman of Pharma. Aero adds: “The pharmaceutical shippers are at the core of Pharma.Aero’s cross-industry collaboration initiative. Therefore, we are very happy to welcome Zoetis into Pharma. Aero and look forward to their active participation in our project groups. We will continue to listen to the expectations of our four pharmaceutical shipper members. We aim to further intensify collaboration with our pharma shippers members in Pharma. Aero.” 5. A growing number of US airports are investing in improving facilities and processes, as well as exploring cargo community systems and expedited custom clearance schemes, to facilitate cargo flows and stimulate new traffic. With Pharma.Aero partnering with pharma gateways like Brussels and Changi Airport, will Europe and Asia follow in the US’s footsteps? The pharma industry is not only demanding faster and more reliable transportation, but also higher supply

chain visibility. In addressing these, supply chain players are turning towards data-sharing, real-time visibility and collaboration. In September 2017, Pharma.Aero kicked off the Digi 1.0: Certification of Pharmaceuticals Air Trade Lanes through Digitisation to examine whether data from different stakeholders could be ingested and displayed on a single platform to achieve greater visibility and insights throughout the supply chain. Subsequent to Digi 1.0, Pharma.Aero transcended from a proof of concept to a prototype, with Digi 2.0: The Global Pharma Tracker Prototype, where real data from live pharma shipments were integrated into the platform and allowing the users to visualise the door-to-door performance of the entire pharma supply chain and, at the same time, control visibility of data based on the agreed data sharing and governance framework. Both projects were co-championed by Brussels Airport and Changi Airport. The prototype lane is Brussels-SingaporeSydney with Singapore Airlines as the carrier. A white paper summarising the key findings of the project will be published in the coming months. As a next step, Pharma.Aero and Nallian will be launching an early adopter programme for operational use. At present, Brussels and Singapore are connected through freighter services offered by Singapore Airlines. Come October 2020, Singapore Airlines will introduce non-stop passenger services between our two cities, strengthening our certified trade lane positioning, enabling safe, reliable and speedy transportation of pharma shipments In 2019, Pharma.Aero kicked off a second project, aimed at increasing the transparency of pharma handling. Where the GPT focused on performance of the pharma handling, the pharma corridor mapping project focusses on the capabilities of all the operators involved in pharma handling on a specific airportto-airport lane. Both performance and capabilities are in fact two sides of the same coin. Pharma.Aero performed a first pilot project for the Brussels – Hong Kong Spring 2020 Volume 12 Issue 1

Logistics & Supply Chain Management route with Cathay Pacific as the carrier. The capability mapping allows the user to visualise the internal handling SLAs of the operators in the pharma corridor, and gives an indication on how the actual door-to-door performance is aligned with these SLAs. This level of transparency of the entire pharmaceutical supply chain is unprecedented, giving an insight into the internal processes that very often remain hidden for pharmaceutical shippers. As a result, the information obtained by this corridor mapping can be used to optimise the packaging of pharmaceutical shipments or to work with operators to optimise procedures in order to eliminate temperature deviations. 6. The pilot for the CEIV Pharma certification took place at SATS in Singapore. Brussels Airport was the first cargo community in the world to start a community certification approach with the CEIV Pharma Certification, with 18 companies active at BRUcargo being CEIV Pharma Certified. What percentage of companies will be certified in 2020 and why? The CEIV pharma community certification at Brussels Airport involved all the operators that are active in maintaining the cool chain through the airport. Airlines, forwarders, handling and trucking companies participated. The community certification was obtained five years ago, and all the participating companies have already renewed their certification after the three-year validity period. The group of local certified entities continues to grow and today more than 95% of all pharma shipments transiting via Brussels Airport are handled in a 100% certified supply chain at each step in the transit. This quality guarantee gives peace of mind to pharma manufacturers and improves the risk profile of Brussels Airport compared to other gateways. As a result, the pharma volume passing through the specialised pharma premises at the airport continues to grow every year. 7. Brussels Airport has publicly stated that ‘The Airside Pharma Transporter aims to close all risks in the cold chain and offer more transparency and increased confidence to the pharma industry’. Can you explain to our readers how Pharma.Aero will plan to work alongside its airport members www.ipimediaworld.com

to increase confidence in the pharma industry? The Airside Transporter is only one of the examples of handling pharma shipments within the airport. Pharma. Aero embraces different innovative solutions, such as this one, to testcase within wider and larger projects. For example: recently a Pharma Corridor Pilot Project was launched and executed between Brussels Airport and Hong Kong International Airport. Different solutions, different KPIs and CEIV standardised practices were taken into account to map this corridor project. Another project that was recently finalised is the Air Transport Benchmark Survey. In this project, Pharma.Aero concentrated on identifying the pitfalls that might occur on tarmac and the common practices that have been adopted in major cargo hubs, such as specific pharma transport vehicles. 8. To drive forward the airport’s activities and uphold the connectivity and the economic growth of the country, the infrastructure of Brussels Airport and Changi Airport had to be/will need to be adapted. How does Pharma.Aero plan to engineer these changes? Through the championing of thought leadership and projects, Pharma.Aero hopes to be able to contribute to the airfreight industry through identifying and setting best practices including, but not restricted to, physical and digital infrastructure, SOPs and processes in the area of air pharma transportation. In addition, the role of Pharma.Aero is to testbed innovative ideas and solutions on a wider scale and offer technical feedback and advice for the industry, and for its airport members in particular. 9. As the economies of Singapore and Belgium are open economies which are heavily focused on exports, it is only natural that highly efficient logistics are required. Can you tell our readers more about how air cargo transport plays a central role in this? Singapore is an open and trade-oriented economy. Logistics and airfreight play an integral role in enabling Singapore’s global trade. Pharma is an important manufacturing pillar of Singapore. Today, four out of the world’s top 10 drugs are manufactured in Singapore. Between 2018 and 2018, Singapore’s air pharma trade has achieved a CAGR of 9.4%1 per annum.

Though 7% of our pharma exports by volume were airfreighted in the first nine months of 2019, it represents 78% of SIN’s pharma export value2. In supporting this key manufacturing pillar, Changi Airport and our air cargo community have continuously improved on our pharma handling capabilities through local and global community collaboration. Locally, we are the first airport in Asia Pacific to forge an airport community to attain the IATA CEIV Pharma certification. On a global basis, Changi Airport is collaborating with other airport communities under the ambit of Pharma.Aero on a few projects, notably Digi 1.0 and Digi 2.0. Like Singapore, the Belgian economy is very open and trade-oriented. On top of this, there is a large presence of pharma R&D and production facilities in the country, with the pharmaceuticals that are produced there destined for patients all over the world. In that perspective, Brussels Airport plays an important role in offering good connectivity and air cargo transport options for the Belgian economy. In the past three years, the flown export pharma volumes have doubled, representing 10.5% of the total cargo volume handled at the airport. The size of the pharma segment is three times bigger than the average at other European airports. 10. Brussels Airport is widely recommended as the ‘preferred European pharma gateway’, specialising in the handling of time- and temperaturesensitive goods. Why, in your opinion, is this? For Brussels Airport, the life sciences, pharma and medtech segment of the market has been a strategic priority. Perishables handling is a second strategic market segment. Pharma and perishables have different operational requirements. However, the business logistics, the expertise and type of infrastructure required are similar. So, the combined efforts and investments by all the operators at Brussels Airport have resulted in cold chain expertise for both market segments contributing to our reputation of the preferred European gateway. REFERENCES 1. 2.

Includes medical devices. Source: Seabury 2019 Includes medical devices. Source: Seabury 2019 INTERNATIONAL PHARMACEUTICAL INDUSTRY 87

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Automated Quality Systems in Supply Chains Save Lives Logistics for Pharmaceutical Organisations Require Lean Processes

Ensuring high product quality while simultaneously increasing efficiency along the supply chain is only possible if suppliers and logistics service providers consistently supply customers with high-quality materials. Precise control of the material is indispensable. This is particularly true when it comes to handling pharmaceuticals and biotechnological goods that are intended to save lives.

To ensure quality, many companies rely on a detailed internal quality management system based on Lean and total quality management (TQM) processes. The challenge is these companies often overlook quality related to manufacturing and material handling as part of the delivery process of warehousing, port transfers, and inter-modal transportation and the advantages from which they could benefit: By providing automated quality proofs during the production and delivery cycle, companies can ensure compliance, minimise material waste, and effectively save time and money on internal quality measures. Challenging Industry Demands Innovative Solutions The pharmaceutical industry is the most challenging and specific industry in the world. Logistical processes, temperature- and time-related issues, and compliance, in particular, are more complex than those of conventional goods. A large number of raw materials for pharmaceuticals and goods used in biotechnology require transport under special conditions. The real-time control of materials along the entire production and transport chain is an important factor in quality assurance for both suppliers and customers. This approach enables companies to move from purely reactive management to proactive problem prevention throughout the global supply chain. Now imagine the following situation: a single drug, utilised in thousands of hospitals, doctors' surgeries and pharmacies across Europe, is distributed 88 INTERNATIONAL PHARMACEUTICAL INDUSTRY

worldwide – or the individual raw materials for this drug are produced in different companies all over the world. A widespread circulation of drugs like this complicates the tracking and the managing of quality, orders, inventory, and shipments. As more and more of the supply chain today falls outside of the direct administration of the pharmaceutical manufacturer, digitisation of supply chain processes is key to maintaining control and visibility. More importantly, digitisation is required to help meet government regulations of track and trace of materials, from raw material suppliers to patients. A digital supply network that extends control and visibility beyond the four walls of the manufacturer to all partners, including material suppliers, distributors, hospitals, pharmacies, packagers, and transporters will allow everyone on the network to see relevant information so they can better manage their component of the supply chain and guarantee high quality. Capturing Quality Information of Raw Materials Track and trace from raw material suppliers through to the end patient requires data structures that support batch numbers, lot numbers, serial numbers, packaging levels, quality information, etc. and are able to link

across raw materials and finished goods. In fact, a finished good certificate of analysis (COA) ideally will reflect the quality characteristics of the finished goods and each of its components. The certificate should include all details (manufacturing, movements, operations, quality, etc.) of raw materials and finished goods as they move through the supply chain and ultimately to the patient. Today’s pharmaceutical companies often rely upon contract manufacturers to maximise flexible, high-quality production at minimum cost. Possibilities to check the quality results of the contractual partner should be as relevant as the costs. Using digitised internal and external quality controls of the pharmaceutical manufacturer through the logistics processes eliminates the possibility of tampering with specifications that drive counterfeiting in the supply chain. With continuous controls of the entire supply chain, inferior materials and mishandling during transport would be prevented. In the long term, waste can be reduced, spoilage is minimised and the patient receives a high-quality medication that helps to improve his or her health. In order to improve process quality, it is necessary to integrate all quality-relevant functions and processes throughout the entire company and within the global supply chain. If the processes Spring 2020 Volume 12 Issue 1

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Logistics & Supply Chain Management produced using living organisms, requires a strict temperature range of two to eight degrees Celsius and can be worth up to 45 million Euros. The necessary temperature-controlled containers and storage facilities is a capacity issue in certain global regions. According to the current state of the art, this data can be collected, for example, by sensors or smart pallets where applicable.

Logistical processes, temperature- and time-related issues, and compliance for pharmaceuticals are more complex than those of conventional goods. © iStock.com/LeoWolfert

along the supply chain are precisely coordinated, the medical provider or patient will always feel confident in the quality of the medication. Thanks to optimised incoming goods processes, pharmaceutical manufacturers benefit from reduced inventory levels. With a trend toward more specialised, smaller batches of medicines produced, the systems of the extended supply chain need to be integrated to provide “pull” synchronisation of demand signals and process visibility. Data flows from these systems need to be orchestrated, including raw material and packaging orders; contract manufacturing orders; raw and intermediate materials and finished goods movements; transportation orders and status; shipment status; receipt of goods status; etc. In addition, a global supply chain is extremely error-prone due to poor internet connections in specific geographies or data capture methods. Imagine a scenario in which dispersion of medications in specific regions are in the wrong packaging quanties based on cold chain stocking levels. Or inventory updates for re-ordering cannot be updated quickly based on poor internet connection of actual consumption rates. The entire supply chain is exposed in the blink of an eye relative to stocking levels, wastes, and shortages. Such risks can only be minimised if downstream partners operate in a secure environment with upstream fulfilment needs being communicated effectively. Some pharmaceutical companies are currently gaining initial experience in this field with the channels of distribution using blockchain technologies. Though in pilot type projects today, these innovative 90 INTERNATIONAL PHARMACEUTICAL INDUSTRY

approaches will also considerably relieve quality management concerns in the future. Data Analysis Enables Consistent Quality Another important point is the quality of exchanged data. The quality-relevant data for automated testing processes are already available: The internet of things, social media, structured customer feedback, and human perception generate a wealth of information that is of central importance for analysis. This data could identify early indicators of performance problems, prevent a recurrence of CAPA (corrective and preventive action), and help diagnose customer complaints faster. Many companies are already using the existing data to analyse risks and opportunities arising from the entire product development cycle and the customer journey. In the case of temperature-dependent goods within the pharmaceutical industry, monitoring of temperature fluctuations and handling is necessary and has significant impacts. Transporting biologics is neither an easy task nor inexpensive. Each shipment of these specialised medications, which are

A large number of raw materials for pharmaceuticals and goods used in biotechnology require transport under special conditions. © iStock.com/kadmy

In order to meet high-quality requirements, the regulation of temperature fluctuations is not the only decisive factor. Improper container movements and time-sensitive formulations such as vaccines at the port or in the warehouse can also be the cause of quality losses. The aim is, therefore, to use the analysis to identify trouble areas and support logistics providers and suppliers in optimising their processes. Other aspects that should be taken into account are fluctuations in the actual formulation of the medication. Statistical process control and Pareto analysis based on global regulated guidelines for production are good methods for the tracking of material fluctuations. Typically, this is a cumbersome and labour-intensive activity. Non-conformance and corrective actions can be implemented for the logistics process. The ideal solution for suppliers and logistics service partners is to provide all material properties and formulations digitally, so that drug variations can be found immediately and shared between suppliers, producers, and the channels of distribution. Track and Trace for Product Recalls The complexity of today’s global supply chains leaves companies increasingly vulnerable to unexpected supply disruptions, forcing many companies to view returns and recalls (due to cross-contamination with another drug or impurity substance) as a cost of doing business. A drug recall is the most effective way to protect the public from a defective or potentially harmful product. According to governmental regulations, a recall needs to be communicated to the public to remove a defective drug product from the market. This communication is supported through supply chain processes related to serialised track Spring 2020 Volume 12 Issue 1

Logistics & Supply Chain Management and trace, both forward and backward from consumers to the pharmaceutical manufacturer. Future recalls can be reduced as a part of extending the quality management solution into the logistics process for greater results. Traceability of raw materials is possible in two directions: The first direction leads to product tracking. Using product tracking, the available data from the network provides information about where the raw material or medication is currently located – within the entire supply chain. This allows companies to find and remove necessary medications at the stocking level and goods in transit. Product tracing, on the other hand, identifies the origin of the drug or a group of raw materials. This allows companies to trace the product origin down to the smallest detail. Product recalls, quality defects and customer complaints can thus be traced down to the last detail and health concerns remedied. Individual Treatments Need Supply Chain Transparency In addition, the paradigm shift in the biopharmaceutical manufacturing away from general treatments to personalised therapies for smaller patient groups creates new challenges for the area of quality management and the supply chain. These include a proliferation of stock keeping units (SKUs) to manage, production issues around producing very small batches of time-sensitive medications, and the logistical issues of delivery. These cell and gene therapies have to be tailored to the individual patient and bred individually. These complex and highly targeted treatments can be lucrative but present

a number of challenges in the era of personalised medicine supply chains. Precise, real-time control is crucial to avoiding quality issues, so the usage of regional manufacturing hubs will be necessary for these small batch items. To meet changing market demands, manufacturers are realising that technology, digitisation and especially connection along worldwide supply chains will be decisive components of the process. These new personalised therapies are much more complex to produce, manage, and distribute than traditional medicines and cannot be made on the scale, the speed, reliability, and traceability required. The impact on the quality assurance functions in the organisation and across the supply chain are of paramount difference. The necessary error rates of nearly 0% will pose the biggest challenge as unique medications and treatments are added to the process. With 25% of pharmaceutical costs and 40% of medical device costs tied to the supply chain, there are opportunities for significant cost savings. Improving the cold chain capabilities throughout the supply chain for transportation and storage requires a digital supply network integrating with time and temperature sensors from factories, warehouses, trucks, labs, and pharmacies that can monitor and send this information for both clinical trial supplies and approved products. These IoT tracking sensors tied to a digital supply network help pharmaceutical organisations to ensure the safety of their products in transit and in storage. The need for complete visibility and

ability to respond quickly when needed will have an enormous impact on the current pharmaceutical supply chain model. Conclusion In today’s global marketplace, quality management needs to be extended across the supply chain from manufacturer to logistics service providers, hospitals, pharmacies, and patients. Operational silos can be eliminated by having all participants connect to a digital supply network, fostering improved communications and collaboration to all. With a supply chain quality management solution built within a digital supply network, all participants on the network are privy to data, analysis, and information on what is happening across the supply chain. The data collected across the network gives deeper insights into quality information. This is necessary since in the future the manufacturing of pharmaceuticals will become more automated and personalised. Track and trace and quality management solutions will be embedded in the everyday workings of pharmaceutical manufacturers, making it easier to solve the counterfeit drug challenges and to save lives.

David Cahn David heads up Global Marketing at Elemica, the digital supply network provider for manufacturing industries. He has been implementing, marketing, and product managing leading enterprise applications for over 30 years, including ERP, SCM, TMS, and WMS solutions, and lived the world of customer-facing solutions and customer experience for the past few years. David has held leadership positions at Phillips, KPMG, CA, AMR Research, Aptean, and Infor. Additionally, he has started, built, and sold his own e-commerce and supply chain software company during the dot-com days, and had his own corporate development consulting company to the software industry for over ten years.

Real-time control of materials is an important factor for quality assurance. © iStock.com/industryview www.ipimediaworld.com

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New Tools and Models Designed to Optimise Costs and Protect the Environment Predict, Anticipate, for Better Selection. Reuse to Protect and Make Savings. Increasingly Efficient but Expensive Passive Packaging… Over the past five years, highperformance passive isothermal packaging based on materials such as VIP (vacuum insulation panel) or PCM (phase change material) have been introduced to the market. They make it possible to maintain pharmaceutical products at negative temperatures, between +2°C and +8°C or between +15°C and +25°C for five days or more, depending on the outside temperature. These "PREMIUM +" products offer very high levels of performance that make it possible to limit or even eradicate temperature excursions. Their acquisition price is nevertheless high and this type of packaging remains reserved most of the time for products with high added value. Except when they are associated with a rental or reuse service, which makes them less expensive to use than "STANDARD" isothermal packagings, which are less efficient.

…That Reusability Makes Affordable The quality and lifespan of the new materials used in the manufacture of passive isothermal packaging make it possible to reuse this packaging many times. Precise rules defined upstream by the supplier's quality department, and thorough cleaning and control after each use is nevertheless necessary in order to validate the subsequent performance of the isothermal packaging. Reusing isothermal packaging also brings many environmental benefits by significantly reducing CO2 emissions related to the production and destruction of packaging. The end customer is relieved of the burden of waste management. This is highly appreciated and meets a real need, particularly for pharmacies and hospitals which are overwhelmed by packaging. However, some argue that returning isothermal packaging to its place of manufacture for reuse has a high environmental cost. In a Collaborative and Virtuous Model It cannot be denied that returning isothermal packaging after use to a supplier's service centre to monitor the cleaning and quality control circuit has a cost and an impact on CO2 emissions. 92 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Nevertheless, these costs are largely optimised if the supplier of isothermal packaging has built up a global network of service centres that allows the packaging to be re-positioned close to the final destination. All the more so if the supplier pools the returns from its various customers by consolidating the return packaging before re-positioning it. Air Transport is More Prone to Temperature Excursions than Sea or Road Transport The multiplicity of operators, particularly in air transport, makes it difficult to identify the origins of temperature excursions and to set up processes to avoid them. Data logger technology has evolved considerably over the last five years, and it is now possible to have real-time information on product temperature. Some technologies are allowed on board aircraft because they do not interfere with the aircraft control systems. These expensive solutions can help avoid temperature excursions before they happen, by means of an alert message relayed in real time to the responders. Positive feedback has already been presented by pharmaceutical laboratories. Currently, these solutions are not frequently used for operational and financial reasons. But access to these solutions should become more democratic and help the many operators move in the right direction. The detail of the information provided in real time by these data loggers (internal and external temperature) will enable the rapid identification of loopholes and transport contracts that are not respected. Decision support tools will progressively be at the heart of the reduction of temperature excursions.

Tools to Qualify One’s Suppliers and Airlines Decision support tools such as the Validaide platform allow pharmaceutical companies to have an overview of the performance of the different operators on each air route and thus to build a transport plan, taking into account both risks and costs. The upcoming integration of these decision support tools such as weather forecasts will allow to refine the choices made. Adapting One’s Packaging According to Lanes and Seasons Is it best to choose a single isothermal solution that works regardless of the destination, supplier or season, or refine your choice depending on the shipment? To optimise the cost of transporting medicines, refining the choice of isothermal packaging or its composition (PCM or water) for each shipment is the best solution. The range of isothermal packaging on the market makes it easy to do this. The suppliers of isothermal packaging have an important advisory role in helping the customer to choose the most suitable solution. Here again,

Spring 2020 Volume 12 Issue 1

Logistics & Supply Chain Management of packaging and reverse logistics. Priority 3: Intelligent packaging. Will 2020 mark a turning point in cold chain logistics? What concrete actions can be implemented to integrate these environmental priorities?

decision support tools that simulate the internal temperature of the packaging according to the external conditions and the lanes selected will enable an informed choice to be made of the isothermal packaging best suited to the situation. The final goal is obviously to optimise costs. This dynamic (adapting the isothermal packaging) and predictive approach (simulating the temperature according to multiple criteria) only makes sense when the stability data of the transported pharmaceutical products are integrated. Integrating Stability Data to Reduce Costs Exploiting stability data and integrating them into a decision support tool is an effective lever to reduce logistics costs. Novonordisk understands this and has already made significant progress in this area, as explained at the 7th Pharma and Biosciences Conference in September 2019 in Paris. This pharmaceutical laboratory uses the data from shipments already made (temperatures from data loggers and data from their carriers) as well as weather forecasts to choose the appropriate isothermal packaging. The integration of stability data for their products in this tool enables them to optimise costs. The implementation of this approach has enabled Novonordisk to use active containers on a single lane from now on.

The ultimate goal is to create “An enhanced decision-making tool that will enable people at every warehouse (3PL) to pack and ship the optimal delivery based on a cognitive engine that takes into account weather, shipping mode, packaging material performance, etc.” dixit NovoNordisk Supply Chain Planning Team. Other alternative solutions are emerging and being developed to help pharmaceutical companies in their choices. "The integration in the same tool of data on the stability of the products transported, packaging performance and lane validation enables the decision-making process and costs to be optimised by avoiding the use of packaging that is oversized in relation to requirements," explains Yann Martin, EMBALL'ISO. And he goes on saying, "This is not the only cost optimisation lever. Beyond the advice we give them to select the right packaging, we offer them all-inclusive reusable solutions that allow them to optimise their costs and their impact on the environment." The Environment is Becoming a Priority As DHL states in its study "Rethinking packaging", three priorities are identified for packaging in the broadest sense of the term in 2020. Priority 1: The use of sustainable materials. Priority 2: Reuse

Use lightweight packaging to limit CO2 emissions, i.e. give preference to passive solutions over active solutions. Use reusable packaging to limit CO2 emissions linked to the production and destruction of packaging. Optimise the filling of packaging. Favour reusable solutions that do not require repositioning by plane but rather by boat or to local service centres. Favour isothermal packaging that is flattened after use to optimise cost and CO2 emissions during transport. When the use-by dates allow it, give preference to maritime transport that is less prone to temperature excursions, more economical and more ecological by combining it with additional protection such as isothermal blankets that limit the rise in temperature during periods when the reefer is not plugged in. Favour large network isothermal suppliers that sell and rent again isothermal packaging at the final destination. It is important to note, as this is not always the case, that taking an environmentally sound approach to temperature-controlled medicine transport can result in cost savings.

Florence Lehec Florence Lehec is Head of Marketing for EMBALL’ISO Group, and its eight worldwide productions sites and 14 services hubs. She joined EMBALL’ISO three years ago. Besides her marketing and communication activities, she has worked on the development of isothermal solution Reuse and Reverse Business Model together with the Sales Team and the Supply Chain Team. Before taking these responsibilities, she held several sales and marketing positions for Air France. She is a graduate of ESSEC MBA. Email: f.lehec@emballiso.com

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How Advancements in Logistics Technology will Play a Role in Combating COVID-19 Coronavirus continues to dominate headlines as it spreads around the world. At the time of writing, there have been over 92,000 reported cases worldwide resulting in the deaths of more than 3100 people. As well as China, some of the hardest hit countries are Iran, South Korea and Italy, showing the truly global scale of the spread.

COVID-19 obviously has no known antiviral cure or vaccine at this point with pharmaceutical companies scrambling to find effective means to help curb the spread of the virus. However, once a vaccine is developed, the next stage will be to distribute it globally. In a normal situation, getting pharmaceuticals in large enough quantities to key locations is critical. In the event of a pandemic, it is a question of life or death and there is no room for failure. The Importance of Simulations The lack of a vaccine or cure for COVID-19 and the fast spread of the disease has meant that getting various medications to infected areas has had to be rapid. Work that would normally take between 12 to 18 months is being condensed into weeks and months. At the moment, China has more than 80 live or pending clinical trials on potential treatments for COVID-19. This has resulted in an increased transport volume of antivirals and experimental drugs to China. Because of this, even the scale of temperature-controlled containers needed for the transportation of vaccine trials is enormous. While these trials run their course, though, pharmaceutical logistics companies are using this time to generate supply route simulations to establish how they will distribute medications to locations in China and around the world. Any temperature excursion experienced during the supply chain could spoil vaccines, causing them to be ineffective or require chemical testing, delaying release of the product to market increasing inventory and forcing express reordering to cover the 94 INTERNATIONAL PHARMACEUTICAL INDUSTRY

gaps in supply. Simulation allows you to significantly de-risk this process at low cost. Simulations are vital in modelling the transportation of treatments. Bio-vaccines, such as those that will likely be used to counter the COVID-19 outbreak, will need to be transported at temperatures between 2oC and 8oC. Maintaining these temperature ranges can be increasingly difficult considering the complexity of the supply chain. There are many different phases in the supply chain of a bio-vaccine including the transfer of the pallets, from air freight – which experiences very low temperatures during transit, to road freight – which can experience higher temperatures. Added to this the customs requirements at borders and the handling of the pharmaceuticals on the ground and the process becomes fraught with moments when temperatures can occur. Our Transport Planner models variables such as time, external temperature and internal temperature to assess the viability of the journey. By using the largest data pool of its kind containing real-world temperature analysis of cold storage containers travelling around the world, pharmaceutical companies are able to simulate routes, eliminating the need for time- and cost-intensive tests. By using simulators such as this, logistics companies and pharmaceutical businesses can effectively model entire supply chains in advance; eliminating real-world spoilage. In fast-moving cases such as COVID-19, door-to-door modelling is an important factor: as limiting the exposure of pharmaceuticals to external factors will limit temperature deviations and thus increase the likelihood of the vaccines remaining effective. Dealing with Outbreaks Across the World At present the virus is in 79 countries, but this is likely to continue to grow at pace. With this in mind, biopharma manufacturers and pharmaceutical

logistics need to be prepared to ship anywhere in the world. Prior to the COVID-19 outbreak, all shipments to China had to be unloaded to another container as the pallets and containers they arrived on were not allowed to leave the airport. This meant bio-vaccines and other temperaturesensitive pharmaceuticals were often spoiled (or had to be retested) in transit due to being exposed to high temperatures. In the modern world, however, the use of IoT containers mitigates this issue. Since the outbreak, these regulations have been relaxed, allowing door-todoor routes to be used. By doing this, it’s easier for logistics companies to track deliveries and ensure that once ready, vaccines that arrive are viable and can be used immediately in hospitals to help contain and then reduce the amount of infections. Even just five years ago, the pharmaceutical industry had no other choice but to accept a gold standard of around eight per cent of biologics spoiling in transit. In fact, the IATA Air Cargo Handling report produced at the beginning of 2019 estimated that it was as much as “20% of temperaturesensitive products are damaged during transport due to a broken cold chain”. Much of this occurs due to a “lack of compliance, standardisation, accountability and transparency across the air transport supply chain”. With SkyCell’s patented IoT enabled smart containers, we are now looking at a spoilage rates approaching zero. To put this in context, a standard shipment of vaccines, similar to that which any COVID-19 vaccine would travel in, would be around 100,000 vials. The reduction in spoilage rate would see an additional 8000 viable vials today compared to five years ago. This is a significant improvement – each one of these bio-vaccine vials will save lives and are therefore extremely valuable. Being able to deliver the vaccines to key areas in the Spring 2020 Volume 12 Issue 1

Real-time, IoT-driven supply chains are driving the industry forward Cold Chain as a Service® Integrated technology and services for your end-to-end supply chain.

Real-time temperature monitoring

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Controlant is pioneering the development of next-generation visibility solutions for digitally connected global supply chains. Our solution consists of reusable Internet of Things (IoT) data loggers that send mission-critical quality data and insights in real-time to a proprietary, cloud-enabled software platform, and costreducing operational services. Businesses are leveraging the improved visibility to collaborate with stakeholders, support their corporate sustainability objectives, and achieve supply chain improvements leading to an annualized value in the tens of millions of dollars. For more information, visit controlant.com contact@controlant.com Follow us on Twitter @controlant www.ipimediaworld.com

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first instance and then across the world with spoilage rates approaching zero per cent will be the key to containing the spread and prevent further infections and deaths in the medium term. Example of Temperature Control at Work Recent data taken on a shipment from Germany to China, a route many of the vaccines may take in the coming months, took four days to reach Beijing from Munich in the middle of June. As this was during the summer months – where outside temperatures vary from a low of 4oC to a high of 31oC – these antibodies needed to be kept between 2oC and 8oC throughout the duration of the journey. Due to the IoT in the smart container, the internal temperature was recorded at a stable 4.5oC to 5oC throughout, resulting in 100% of the antibodies arriving in just four days – as opposed to an industry average of seven or eight days – and in working condition, meaning they could be released to market immediately. The graph below illustrates the temperature changes during the journey and stability of the internal temperature. The container was also able to recharge during the journey when in a refrigerated

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environment, meaning that there was no need to remove the antibodies from the SkyCell container, eliminating the risk of breakage, temperature deviation and risks of counterfeit or theft. The container was simply shipped from door to door without exposure to external temperatures. The use of IoT smart containers offers governments and health organisations another opportunity to use technology to respond quickly to the spread of COVID-19. The connectedness of the world in terms of air freight and transport not only offers the virus a chance to spread, but also the fast worldwide distribution of a vaccine once developed. However, ensuring any vaccine reaches areas intact will be key in combating the longer-term hold of this virus. Ultimately, the COVID-19 outbreak and the logistical response that we as an industry take will serve as a test of both the technology that we have developed and of our cohesive and integrated response from across the production and delivery industries. This outbreak, which has been the most severe since the SARS virus in 2002, will act as a testing ground and benchmark

for further responses, not just to viral epidemics but any contagious disease, anywhere in the world. The effective response and coordination of all parties, both governmental and private companies, needs to be aligned to help prevent worldwide outbreaks as much as possible, in our increasingly globalised world. We are in a stronger position than ever to offer rapid and intelligent logistics to combat outbreaks of any kind. We need to ensure that we learn any lessons from this outbreak and continuously improve upon the technology we have already developed to help deliver medicines.

Richard Ettl Richard Ettl, the CEO of SkyCell, holds a Bachelor of Arts in Management from the University of Fribourg and attended the Executive Leadership Program at Harvard University and the Stanford University Graduate School of Business. Prior to founding SkyCell, Richard worked for Bobst SA in the company's production and logistics team. SkyCell is based on a strong set of values – innovation, reliability and sustainability – and has become the third largest pharma container provider within seven years. Richard helped establish the Institute for Value-Based Entrepreneurship (IVE) in Switzerland, which to date has offered business plan creation courses to more than 2500 students.

Spring 2020 Volume 12 Issue 1

Your preferred European pharma gateway

Your temperature-sensitive goods are in the best hands at Brussels Airport! From warehouse to aircraft, they benefit from a fully controlled refrigeration process. Our dedicated infrastructure, closed cool chain and specific pharma services make us unique in the business. And we take pride in collaborating with our partners and suppliers to implement global standards and innovations. Give your pharmaceuticals special care and ship your cargo via Brussels Airport your preferred pharma cargo gateway in Europe.

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Real-time, IoT-driven Supply Chains are Driving the Industry Forward The opportunities that Internet of Things (IoT) technologies provide in leading digital transformations throughout the pharmaceutical supply chain aren’t new. In the industry, IoT has transitioned from a passive technology to a mission-critical component that can provide continuous visibility and supply chain improvements.

IoT-driven temperature monitoring and visibility technology is making it easier to integrate key stakeholders from the first mile to the last, generate analytics into supply chain performance, ensure product integrity, and reduce costs and waste. The pharmaceutical supply chain has become increasingly complex in recent years, while the industry has become more competitive. A growing number of drug therapies include active pharmaceutical ingredients that require low-temperature storage. Increased emphasis on improving patient outcomes, developing customercentric models, reducing drug pricing, and expediting drug development has put the industry at odds with regulators and the patients it serves. Drug pricing pressures are driving focus on operational efficiency. In turn, manufacturers are turning to next-generation technologies to streamline processes and reduce waste, including new ways to handle, store, distribute, and administer their specialised, highly sensitive therapies to patients. The costs incurred from temperature excursions are not limited to the direct costs of the ruined product and the costs associated with replacing it. Supply chain waste includes the operational costs incurred from the reporting, root cause analysis, and corrective and preventive action (CAPA) taken after a temperature excursion occurs. These operational costs have been reported to range from $3000 to $10,000 per investigation, at a per-incident average of approximately $6500. For enterprises managing global supply chains, the costs 98 INTERNATIONAL PHARMACEUTICAL INDUSTRY

associated with both operational and product waste can add up to several million dollars annually. Adapting the pharmaceutical supply chain to accommodate new, personalised medicines and therapies for efficient, cost-effective patient delivery will require change. Real-time IoT and cloud technology provide an opportunity to optimise supply chain and operational structure so as to eliminate or reduce steps and streamline timelines and costs. These cost-saving and efficiency gains are simultaneously enabling the industry to fulfill its social sustainability responsibilities. Today’s IoT-driven Supply Chain For pharmaceutical manufacturers and other stakeholders, consolidating the supply chain “under one roof” brings a large range of benefits. Until recently, data has remained siloed among stakeholders, thereby inhibiting end-to-end temperature and location traceability drug products during transit and storage. Data collected by IoT data loggers, while current while it is collected, was not always immediately available for review and analysis to assure the quality and safety of products at the end of the supply chain. A lack of visibility has

limited businesses to decision-making based on data at the end of a journey after degradation or waste has occurred. Today, IoT technology can remain with drug products as they travel throughout the supply chain, providing continuous transport, storage, and distribution data to supply chain stakeholders. Continuous product quality information is transmitted to a cloud software system and can be accessed by quality, logistics, and other stakeholders. Real-time deviation alerts make it possible to proactively respond to temperature and other environmental issues in the supply chain as they arise to prevent product waste. The improved visibility and control are tangibly leading to a substantial reduction in risks and overhead, assurance of supply and compliance, tighter quality control, and even greater innovation. The Differences in IoT Technology While IoT temperature monitoring technology has been widely used throughout the industry for years, it is important to consider how the technologies can differ. Passive IoT loggers have been considered a lower-cost alternative for meeting the regulatory requirements, but they generally lack continuous connectivity to a cloud software system. Data is

Alarms 24/7

Hypercare and escalation

Continuous improvements

Exception based quality release

Spring 2020 Volume 12 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 protection in HOT and COLD - Very light weight + water resistant - Tailor made for Euro pallets / Block / Airplane pallets - Protocols and S.O.P.’s available Qualifications & Validations - Ambients (+15°C/+25°C) in stress test 8% products mass - Qualification 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 qualification Ecological notes - UNIQUE = Recyclable due to non-laminated composition - Re-use of recycled compounds = LOW Ecological footprint - Recycle machines in Temax manufacturing plants Also used in REEFER container transports for unplugged temperature protection

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Product

Manufacturing

development

available at the end of a shipment and must be manually retrieved from the IoT device, sent to a quality team to review the shipment data, and then accepted or rejected. GPS trackers traditionally have been used for one-off volume shipments. This may not provide the flexibility needed for large, complex deployment. In addition, managing devices, as well as the costs of the quality review process, can prove cumbersome for enterprises with global operations. IoT devices with sensors that rely on a local hub or gateway require the installation of a hub or gateway on the vehicle or at a site. This may not provide a viable solution for shippers and typically generally requires a substantial operational investment for installation. Real-time IoT technology automatically connects to the cloud and does not require the installation of gateways or hubs. Data loggers that are validated and compliant for use by air, road, rail, and sea, provide scalability and intermodal visibility through a single, integrated technology. Becoming Smarter with Data As pharmaceutical supply chains are increasingly digitised through IoT tracking, larger amounts of big data are being generated. Pharma 4.0 demands the gap between the digital and physical is closed, allowing for a 365-degree view of business operations. In a global supply chain, this can be difficult to achieve. Businesses often are still lacking a structured process to capture, evaluate, and act on the big data opportunities in their supply chains, held back by legacy IT systems, skillsets, and a lack of integration.

Distribution

Pharmacies

Packaging

Healthcare clinics

3PLs/4PLs

Hospitals

Last-mile

Wholesalers

demand-driven pharmaceutical supply chains, ultimately increasing profitability across the sector and improving health outcomes. Big data generated from these technologies can also give pharmaceutical companies a more granular, real-time picture of events taking place along the supply chain, from manufacture to the last mile. By managing and recording real-time data centrally in the cloud, the opportunity for larger-scale reporting becomes possible through insights on supply chain performance and trends. Through IoT and cloud-based technology, custom dashboard analytics can capture value-rich insights associated with shipments, including on the supply chain (origins, destination, routes, and sub-routes), on partners (freight companies, airlines, and packaging solutions), and external points of interest (cross-docks, harbours, airports, and borders). This is providing an unprecedented level of visibility for the industry. Connecting the Dots In addition to value-rich insights, real-time

Patient

IoT technology can facilitate supply chain automation in a number of ways. •

•

Control tower visibility: A combination of continuous distribution and storage data that is viewable centrally through a software platform and 24/7 monitoring and response services can provide protection and control over shipments, as well as the ability to intervene if temperatures start to deviate beyond designated boundaries. Shipment escalation: In addition to temperature and product quality information, real-time IoT technology can be used to identify odd shipments requiring review based on custom business rules. For example, there may be a mandatory truck driver stop of eight hours. If a stop extends to 12 hours, the shipment may be flagged for attention. If a shipment has travelled through an unexpected route or harbour, this may similarly trigger a required review. Automated releases: Real-time IoT-driven supply chain visibility provides for an exception-based quality review process. Quality

When end-to-end visibility is the goal, fragmentation is the enemy. It is not an overstatement to say data holds the key to creating efficient, compliant, and 100 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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•

managers gain access to product quality conditions while shipments are en route and can take alternate measures needed if an issue arises during transport. The availability of on-demand data enables a faster review and quality release process. Problem shipments are automatically segmented for review, reducing the operational resources needed for investigations. Environmental sustainability: Manufacturers are setting lofty sustainability objectives to reduce their carbon footprint. Some are aspiring to be carbon neutral or carbon negative within the next 10–20 years. Moving ahead, reducing waste in the supply chain will be a primary focus. The shift to reusable packaging and IoT data logger technology will provide measurable and substantial consumption savings, in addition to product waste savings.

Value at Each Step of the Supply Chain Visibility generated through real-time IoT monitoring supports stakeholders throughout the supply chain. •

Pharmaceutical manufacturers are able to achieve end-to-end traceability of their products from manufacture through transport, storage, distribution, and las t-mile delivery. Working with suppliers and logistics providers, they are able to take ownership of their supply chain data, gaining valuable analytics and insights into what is working and what requires attention. Data can be shared with their supply chain stakeholders to facilitate

risk mitigation and continuous improvement throughout. As an example, products travelling by air freight transporting a launch product were split up at Dublin airport. Products left behind weren’t kept in an adequately controlled environment. Real-time IoT technology identified both issues. The pharmaceutical manufacturer’s logistics provider facilitated intervention saving millions of dollars worth of product and preventing a downstream stock outage. •

•

Freight forwarders, 3PL/4PLs, and distributors and wholesalers can provide a differentiated, value-add service to their clients through real-time IoT-driven visibility. Supply chain data can be integrated into their client-facing system to provide shipment visibility. By managing real-time temperature alerts on behalf of their clients, they are able to facilitate corrective response to prevent product wastage from occurring. Packaging providers can utilise real-time monitoring to provide a competitive, value-add service to track the location and environmental conditions of products used with their technology. Through the use of real-time IoT technology, lane and packaging validation studies can be concluded more efficiently, with data automatically made available during and at the end of each shipment.

The Future of IoT-driven Data Through the evolution of real-time IoT traceability data and cloud capabilities in delivering real-time and predictive and

prescriptive analytics, the opportunities for stakeholder collaboration throughout the pharmaceutical supply chain and industry are substantial. Moving ahead, industry participants can contribute their anonymised supply chain data into a data ocean. This would allow enterprises to compare their supply chain performance with industry performance at large while providing value-rich data for the global supply chain. Industry-level benchmarking data and data sharing enables businesses to improve their supply chains and help the industry strengthen the supply chain as a whole. Conclusion While complete eradication of temperature excursions within the pharmaceutical supply chain is unlikely, realtime, IoT-driven visibility is providing measurable benefits for waste reduction, sustainability savings, and operational improvements leading to substantial cost savings. Through data, trends begin to surface, strategic decisions can be based on facts and data, and risks can be identified and mitigated, and annualised product and operations cost savings can be achieved. Moving ahead, this technology will strengthen the industry as a whole.

Ada Palmadottir Ada Palmadottir is Business Development Director at Controlant. With more than 20 years in pharmacy, management, and technology, Ada has extensive international experience in sales, operations, and marketing, specifically in the areas of product, vertical alliance sales and partnerships related to pharmaceutical products. She is a licensed and experienced pharmacist and earned a Master of Pharmacy from the University of Iceland and a Master of Business Administration from the Norwegian School of Management in Oslo. She has been working with Controlant’s Cold Chain as a Service® solutions for the last eight years. Email: ada@controlant.com

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News Gerresheimer is a Specialist for Primary Packaging for Biologics The most important trend forecast by pharmaceutical experts is the continuing, worldwide increasing demand for biological drugs and biosimilars. With the recently founded, Gx Biological Solutions organization, Gerresheimer installed a dedicated team to serve the highly specific demands in the Biological playfield. The global biopharmaceuticals market is driven by various factors, such as the increase in elderly population, surge in prevalence of chronic diseases like cancer and diabetes and growth in the adoption of biopharmaceuticals globally. Furthermore, a rise in strategic collaborations among biopharmaceuticals companies is also anticipated to supplement the growth of the biopharmaceuticals industry. Biological drugs are specifically being used to treat e.g. rheumatism, diabetes

From Clinical Phase to Industrialization: Gx RTF Vials – top quality depyrogenated sterile ready-to-fill vials for injectables Gerresheimer, a leading global manufacturer of primary packaging for the pharmaceutical industry is presenting its new Gx RTF vials product offering. Gerresheimer offers both its own packaging, as well as the familiar Ompi EZ-fill packaging design. Gx RTF vials – ready for filling The Gx RTF injection vials are made from type I borosilicate glass and meet all current requirements of the applicable ISO standards and pharmacopeias (USP and Ph. Eur.). They are manufactured in accordance with cGMP, washed in a cleanroom, packed in trays or in nests and tub and finally sterilized. Gerresheimer offers its own packaging as well as the well-known Ompi EZ-fill packaging design. This means the vials are ready for the next steps in the filling process without any further and/ or additional handling. The benefits are obvious: sterile delivery, a simplified fill and finish process, the highest quality standards, flexibility thanks to various possible packaging options and a wide range of filling and sealing technologies. These all lead to a significant reduction on overall manufacturing costs across 102 INTERNATIONAL PHARMACEUTICAL INDUSTRY

or cancer and are usually administered parenterally. They differ from conventional drugs in their molecular structure, hence special demands on the primary packaging are to be taken care of. Gerresheimer has developed a complete package of services and products for these biological drugs and biosimilars. This includes a dedicated innovative product portfolio consisting of specialty syringes and vials, safety devices, etc. that meet the specific requirements of this continuously growing market segment. At the same time, Gerresheimer also offers a wide range of services, especially for small and medium-sized biotech companies. Whether it is advice on the right primary packaging to be used in the appropriate clinical phase or support with approval and regulatory processes, lab services and much more. Gx Biological Solutions – new founded team of specialists At Pharmapack in Paris, Gerresheimer presented its products for the safe, innovative and sustainable packaging of biologicals. "We want to provide our the product’s entire lifecycle and improve patient safety. Top quality requirements The Gx RTF injection vials meet all established requirements of the applicable ISO standards and pharmacopoeias (USP and Ph. Eur.). By using its own or the Ompi EZ-fill packaging formats, the risk of glass-to-glass contact, which could result in breakages, cosmetic defects, and particle contamination is reduced to an absolute minimum. Gx RTF products are offered in Gx Elite, Gx Armor and Gx Pharma Plus quality formats to help exceed any of our customers quality requirements. Gerresheimer injection vials for international standards Injection vials set the benchmark for primary packaging for parenteral drugs. Gerresheimer’s come in all sizes and comply with the relevant international standards and pharmacopeias. The company’s range includes solutions for bioengineered drugs and other specialty pharmaceuticals. Flexibility through various packaging configurations and global operational footprint This new product offering currently exists in 2R, 6R, and 10R formats in nest & tubs configurations as well as in formats ranging from 2ml to 30ml

customers in the pharmaceutical industry with customized packaging solutions for their biologics so that they can be assured that all of their requirements are met 100 percent" said Stefan Verheyden, Global Vice President of the new founded Gx Biological Solutions team. Small Batch Production in Germany As a leading manufacturer of syringes, injection vials as well as cartridges and administration systems, Gerresheimer covers a very broad spectrum for the parenteral administration of biologicals within its portfolio. Smaller batch sizes are often requested when filling biological products, hence Gerresheimer has invested in small batch production facility in Wackersdorf – Germany. When the filled biological agent is sensitive to its storage environment, the container must be individually adapted to its properties. During the clinical development phase, Gerresheimer experts can support with advice on the right primary packaging, syringe or drug delivery device, as well as with regulatory approval processes and much more. (clear and amber) in tray configuration. Further formats are currently under development and will follow rapidly. The new packaging solution allows vials to be used from the development phase of new medications into small or large-scale production. Multiple manufacturing locations will enable Gerresheimer to adapt to individual and specific market requirements and to support total cost of ownership requirements from our customers all over the world. Intelligent defect recognition with state-of-the-art HD cameras All Gerresheimer’s tubular glass plants that produce vials work with standardized monitoring, inspection, and packaging technologies, which essentially comprise the Gx G3 and Gx RHOC systems. The inspection systems are developed in house and form part of a close-knit testing system that ensures the highest precision and quality assurance in line with the latest standards. Complete with state-of-the-art HD cameras, the Gx G3 inspection system makes sure that cosmetic defects are identified reliably, for instance. The intelligent software detects and classifies the defects in a few fractions of a second, while the Gx RHOC system ensures dimensional quality with HD matrix cameras and a hyper centric ID camera. Spring 2020 Volume 12 Issue 1

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Articles inside

Five Questions You Should Ask when Developing an

Understanding the Health Dimensions of the Climate Crisis

Excessive Prices in The Pharma Sector: The EU Antitrust Perspective

Enabling Competitive Entry: The Role of Drug Delivery Device Design in the Biosimilars Market

The Future Market Dynamics and Opportunities in Immune Oncology

Driving R&D Towards 2030 – Waging War on Carbon

Challenges of Drug Development in Progressive Multiple Sclerosis

Editor’s Letter