IPI V13 I3 by Senglobal

Volume 13 Issue 3

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Methods to Reduce the Anxiety of Mental Disorder Medication Current Trends in Formulation Development and Implications for Drug Delivery Devices Smart Packaging for Smart Devices Designing a Good User Experience How to Approach an NLG Solution in the Pharmaceutical Industry Sponsor Company:

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Contents 06 Editor’s Letter TALKING POINT

DIRECTOR: Mark A. Barker INTERNATIONAL MEDIA DIRECTOR: Ty Eastman ty@senglobalcoms.com BUSINESS DEVELOPMENT: George DeSouza george@senglobalcoms.com EDITORIAL: Virginia Toteva virginia@senglobalcoms.com DESIGN DIRECTOR: Jana Sukenikova www.fanahshapeless.com FINANCE DEPARTMENT: Akash Shama accounts@senglobal.com RESEARCH & CIRCULATION: Jessica Dean Hill info@senglobalcoms.com COVER IMAGE: iStockphoto © PUBLISHED BY: Senglobal Ltd. J101 Tower Bridge Business Complex London, SE16 4DG Tel: +44 (0) 2045417569 Email: info@senglobalcoms.com www.international-pharma.com All rights reserved. No part of this publication may be reproduced, duplicated, stored in any retrieval system or transmitted in any form by any means without prior written permission of the Publishers. The next issue of IPI will be published in Winter 2021. ISSN No.International Pharmaceutical Industry ISSN 1755-4578. The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright. 2021 Senglobal Ltd./Volume 13 Issue 3 – Autumn – 2021

08 At the Forefront of Innovative Therapeutic Excellence since 2006 Pharmaceutical and Biopharmaceutical sciences continue to find new applications, new modalities and new class of compounds that can improve life expectancy and standards of living for people effected by chronic or degenerative diseases. Mr. Aldo Braca, the founder of BSP Pharmaceuticals speaks with IPI explaining how BSP expects this trend to continue and how the group will consolidate and expand, offering of the highest level of services and technology necessary to produce those innovative drugs. REGULATORY & MARKETPLACE 12 Managing Regulatory Requirements as the MedTech Sectors sees Unprecedented Growth One of the fastest growing sectors within the broader pharmaceutical market is that of global medical devices. Known in the industry as ‘MedTech’, it is a market expected to be USD 613 billion by 2025. Barbara Peralta at Amplexor explains that as the value of the market increases, so does the volume and complexity of the associated regulated information that needs to be managed. 14 Assessing the Environmental Trade-offs of Medical Device Technology Device complexity can be a double-edged sword for sustainability. On the one hand, designers need to find effective ways to encourage patient adherence and reduce the number of wasted devices and treatments. On the other, they need to balance this against the environmental impact of introducing more complex parts to the device to achieve this. Brennan Miles at Team Consulting explores how to determine the environmental trade-offs of device complexity in your medical device development. 18 Biotech in China: Maximising the Global Opportunity Pharmaceutical companies from China are showing an increasing interest in international market opportunities, focusing on new drug developments in the biological field. According to Sy Chyi Yeoh at ELC Group, a raft of changes in domestic market policy and evolving manufacturing practices, along with China joining the ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use), and considerable government support for businesses investing in external markets, have prompted Chinese pharmaceutical companies to review opportunities across Europe and the US. 20 Changing the Face of Infection Prevention As we approach the 18-month mark since the onset of COVID-19, the greatest global pandemic of our times, many are turning their attention to what seems to be the next health crisis – Antimicrobial Resistance (AMR), as patients continue along a path of building up immunity to antibiotics. Dr. Anthony Senagore at PolyPid, Inc, discusses how the paradigm shift could be highly crucial in addressing the oncoming global health crisis of AMR. DRUG DISCOVERY, DEVELOPMENT & DELIVERY 24 Smart Inhalers: A Digital Step Towards Patient-centricity Respiratory infections continue to have the highest incidence rate

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Contents in Europe. Where asthma is considered, there has been a sharp increase in global cases, morbidity, and mortality rates, as well as being an economic burden over the last 40 years. More than 300 million people have asthma worldwide. These figures demonstrate that despite the efforts of the past few years, the reduction of the incidence of asthma has not been achieved yet. Thorsten Lehmann at H&T Presspart analyses how, connected devices, such as smart inhalers, offer a great opportunity to increase adherence and improve the quality of life of patients. 28 Methods to Reduce the Anxiety of Mental Disorder Medication The unprecedented stresses and strains of the last year or so have led to large numbers of people suffering from temporary psychosis or, at the very least, experiencing some form of diminished mental wellness. Trying to treat someone in this broken mental state is complex. Dr. Tanja Kromm and Dr. Patrick Mohr at LTS explores the very real benefits alternative dosage forms such as oral thin films and transdermal therapeutic systems bring to the treatment of mental disorders, combining high levels of patient acceptance with effective therapeutic benefit. 32 Improving Productivity in Discovery Research: Workflow Management Outsourcing has become a staple of pharmaceutical research and development. Its growth over the last 25 years has been driven by cost reduction, productivity enhancement, and de-risking strategies with an increasing use of specialist providers that have a history of success against challenging targets. The outsource model, whether for synthesis, biological assays, or animal studies, presents challenges and opportunities to further increase productivity. Tim Cheeseright at Torx Software Limited discusses the Design-Make-Test-Analyse (DMTA) cycle, central to the discovery of new small molecule therapeutics and agrochemicals, which has periodically received attention as a metric for improving productivity in research and development. 36 Current Trends in Formulation Development and Implications for Drug Delivery Devices The market for parenteral drug device combination products has been evolving over the last 15–20 years, developing innovation both on formulation and device design fronts. The key priority in formulation development is to create a cost-effective drug with proven efficacy and safety that can be scaled up for manufacturing. Factors such as the ability to reduce administration frequency and provide less painful and quicker injections are also important considerations. Julie Cotterell at Owen Mumford Pharmaceutical Services discusses the new trends we are seeing in formulation science. CLINICAL & MEDICAL RESEARCH 38 Managing the Inherent Complexity and Risk of Precision Medicine Clinical Supply Chains Tailoring medical treatment to the individual characteristics of patients based on genetic, environmental and lifestyle factors is quickly superseding more traditional clinical trial models. And with the benefits on offer, it’s clear to see why. Precision medicine, also referred to as personalised medicine, is helping healthcare providers better understand the factors that affect patients’ health, disease, or conditions. Natalie Balanovsky at Almac Group explains that this enables providers to predict more accurately which treatments will be the most effective and safe and to avoid prescribing drugs with predictable side effects. 2 INTERNATIONAL PHARMACEUTICAL INDUSTRY

42 The Case for a Distributable CDx Model The past decade has been an exciting era in healthcare for patients and providers with the increasingly broad adoption of precision medicine in drug development, clinical trials, and approvals. The rise of precision medicine means patients have access to targeted, potentially more effective, therapies based on their genetic responses to treatment pathways. Jane Li at Thermo Fisher defines why in many regions, a distributable NGS CDx may be far more advantageous than a centralised lab service NGS CDx as a global solution that can be deployed locally, cost effectively and with fast turnaround time to drive the broadest adoption of targeted therapies. TECHNOLOGY 44 Beyond the Pill – Why Reliable Electronics is Key to Healthcare Technology is a driving force in improving and enhancing healthcare, with advanced electronics integral to many medical developments. Today, medical improvements go beyond the pill. Electronic solutions are now imperative to improving the population’s health and wellbeing. Jay Tourigny at MicroCare Medical discusses how medical device manufacturers must ensure that their products are produced efficiently to meet the required time to market, whilst guaranteeing long-term performance and reliability. 48 How Technology is Making an Impact in Improving Managed Access Programs In the pharmaceutical industry, it’s critical to deliver medicine quickly to patients that need it most. Managed Access Programs have helped make new treatments more accessible and available to critically or terminally ill patients, but there is still work to be done in addressing rising patient needs. The goal of technology is to expedite and redesign familiar endeavours to make them easier to use for as many people as possible. As a result of technology, transparency, speed, and collaboration are more critical than ever. Mark Layden at CyberGrants discusses why pharma companies should embrace flexibility as often as possible, not only when dire circumstances require it, to ensure that they’re providing the best care and in turn best outcomes for their customers who need it the most. 50 Building Common Ground for Collective Intelligence: How Digital Supply Networks Can Provide a New Era of Collaboration for Industry 4.0 In the pharma industry, new ground is gained every day in understanding how digitally connected supply networks can help drive innovation, respond rapidly to disruptions, and ensure business continuity. The journey to digital supply network adoption begins where many organisations are suffering from a lack of supply chain visibility and ends with an opportunity to leverage the power of collective intelligence. In this article, John Bermudez at TraceLink, explores how organisations can create their own digital supply networks on demand to forever change the way they work with their suppliers and partners. MANUFACTURING 52 How to Future-proof the Manufacture of Sterile Drug Products The aseptic pharmaceutical processing market is growing incredibly quickly. This strong and sustained performance is being fuelled by greater demand for sterile drug products. A factor that is driving this growth is the way in which modern therapies have changed the approach to helping patients. As with any significant shift in process, any changes that are implemented need to be ones that are functional in the long-term, especially in today’s rapidly changing environment. Christian Dunne of ChargePoint Technology explores Autumn 2021 Volume 13 Issue 3

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Contents the latest trends in containment and advises how pharma companies can adapt and thrive in a fast-evolving environment. 56 Formulation and Process Considerations for Optimising Spray-Dried Solid Dispersions Spray drying active pharmaceutical ingredients (APIs) in solution to overcome solubility hurdles requires part craft and great attention to process variables. Today’s APIs are increasingly insoluble and that is presenting new problems for formulators looking to manage the bioavailability and dosing of their formulas. In this article, Javier Gurrea from Idifarma, explains how expertly applied spray drying technology offers drug innovators a faster route to higher-performing drugs. 60 From R&D to Production: How the Bioreactor Choice Can Streamline Biologics Scale-up Transferring a biologic candidate from the research and development phase to commercial production usually requires increasing the working volume of the upstream bioprocess. During scale-up, process performance optimised at small scale needs to be reproduced at larger scale, ideally without much need for process optimisation at large working volumes. This requires reproducing the cells’ growth environment across scales. In this article Amanda Suttle, Ulrike Rasche, and Ma Sha at Eppendorf discuss why certain bioreactors’ engineering parameters are critical to make this possible. 64 Small-scale Batch Production for Clinical Gamma Scintigraphy Studies of Pharmaceuticals Pharmaceutical gamma scintigraphy is a technique which has been adapted from clinical diagnostic applications to enable the in vivo fate of pharmaceutical dosage forms to be accurately determined in patient populations, or healthy volunteers. It is the gold standard for deposition, retention and transit studies and has been used in many 100’s of clinical trials since the 1970’s. Glyn Taylor and Simon Warren at Scintigraphics shows how evaluation of pharmaceutical dosage forms using clinical gamma scintigraphy in early phase clinical development can provide critical information on drug delivery to the site of action/absorption. 72 New DPI Data Insights Shaping Future of Global Healthcare Needs Innovative inhalation therapies and drug delivery are legacies of the COVID-19 pandemic, as pharma and biopharma formulators address growing demands for new healthcare solutions. Lactose-based dry powder inhaler (DPI) formulations are the most significant form of inhaled treatment for respiratory conditions such as COPD and asthma. Now, they also being used to treat COVID-19, leading to an increase in demand for lactose-based excipients. Harry Peters at DFE Pharma describes a multidisciplinary study which aims to help manufacturers save time and money in the development process by testing various formulations of magnesium stearate-coated lactose in the blending and filling process. 76 Aseptic Processing and Cleanroom Technology The cleanroom technology market is a growing segment of the manufacturing industry that is expected to expand from a value of $3.87bn in 2019 to $5.04bn by 2025. One of the main drivers of this growth is an increase in sterile drug products, such as injectable biologics and ophthalmic formulations. Market data shows that over half of clinical stage projects are injectables, and programs for eye diseases have doubled in the past five years alone. Robert Lee and Jason Steele at LLS Health – CDMO Division discuss the importance of cleanroom technology being fit for purpose in aseptic processing and how changing R&D pipelines have led to a rise in the number of 4 INTERNATIONAL PHARMACEUTICAL INDUSTRY

companies outsourcing their sterile product manufacturing to CDMOs. PACKAGING 78 Smart Packaging for Smart Devices: Designing a Good User Experience As the use of health apps among the general population continues to grow, medical device developers are beginning to look to companion apps to tackle the challenge of poor adherence, improve patient experience and ultimately improve healthcare outcomes. Paul Greenhalgh and Ben Cox at Team Consulting describes how using behavioural design theories and applying UX design principles, we can help lower the barrier to adoption of new technologies, whilst ultimately enabling new tools to support patient adherence. 82 Innovative User-friendly Child-resistant Packaging Solutions In the European Union (EU), poisoning is the fifth leading cause of unintentional death for children and adolescents, with one of the most cited causes being medicinal drugs. Despite increased efforts over the last fifty years to improve parental education in childproofing homes and developments in child-resistant packaging that have steadily decreased the number of cases, accidental poisoning remains a considerable risk in the home. This article by Najet Mebarki at SGD Pharma and Dr. Rolf Abelmann at IVM Childsafe GmbH will explore how the pharmaceutical industry faces this global medical challenge, evaluating existing and future pharma packaging trends. 86 Addressing Value-based Care Needs with Parenteral Packaging Three Key Considerations to Boost Quality of Care and Outcomes Amid Demographic Shifts According to the World Health Organization (WHO), the pace of the population aging is faster today than ever before. From 2015 to 2050, the number of people aged over 60 is predicted to increase from 12 percent to 22 percent, creating challenges for countries around the world to ensure both health and social systems can deal with what the WHO refers to as a demographic shift. Carina Van Eester at DATWYLER identifies that, as more people are diagnosed with chronic health conditions and costs continue to rise, it has never been more important to maintain the highest level of care using all available tools and resources, including parenteral packaging. LOGISTICS & SUPPLY CHAIN MANAGEMENT 90 Minimising Vaccine Wastage with Advanced Refrigerator and Freezer Technologies Despite intense global efforts to ramp up COVID-19 vaccine production and distribution, many of these doses are still not reaching people’s arms, with hundreds of thousands of vaccines being wasted. A leading cause of vaccine wastage is exposure to inappropriate temperatures during cold chain storage. Chase Heibel at Thermo Fisher Scientific discusses that a new international standard will help healthcare providers to select high-performance refrigerators and freezers with the precise temperature control necessary to protect the quality and integrity of the vaccines stored inside. 92 How to Approach an NLG Solution in the Pharmaceutical Industry NLG is a section within AI technology that develops solutions to automatically generate natural language – or language spoken and written by humans. NLG platforms can create high-quality texts depending on the solution, based solely on Machine Learning (ML) or on the insights gained from data. Robert Weissgraeber at AX Semantics explains why use cases for NLG are continuing to expand as more and more companies work to leverage their data. Autumn 2021 Volume 13 Issue 3

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Editor's Letter I hope everyone has enjoyed the summer and have now had the opportunity to get fully vaccinated against Covid. This past pandemic has affected us all in different ways, especially out relationship with our community. I certainly think one lesson we should all learn from this pandemic is that we must look after each other much better, even if that is just asking people how they are or how we can help. I am also excited to see what new developments we have achieved over the beginning of the pandemic. Mr. Aldo Braca, the founder of BSP Pharmaceuticals in the Talking Point Segment, discusses the advancement they have made to their company, to service the pharmaceutical sector better. He speaks about being at the forefront of the fight against cancer. As it is now, roughly 9.5 million people died of cancer worldwide, a statistic we can only assume will ride due to Covid-19 effecting in person diagnosis. Barbara Peralta at Amplexor talks about managing Regulatory Requirements as the MedTech Sectors sees Unprecedented Growth, with the Internet of Medical Things (IoMT) market estimated to be worth $158.1 billion in 2022. How can we ensure that complexity of associated regulated information that needs to be managed plus all the different players in the market as well? I am hoping that the past two years has clearly shown that we must collaborate as a whole planet for the best of humanity, with this in mind, Sy Chyi Yeoh at ELC Group is looking at Biotech in China and maximising the global opportunity. We surely cannot become nationalistic thinking in our industry, and we must continue to be an international industry. Mental health was certainly a topic being talked about before the pandemic, but it has become more apparent during Covid-19 due to lock downs and isolations. Our industry is trying to help the patients who can get better and survive their disease while also understanding that mental health can be a long-term disease that patients will have to learn to live with. Dr. Tanja Kromm and Dr. Patrick Mohr at LTS talks about Methods to reduce the anxiety of Mental Disorder Medication.

Jay Tourigny at MicroCare Medical discusses Beyond the pill and why reliable electronics is the key to healthcare. We have seen a real shift towards being able to access a doctor virtually and being able to get a prescription being sent to the pharmacy, which is great, but I do also worry about the elderly generation who may not have access to this. We must ensure that there is inclusion for everyone moving forward. Plus, The COVID-19 pandemic did not seriously impede the production and shipment of pharmaceuticals in the first quarter of 2020, although the months ahead will be critical as chemical deliveries slow down and inventories of backup supplies dwindle. What the pandemic has done is wake up regulators and world leaders to the extent to which China dominates the world’s supply of active pharmaceutical ingredients and their chemical raw materials. An ongoing industry effort in the US and Europe to rebalance the pharmaceutical chemical supply chain is likely to be energized by government initiatives to ensure domestic production of drugs. Pharma operations leaders have increased their focus on network risk management, agile and transparent operations, and shaping the workforce of the future in the post-COVID-19 path to recovery. Some might argue that leaders of operations in the pharmaceutical industry have been historically slow to respond to changing times. During the COVID-19 pandemic, however, many across the industry have been highly responsive. Industry operations leaders have rallied to enable the supply of key medicines across borders, manage workforce safety, and handle evolving government restrictions all while beginning to prepare for new vaccines and therapeutics. And most companies have put crisis-response command centers in place to appropriately manage and bring stability to an otherwise unstable time. With these initiatives established, companies can begin taking stock of what lies ahead. Given the shifts that have taken place seemingly overnight

we need to make this safe so that should the cloud fall out of the sky, we have a backup plan. I really hope everyone enjoys this edition of the magazine and that we all have a great autumn plus we remember to do the things that we enjoy in our lives and be nice to each other. Lucy Robertshaw, CEO LucyJRobertshaw in response to the immediate crisis, companies are also turning their attention to recovery and the path to the next normal. This will likely bring about fundamental changes in pharma operations. While individual companies will drive many of these changes, some will be driven industry-wide, and external factors, including government’s involvement, will also have impact on shaping the post-COVID-19 recovery. We will see the comeback of one of the biggest Pharma Outsourcing exhibitions in November. Taking place for the first time since October 2019, CPhI Worldwide will return in-person on 9-11 November 2021 at Fiera Milano in Milan, Italy. The eponymous pharma platform that unites the industry, with six events covering all aspects of the supply chain – from ingredients and finished dosage to machinery, packaging, outsourcing and biopharmaceuticals. To further enhance your experience, running alongside the in-person edition will be a digital platform hosted October 25th until November 19th. This platform will empower pharma with even more resources to meet, source and discover by providing improved networking opportunities as well as the chance to pre-qualify leads ahead of the event. Additionally, the digital platform will host key insights from thought leaders spanning some 45 + sessions and content, including keynotes, webinars, podcasts, and whitepapers. I hope you all enjoy this edition of the IPI Journal, and hopefully I will meet some of you at Pharmapack and CPHI. Till then, stay well, stay healthy and I look forward to bringing you more informative articles in the December issue. Virginia Toteva, Editorial Manager – IPI

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

Georg Mathis Founder and Managing Director, Appletree AG

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

Catherine Lund, Vice Chairman, OnQ Consulting

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

Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

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

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

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

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

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

Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group

Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

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

Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

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

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

Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting Stefan Astrom, Founder and CEO of Astrom Research International HB T S Jaishankar, Managing Director, QUEST Life Sciences Autumn 2021 Volume 13 Issue 3

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Talking Point

At the Forefront of Innovative Therapeutic Excellence Since 2006 Mr. Aldo Braca, the founder and CEO of BSP Pharmaceuticals speaks with IPI explains how BSP will consolidate and expand offering of the highest level of services and technology necessary to produce innovative drugs.

Q: BSP Pharmaceuticals has been at the forefront of the fight against cancer since 2006. Can you tell our readers the brief history of the company, how the company started and your growth so far? A: BSP was created with the mission to become a valuable and trustable partner for innovators, engaged in the research of new effective therapies against cancer. Our original focus was on small molecules, mostly used in classic chemotherapy, but very soon, with the objective of supporting innovative therapies, we also found ourselves engaged in manufacturing biological large molecules as they were more promising innovative products for new generation of oncology therapies. After successful results and receiving certification of our quality system, we were capable to meet requirements of the most demanding regulatory agencies, our growth has been driven by the increased demand of capacity for Oncology products (that was mainly planned as part of the intelligence work at the beginning of the project) and by the strategic decision to strongly support the development and evolution of ADCs and oncology biological derivatives. Operating world class technology, paying attention to market demand and subsequently investing to expand available capacity which could be offered to partners, have been the most important hallmark of BSP. Now the company has a consolidated role in supplying anticancer products and is a reference for the ADCs scientific

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community and is ready to initiate a new step in its history by opening capacity for additional therapeutic areas. Q: With all the different health issues your company could have explored, why did your company choose to go into the oncological research and development? A: In 2006, when BSP Pharmaceuticals was incorporated, the Global Pharma Industry was experiencing a serious and extended shortage of oncology drugs, as well as a lack of products that could be available for patients worldwide. This issue arose mainly due to a general insufficiency of qualified manufacturing capacity suitable to cover the global increased demand of oncology therapies which was made worse when the European and American Agencies formalised regulatory actions against consolidated CMOs who were forced to temporary or permanently close production sites. As a result of this emergency, Pharma Companies had to work hard to assess their outsourcing strategy and partnership selection processes. Companies started to look for reliable partners that could ensure the proper level of technology and flexibility to cover their needs in combination with consistent reliability to comply with the highest quality requirements, applied by worldwide Regulatory Agencies. This scenario outlined a space with a high potential for developing a new project that could be specifically designed to satisfy a clear need and defined the space where our company wanted to enter.

Q: Your company focuses on essential elements of its supply chain safety, clinical and commercial production. With this in mind, how have you made a difference within the industry? A: As a new player in the arena, BSP has been differentiating from the already consolidated CMOs by offering specialised, world class technology with a strong aptitude to look at innovative compounds, new class of products, new modalities and developing a range of capabilities designed to handle intricacies associated with the manufacturing of complex formulations. Of course, the first point of differentiation is the initial decision to focus on a specific therapeutic area (Oncology), instead of opting for a wider basket of compounds and products. On one hand, this initially l looked like we were limiting our business opportunities, but on the other hand, this enabled us to clearly characterise the company and stand out as a specialist in the services we were offering. The second point was the choice to apply the highest standard of technology and develop a full contained facility suitable to safely handle High Potent APIs, which is normally used to manufacture oncology drugs. An additional point was the possibility to cover the entire life cycle of a product, from pre-clinical to clinical and commercial phase, combining development services and cGMP capability, with enough flexibility and capacity to quickly address forecast’s variations and offering an end-to-end solution for pharma.

Autumn 2021 Volume 13 Issue 3

Talking Point

Last but not the least, it is our attitude to continuously upgrade and increase the level of services and capacity available for existing and new partners, while also supporting the rise in forecast and growing market demands. Q: What major events have occurred in the industry and what has been its effects? A: As the average age of the population in developed nations increases and the request for treatments of aged-related pathologies are becoming more and more relevant, the demand for innovative cures that could be beneficial for patients has been growing accordingly. Pharmaceutical and Biopharmaceutical sciences continue to find new applications, new modalities and new classes of compounds that can improve life expectancy and standards of living for people effected by chronic or degenerative diseases. We expect that this trend will continue to grow and BSP will be requested to consolidate and expand offering of the highest level of services and technology necessary to produce those innovative drugs.

ideas helping to treat cancer, we wanted to stay close to this scientific community with the objective of helping scientists to execute their ideas. With this in mind, we communicate and listen to the scientific community to learn and understand their needs and offer customised solutions to help them in promoting the progress of ADCs in the clinical and commercial environment. In 2011 we developed and introduced the concept of “integration of services” and in 2013 we have been the first CDMO

to offer an integrated supply chain for ADCs. Manufacturing drug substance in conjugation suites and drug product in fill finish suites, all under the same roof and all combined with QC and development services. We also designed our capacity with flexibility to handle small/mid-size batches suitable for initial clinical needs and bigger size for commercial requirements, with the possibility to scale up process to 6.5 Kg mAb with a significant improvement, compared to

Q: With ADCs being a relatively succinct form of Cancer Treatment (with only 56 companies producing them in 2019), can you tell our readers how your company's development stands out from the rest? A: We have always been interested in ADCs, not simply as new classes of compounds that could be significantly beneficial in the fight against cancer, but more importantly as a new scientific approach to oncological diseases. By generating an immense number of new wwww.international-pharma.com

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Talking Point The objective of this plan is to continue the process of integration of already available services initiated few years ago and expanding to other therapeutic areas. Considering how Big Pharma and Small Biotech’s are distinguishing their pipelines by prioritising their focus on oncology, immunology, immunotherapy and evaluating the growing number of biological compounds entering as NBE within the clinical and the commercial phase, we started the construction of a new site in our plant in Latina, Italy in 2018. This plant will incorporate the same level of technology we already use on site but will be dedicated to the manufacturing of noncytotoxic products and will host six filling lines with significant capacity for liquid and lyophilised formulations. The original plan was scheduled to be completed by 2026, but with the crisis created by the worldwide COVID-19 emergency and the subsequent extraordinary need of qualified capacity for strategic products (like the ones BSP is already producing) BSP pushed the top Management to speed up the completion of the project, which is now expected to be finish by end of 2023.

what other CMOs can offer. Finally, we have high annual capacity for either DS and DP manufacturing. We are currently engaged in a significant number of ADC programs in different clinical stage and producing 7 of the 11 ADCs approved for commercial use, applying several conjugation technologies and payloads, with high annual capacity for either DS and DP manufacturing and ongoing expansion that will be available in the next months. In the last decade, BSP has become a reference point CMO for the ADCs’

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community and wants to consolidate this role by continuing supporting the growth of this class of compounds. Q: Innovation is one of the Company's key values: This brings forth the question of if or when you plan to expand into other areas? Which areas are you expanding into? A: In 2017 BSP approved a new step in its strategic growth plan, which incorporated significant investments on the site, which will drive the future growth of the company.

With this new extension of capacity, the Company intends to consolidate its current role in producing Oncology drugs as well as expanding into additional therapeutic areas like Immunoncology and immunotherapy by keeping the original focus on innovative compounds.

Aldo Braca Aldo is the Founder and CEO of BSP Pharmaceuticals and has several years’ experience in the pharmaceutical business. Aldo has been President of Patheon Europe, a subsidiary of Patheon Inc., since 2010 and developed the company in Europe starting from 1999. Aldo's career includes 29 years with Bristol Myers Squibb European operations, where he held positions of increasing responsibility. He served Bristol Myers Squibb, as President – Worldwide Manufacturing Operations at Medicines Group. Autumn 2021 Volume 13 Issue 3

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Regulatory & Marketplace

Managing Regulatory Requirements as the MedTech Sectors Sees Unprecedented Growth Amplexor’s Barbara Peralta on how and why MedTech manufacturers must adopt a more joined-up and better coordinated means of refining technical content in order to manage increasing regulatory requirements. One of the fastest growing sectors within the broader pharmaceutical market is that of global medical devices. Known in the industry as ‘MedTech’, it is a market expected to be USD 613 billion by 2025. As the value of the market increases, so does the volume and complexity of the associated regulated information that needs to be managed. In May 2021, the EU Medical Device Regulation (MDR) came into force across EU member states, and the equivalent In Vitro Diagnostic Regulation (IVDR) will follow in May 2022. It is a similar story of increased regulatory requirements in the rest of the world. Other regions are heading in a similar direction to the EU, with health authorities keen to make devices more traceable and enforce more consistent monitoring of device safety, prior to products entering the market and once they are in use. This all means that organisations must define and implement a clear and robust content strategy to meet global requirements and to reap their own business benefits from them. Manufacturers will need to decide how they will optimise processes, manage resources and fill any gaps in their current skill sets. Although regulatory compliance can feel onerous, increased information and process rigour can positively affect any MedTech business. Removing content siloes Organisations in many industries commonly store content across repositories. This siloed approach also exists in MedTech, which exacerbates this by adopting a relatively ‘loose’ approach to change management. This includes amending labelling, quality, and marketing content in a siloed manner rather than scheduling the updates centrally. 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

To stay on the right side of the new regulations, to maintain the highest level of patient safety, and to take advantage of economies of scale, manufacturers need to adopt a more joined-up and co-ordinated means of refining technical content. This should involve looping market feedback back into product lifecycle and labelling management and a holistic and systematic approach to planning and scheduling content updates. This establishes good practice for any immediate requirements and readies them for increased regulatory measures in other major regions worldwide as and when they evolve. Adopt a realistic timescale and plan of action No company can do everything at once, so to understand the scale of work and the priorities, MedTech firms should begin with a gap analysis. This allows them to prioritise and plan much more effectively. Each MedTech company's situation will differ depending on their product portfolio, device classes, current CE marks and their time to expiry, and what it will take to make each product compliant with the new requirements under MDR or IVDR. Regulatory experts will be able to help with these assessments and with regulatory planning. The next logical step is to assess what it will take to bring content into a compliant state and how to do this efficiently and economically, aligned with other change requirements – especially if there are high volumes of technical and quality documents or labels to update. There are no shortcuts to doing this properly, so a long-term plan will be required. Ensure content is managed centrally Up to now, each team in an organisation has pursued its own agenda, without much thought to combined efficiency or consistency of content or its presentation. Quality, Regulatory Affairs and Marketing all hold their own information and content, and all work with it in different ways.

The MDR and IVDR focus on clinical evaluation and post-market surveillance, means that MedTech manufacturers will be able to more efficiently manage changes and updates, as they develop a co-ordinated content management and translation strategy that spans and consolidates common information sources. It should drive higher quality, greater content control and streamlined change management across the board – serving the needs of Quality and Marketing as well as regulatory compliance from a single, master source of truth. Being strategic about all of this will enable companies to start capitalising on the wider benefits of holistic content management. These include new scope for structured content authoring/automated publishing, dynamically calling up and reusing agreed fragments of content/topicspecific information to create content for Regulatory, Quality, or Product Labelling requirements. Selecting the right solution There are many content management and authoring systems for MedTech firms to choose between. Once they have a good grasp of their starting point and where they need to get to, medical device manufacturers can begin their search for the right system for their particular circumstances. Some tools are more technically complex, requiring retraining, which might feel a step too far. Other systems look and feel more like Word while still delivering the XML output needed to support dynamic search and structured authoring/automated publishing. A good partner will be able to help with a pilot project and ROI modelling to show the savings that will be possible from adopting a particular approach and system. As a rule of thumb, companies should allow 1-3 months for the assessment and pilot and another 3–6 months for the phased transition to the new way of managing content, labelling and document publishing. So while the MDR/ IVDR deadlines are looming – there is still time to make this strategic change and reap the long term benefits from it post-deadline. Autumn 2021 Volume 13 Issue 3

Regulatory & Marketplace critical the role of the device, the more important regulatory rigour – close monitoring and reporting of their efficacy, safety and reliability – becomes. Content is one of the most important assets any MedTech firm has at its disposal. But it needs to be managed effectively in order for organisations to reap the most benefit from it. This is true now and will be even truer in the future when regulatory compliance requirements become even greater. Therefore, any MedTech manufacturer should begin this process of change sooner rather than later.

Retaining content control As combination products – those combining devices and drugs – continue to multiply, and as these products become smarter and more sophisticated, maintaining high levels of content control will become more important too. The evolving role of combination treatments in diabetes care highlights the

more embedded role MedTech is playing in patients’ everyday lives. First, home kits were used simply to test for glucose levels following a pin-prick blood test. This scenario progressed to continuous monitoring using patches or implants, and now the latest MedTech innovation goes one step further – automatically administering glucose once a lower threshold has been crossed. The more invasive and safety-

Barbara Peralta Barbara Peralta is Director of Life Sciences Solutions at Amplexor. Web: www.amplexor.com Email: barbara.peralta@amplexor.com

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Regulatory & Marketplace

Assessing the Environmental Trade-Offs of Medical Device Technology Device complexity can be a doubleedged sword for sustainability. On the one hand, designers need to find effective ways to encourage patient adherence and reduce the number of wasted devices and treatments. On the other, they need to balance this against the environmental impact of introducing more complex parts to the device in order to achieve this. So how do you determine the environmental trade-offs of device complexity in your medical device development? Adherence & digital technology Before you can make an informed decision on the environmental trade-offs of added device complexity, it’s important to understand the adherence issue and how this also contributes to the sustainability challenge. Treatment through ‘at home’ or ‘on-the-go’ drug delivery is fast becoming normal practice for many conditions. Despite this, several years ago the World Health Organization (WHO) estimated that only 50% of patients successfully take their medication as prescribed.1 The WHO also suggested that poor adherence is not only detrimental to patient health, it also has a direct impact on the environment due to overuse of both medicines and devices.2 In order to tackle this, device developers have been confronting the issue of nonadherence from the ‘bottom up’. Following a user-centred approach, designers are striving to ensure patients have the right tools, instruction, and support to help improve device usability and reduce the burden of taking medication. As part of this, many developers are looking to new technologies to help.

patients to become more likely to adhere to treatment regimens and better equipped to manage their own health conditions. This could then in turn reduce the need for further environmentally costly healthcare interventions. The environmental trade-off of increased complexity While these new device technologies could help improve the issue of patient adherence, there is inevitably an environmental cost. In order to achieve improved usability, devices have become increasingly complex, using more intricate components and manufacturing methods. Not only is substantial energy needed to achieve this during production, the amount of environmental waste also increases when these complex products reach their end of life. To date, the regulatory position has been that the health benefits for the patient should outweigh the environmental impact of the device. This way of thinking is however quickly becoming outdated, with an increasing drive in the industry to ensure that complex device technology is only used where it really adds value. Compared to other sectors, such as consumer goods, the healthcare industry has been relatively slow to adopt the principles of environmental sustainability. While there has been a general lack of published data on the topic, particularly in the drug delivery space, it is up to medical device developers to incorporate environmental assessment tools into their developments, to help support more sustainable decisionmaking.

Using Life Cycle Assessment There are a number of tools for measuring carbon footprint within a device development. One of these is the Life Cycle Assessment (LCA) methodology. An LCAbased approach offers a valuable means for carrying out a systematic evaluation of carbon footprint for device technologies that contain many different materials and use various manufacturing methods. By following an LCA methodology, medical device developers and manufacturers can gain an effective framework for the systematic evaluation of the environmental impact of mass-produced medical devices. It is a relatively simple process that can be effectively implemented into a development process, to help drive environmentally sustainable decision making and strategies. An LCA can be deployed from the beginning of a new device development (or selection) process to ensure that data driven decisions can be taken at key milestones or phase exit points. With the correct tools and templates, the assessment can be relatively simple to carry out and produce results that are easy to understand. The ISO 14040 series of standards provide a methodology for carrying out an LCA in a phased approach, covering four main phases:3 1. 2. 3. 4.

the goal and scope definition inventory analysis impact assessment the interpretation phase.

The process should be iterative, with the results of one phase forming the inputs for the next. There are then a few variations of LCAs which can be used, depending on the data that is available and practicality.

Advances such as on-board electronic sensing, monitoring and connectivity have indeed paved the way for improvements in patient adherence. Digital connectivity within inhaler devices, for example, can provide users with feedback on correct usage and help them monitor and log other valuable data. While real world data on the benefit of digital technologies is limited, the goal of the medical device industry is for 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Regulatory & Marketplace

A cradle-to-grave, or ‘full’, LCA follows five general stages: 1. 2. 3. 4. 5.

raw materials extraction materials manufacture product manufacture transport and usage disposal/waste.

When a full LCA is not feasible, there are also some variations. A ‘cradle-to-gate’ LCA assesses the product up to the stage it leaves the factory, while a ‘cradle-to-cradle’ LCA replaces the disposal and waste stage with a recycling process, whereby raw materials would be reused for another product. Conducting an LCA requires a vast amount of valid input information to provide an estimate of carbon footprint, (this being the measure of carbon dioxide and other gases which accumulate in the atmosphere and in turn increase the earth’s average temperature). Here the term carbon footprint acts as a proxy for the larger impact factor referred to as Global Warming Potential (GWP). The results for an LCA are typically given in grams of CO2 equivalent (g CO2-eq), using the IPCC 2007, 100-year GWP.4 This value is determined by the sum of each greenhouse gas (GHG) emission, which is then converted to grams of CO2-eq based on their GWP. wwww.international-pharma.com

When conducting an LCA, product specific characteristics, such as the mass of each component, are considered as ‘foreground data’. This is then calculated alongside ‘background data’, or Life Cycle Inventory (LCI) data, such as data on manufacturing processes and material properties. Drawing insights from LCA To illustrate the value of conducting LCAs as part of a development process, Team Consulting recently carried out a cradle-togate LCA on three hypothetical pressurised metred dose inhalers (pMDIs) of varying complexity. The analysis focused on the mechanical and electronic components of the devices in order to assess the carbon footprint of each part. Simple pMDI device: the first device was a simple pMDI inhaler, where the primary container, encompassing a pressed aluminium canister body and canister metering valve assembly, formed the bulk of the product. The device had a simple construction, made up of two injection moulded polymer parts. Complex pMDI device with integrated breath actuation mechanism (BAM): for the second device, we analysed a complex pMDI inhaler with BAM and a dose counter. In addition to the primary container, this device had 17 basic components and contained a

mixture of injection moulded polymer and pressed metal parts, as well as a formed spring. Advanced pMDI device with BAM and digital connectivity: the third pMDI device was based on the same device architecture as the second device, but with an added digital connectivity module. This sensing module was made up of a series of key electronic components, as well as a microcontroller unit (MCU) mounted on a printed circuit board (PCB), along with a replaceable battery. While the study focused only on the device technology, excluding drug formulation, active pharmaceutical ingredients, primary packaging, transportation and usage, the assessment provides an interesting insight into the carbon impact of adding device complexity. The findings show a significant increase in the carbon footprint of the device as the number of components and physical mass of the device technology increases. For the simple pMDI device, without any connectivity or electronics, the canister body appeared to have the greatest single contribution of CO2-eq (35%, 30g CO2-eq). When electronics and a digital connectivity module were added in the third device, these relatively small features almost doubled the CO2-eq compared to all the other mechanism components combined (323g CO2-eq for the INTERNATIONAL PHARMACEUTICAL INDUSTRY 15

Regulatory & Marketplace effect the sustainable credentials of the final product. While carbon footprint is an important factor in sustainable decision-making, it is not the only factor that needs to be considered. Improving the usability of a device is an important factor that should also be considered, owing to the potential to improve adherence and reduce the need for secondary healthcare interventions. Hopefully, sustainability in future medical device developments will be given the same importance and detailed consideration as other commercial factors such as time and costs. However, it will also be important for the environmental credentials for new device technologies to always be carefully balanced against potential usability and adherence gains. REFERENCES 1.

2. 3.

electronics components compared to 332g CO2-eq for the mechanical parts). We often focus on larger materials and plastics when considering CO2 emissions, however smaller components such as electronics clearly also have a major impact on the overall carbon footprint of a device. Circuit boards also appeared to have the most significant carbon output relative to their size. Even without electronic components, a bare printed circuit board contributed to over 21% (151g CO2-eq) of the carbon footprint for the entire device, despite being relatively small. Of course, it is indeed their small size and ready availability that can give the false impression that electronics and sensing technologies come with a lower environmental impact compared to other larger mechanical and plastic components. In fact, the opposite is often true. Intense mining processes are needed to source raw materials, while a vast amount of water and electricity is needed to manufacture the electronic components and PCBs. Clearly, electronics in devices come with a high carbon cost. 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Moving towards more sustainable decision making Pharmaceutical companies are increasingly considering environmental concerns as an important part of device development, with many placing sustainable development at the core of their values and strategy. Product developers therefore have a responsibility (and the influence) to ensure that the CO2-eq ‘spend’ for their future device technologies are monitored and minimised throughout the development stages. Early engagement with tools such as LCA in the development process can provide design teams with valuable data for highlighting carbon footprint hotspots. This can allow them to focus design efforts to mitigate issues in these areas before they are translated into the final product or supply chain. As with other critical development processes such as risk management, future development records could also benefit from including a ‘sustainability management file’, documenting the history of assessment and mitigation of areas that

World Health Organization: Adherence to longterm therapies: Evidence for action 2003 [https:// www.who.int/chp/knowledge/publications/ adherence_report/en/]. Accessed March 31, 2021. Medicines: rational use of medicines. Geneva: World Health Organization; 2010 (WHO factsheet No. 338). International Organization for Standardization. ISO 14040: 206: Environmental management – Life cycle assessment – Principles and framework. [https://www.iso.org/standard/37456.html]. Accessed March 31, 2021. The Intergovernmental Panel on Climate Change, https://www.ipcc.ch/site/assets/uploads/ 2018/05/ar4-wg1-errata.pdf

Brennan Miles Brennan Miles is a medical device expert with an extensive background in managing and delivering innovative, high-value programmes across a range of medical technology and pharmaceutical delivery routes. These include infusion, injection, intranasal, implantable, ocular, oral, respiratory and topical applications. He has hands-on experience of gaining device approval within the regulatory frameworks. Brennan co-ordinates Team Consulting's drug delivery activities to ensure they continue to create exciting technologies, develop more sustainable medical products and deliver exceptional services for their clients. Email: info@team-consulting.com Autumn 2021 Volume 13 Issue 3

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Regulatory & Marketplace

Biotech in China: Maximising the Global Opportunity

Pharmaceutical companies from China are showing an increasing interest in international market opportunities, especially with regard to new drug developments in the biological field. A raft of changes in domestic market policy1 and evolving manufacturing practices,2 along with China joining the ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use), and considerable government support for businesses investing in external markets, have prompted Chinese pharmaceutical companies to review opportunities across Europe and the US. This is not to understate the value of the local market. China is now the secondlargest global market for pharma behind the US. Its value is expected to reach $300.9 billion by 2025, growing at a compound annual rate (CAGR) of just over 12%, according to GlobalData estimates.1 As the domestic market shifts in emphasis from traditional generic drugs to more novel, innovative therapies, capitalising on global opportunities for these more-targeted offerings will be an important part of the commercial plan. For organisations sizing the potential, there are a number of practical considerations. For instance, should they establish proprietary operations in target markets, acquire local companies, or partner with on-the-ground sales representatives? How can they accelerate local compliance in new markets, in particular with the stringent and diverse provisions across the EU – which continue to evolve in line with advances in medicine? And if they do set up a base in Europe, where should that be now that the UK, which used to be the favoured destination, is no longer part of the EU? Channelling pent-up demand The pent-up interest is tangible, and growing. In 2020, 48 new drugs were approved by China’s pharma regulator, the NMPA (National Medical Products Association), 20 of which were domestic, which suggests 18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

there is both huge demand for new drugs for the Chinese market and a surge in new drug development.

comprehensible regulatory demands. Spain, with its advantageous tax environment, is another favoured alternative.

In parallel, global pharma companies are eyeing the sizeable Chinese market with great interest. China’s membership of the ICH and other regulatory moves, such as its adoption of a marketing authorisation system similar to that commonly used across Europe, and enhanced pharmacovigilance (PV) activity, are reducing time to market for drugs from abroad. Chinese populations can now gain access to drugs in sync with a product’s global launch, rather than considerably later and for pharma companies external to China, the prospect of expedited ROI makes the market newly attractive.

Despite harmonised requirements set out by the EMA, each market in Europe has its own interpretation of the rules and its own priorities, presenting a diverse set of parameters for foreign companies to navigate. That’s aside from the myriad languages and the diverse cultural make-up of both the 27 member states and the other European countries – including the UK - that sit outside the EU.

Navigating diverse market requirements Amid these considerable opportunities to break new ground, on both sides, there are also practical challenges to be overcome. Pharma companies must assess the best models with which to maximise their new market potential, while minimising their exposure to risk. One common approach is to engage the services of a global or local CRO/outsourced service provider to bridge gaps in relevant regulatory knowledge, understanding of local market dynamics, or on-the-ground resources. Between China and the US, CRO relationships are relatively seamless to set up and manage because historically, scientists have moved back and forth between the two jurisdictions. The dominance of the English language in the US, and having a single authority in the shape of the FDA, not to mention a favourable environment for biotech innovation, continues to cement that bond. Post-Brexit EU strategies However, since Brexit, Europe has presented more of a challenge for ambitious Chinese pharma companies. The UK, once a natural base for European expansion for reasons of language and its pro-collaboration culture, no longer offers the same bridge to the Continent, so strategies for European expansion have had to adapt. Germany is now emerging as a popular EU base for Chinese companies, with relatively transparent and

Companies entering European markets for the first time will be looking for optimum ways to manage trials and registrations across different territories. Appropriate onthe-ground support from a CRO can prove crucial here. The EU maintains the most advanced quality and safety standards in the world, so this is an important market to get right from a pharmacovigilance and general regulatory/quality compliance perspective. Developing systems and processes to meet European standards should set a company in good stead for accelerated compliance in other markets. Beyond biotech: quantifying new market potential for established offerings Understanding the relative market opportunities for products and performing independent local due diligence is also crucial. For manufacturers from China, external markets such as Europe are not just a chance to blaze a trail with innovative drugs or vaccines: they also offer additional market potential for oncology, immunology and other leading therapies, as well as affordable generics and active pharmaceutical ingredients (APIs). (China accounts for around 40 per cent of APIs globally.) The goal, then, may be to apply or adapt an existing product for EU use, perhaps relocating manufacturing operations in the process to demonstrate a commitment to the market and its quality and safety standards, or forming a local sales partnership with a known EU brand. Similarly, European pharma companies may now look to China and its now more familiar authorisation process as an Autumn 2021 Volume 13 Issue 3

Regulatory & Marketplace

additional market for established products – especially for those that could be considered high-value drugs in the local market. Again, it will be important to understand the true market potential, the evolving regulatory environment in the new market, and the differing organisational structures/criteria on which local decision-making is based, before developing the opportunity. Cross-border collaboration: a growth model with increasing appeal As biotech and innovative drug development ambitions grow globally, collaborative models are proving increasingly popular to build brand profile, gain local population trust and accelerate market access – and this works both ways. Multinational corporations such as Pfizer2 have already established joint ventures with Chinese companies to co-develop new products and smooth local market acceptance. Chinese pharma companies are also taking the acquisition route to gain a foothold in the European market, and expedite local licence approval – whether by acquiring entire small or midsized companies, or purchasing European manufacturing facilities.3 In other cases, we’re seeing Chinese pharma companies invest in European biotechs to stay ahead of the competition at home.4 Identifying enabling partners As intercontinental activity intensifies, identifying appropriate independent help is not straightforward. Global CROs can sometimes charge substantial fees particularly to help facilitate collaboration opportunities - without necessarily having precise local insight and experience. Few large service organisations have truly specialist capabilities that are as deep in China as in other territories. This includes not just language support, or even cultural understanding, but also having a true appreciation of the subtleties that make a wwww.international-pharma.com

relationship work symbiotically, such as the fact that organisations in China favour the use of the WeChat platform as a convenient communication channel for discussion and clarification in project initiation/delivery and information sharing.

Paying steeply for unsuitably generic help is something that pharma companies need to guard against. Having access to reliable, up-to-date intelligence and insights, and appropriate regional and incountry experience is paramount in order to optimise opportunities and contain risk.

Strategy over speed: investing in the right relationships As interest in cross-border collaboration continues to grow, having both a global perspective and deep, specific knowledge of both Chinese pharma and external markets – most notably Europe – will be essential to extracting maximum value from emerging opportunities on both sides. This is something the EU supports: the EMA agreed more than a decade ago to help China implement good manufacturing practice (GMP) and good clinical practice (GCP) standards similar to those applied in the EU, with a view to facilitating the use of products and data coming from China, and achieve a global approach to the manufacture and supervision of medicines in the long term.5 Finally, as an important aside, speed isn’t always the goal here: patience can also pay off. Careful relationship-building and due consideration of every opportunity, from every angle, will ensure that pharma companies extract maximum value from their new ventures and provide for every eventuality in the most efficient way possible. REFERENCES 1.

“4+7” Drug procurement reform in China, China National Health Development Research Center,

March/July 2019: https://www.cgdev.org/sites/ default/files/CGD-procurement-backgroundchina-case.pdf Major Changes in the Newly Revised Drug Administration Law, China Law Insight, August 2019: https://www.chinalawinsight. com/2019/08/articles/healthcare/majorchanges-in-the-newly-revised-drugadministration-law/ Latest patent reforms to further bolster innovative pharma research in China, GlobalData, June 2021: https://www.globaldata. com/latest-patent-reforms-bolsterinnovative-pharma-research-china-saysglobaldata/ Pfizer and LianBio Announce Strategic Collaboration to Expand Development of Novel Therapeutics in Greater China, Business Wire, November 2020: https://www.businesswire. com/news/home/20201119005290/en/ Pfizer-and-LianBio-Announce-StrategicCollaboration-to-Expand-Development-ofNovel-Therapeutics-in-Greater-China Chinese pharma firm to acquire Swiss production facility (Bristol Myers Squibb selling Swiss medicine production facilities to Chinese company WuXi STA), February 2021: https://www.swissinfo.ch/eng/chinesepharma-firm-to-acquire-swiss-productionfacility/46338654 Vivoryon Therapeutics and Simcere Announce Strategic Regional Licensing Partnership to Develop and Commercialize N3pE Amyloid-targeting Medicines to Treat Alzheimer’s Disease in Greater China, Vivoryon Therapeutics, June 2021: https://www.vivoryon. com/vivoryon-therapeutics-and-simcereannounce-strategic-regional-licensingpartnership-to-develop-and-commercializen3pe-amyloid-targeting-medicines-to-treatalzheimers-disease-in-greater-china/ EMA international activities - China: https:// www.ema.europa.eu/en/partners-networks/ international-activities/bilateral-interactionsnon-eu-regulators/china

Sy Chyi Yeoh Sy Chyi Yeoh is Director of Business Development at global regulatory service provider ELC Group, part of global life science consultancy PLG (Product Life Group). She is based in Prague, Czech Republic. ELC provides a range of global regulatory solutions through its three divisions, Pharmaceutical, Medical Devices & Translations, and has worked extensively with the Chinese pharma market for more than a decade. Email: Chyi@elc-group.com Web: www.elc-group.com

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Regulatory & Marketplace

Changing the Face of Infection Prevention

As we approach the 18-month mark since the onset of COVID-19, the greatest global pandemic of our times, many are turning their attention to what seems to be the next health crisis – Antimicrobial Resistance (AMR), as patients continue along a path of building up immunity to antibiotics. Antibiotics have transformed the practice of medicine, becoming essential in the prevention and treatment of bacterial and viral infections. In a way, it’s scary to think about where we would be without antibiotics. So, when microorganisms develop a defence against medications, rendering traditional treatments useless, lives are put at serious risk, and we have the potential of a world without effective treatments. The issue developed due to the success of antibiotics. Thwarting infection and saving lives, antibiotics are often quickly administered in healthcare facilities in an effort to reduce long-term or even fatal effects. However, 20 to 50 percent of all antibiotics prescribed in the United States in acute care hospitals are either unnecessary or inappropriately used. As such, antibiotics, like all medications, can have a serious or even fatal impact if misused. Additionally, studies have shown that it is often not the antibiotic itself, but how it is administered, that impacts its efficacy. AMR is responsible for more than 2.8 million infections and 35,000 deaths in the United States each year, and that number is rising even faster in the wake of COVID-19. And given that we don’t want to return to a world where bloodletting is the therapy of choice for fighting infection, there is a problem to be solved here. Recognising the critical time we are in, Congress recently began re-evaluating two bills in a bid to stop the oncoming AMR health crisis: the PASTEUR (Pioneering Antimicrobial Subscriptions to End Up surging Resistance) and DISARM (Developing an Innovative Strategy for Antimicrobial Resistant Microorganisms) Acts. While this 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

effort is a major step in the right direction innovation in antibiotic development to reduce AMR risk is essentially a barren industry. Drug development can take decades and time is not on our side. However, there is cause for hope as new technologies are being innovated to bring affordable solutions in short timeframes. In order to create and implement effective technologies, we need to unpack the mechanisms of AMR and identify how we can stop its progression in its tracks. AMR and Multidrug Resistance One way AMR spreads is through multidrug resistance (MDR), when a single bacterium is resistant to more than one antibiotic. When MDR plasmids are transferred to other bacteria, they instantly become resistant to many antibiotics at the same time. In hospitals, where bacteria are continuously exposed to antibiotics, MDR can thrive and enable bacteria to spread rapidly, complicating AMR prevention. A major mutation for MDR functionality is enhanced efflux pumps which are bacterial transport proteins used to extrude substrates (i.e., antibiotics) from the cellular interior to the external environment rendering them inactive. While the ability to confer this action to current medications remains elusive clinically, a parallel strategy is to locally deliver higher concentrations of antibiotic to the infection site that overwhelm even the mutated efflux pumps without causing systemic toxicity. Theoretically, this higher bacterial drug exposure coupled with little or no systemic exposure to the patient could allow for “reclamation” of many antibiotics currently presumed to be ineffective due to MDR. Given that there has been no significant progress in carrying out this process of higher concentration it is not surprising that it has never been considered a realistic solution. “Generals Always Fighting the Last War” It is only fairly recently that infectiousdisease professional organisations have initiated support and guidelines to combat the growing threat of antibiotic resistance. It was as recent as 2009 that the Centers

for Disease Control and Prevention (CDC) launched the first educational effort to promote improved use of antibiotics; it was as recent as 2014 that the CDC estimated that more than two million Americans were infected with antibiotic-resistant organisms and highlighted the need for Antibiotic Stewardship Programs (ASPs), to both optimise infection treatment and reduce adverse events associated with antibiotic use. Additionally, the Joint Commission issued regulations in 2017 for all hospitals to have an Antimicrobial Stewardship team. However, while antibiotic stewardship is understood to be a core strategy in addressing resistance and an area in need of critical consideration, hospitals have struggled to uphold such programs due to the lack of sufficient technologies that would make antibiotic stewardship a seamless process. Despite the positive developments that these antimicrobial stewardship programs in hospitals have led to somewhat of a decrease in morbidity, mortality, and overuse of antibiotics, rates of antibiotic resistance continue to rise. These programs and committees exist, but their current focus and effectiveness is appropriately described through a classic military adage: “Generals always fighting the last war.” While they are fighting the AMR issue, the focus has only been on attempting to reduce the risk of creating new AMR issues, rather than effective approaches at treating infections due to resistant bacteria without reproducing the same cycle with a new antibiotic. A Paradigm Shift for Antibiotic Stewardship As the medical field shifted its attention to stopping the spread of COVID, anecdotal evidence has showed an increase in antibiotic usage during the pandemic as antibiotic stewardship was side-lined, exacerbating the AMR crisis beyond what we expected to see. To quickly turn the tables on AMR, we need an urgent paradigm shift that will enable the successful implementation of ASPs that will reduce current treatment failures and lower rising readmission rates, improving patient care outcomes and saving Autumn 2021 Volume 13 Issue 3

Regulatory & Marketplace protective mechanism beyond any margin of bacterial response. The solution is both simple and revolutionary. Wouldn’t it be amazing if physicians across operating rooms had the power to choose to use local drug administration when they need a local solution, and a systemic administration of antibiotics when they need a systemic solution? As this is currently impossible, it would require a paradigm shift to reset conventional thinking around drug delivery. At the same time, if the practicality barriers could be overcome, it would certainly be a revolutionary leap for physicians and the health care system. lives, while minimizing the risk for creation of new versions of AMR bacteria. While it is always important to identify and prescribe the specific drug dose needed to achieve optimal results, it is not enough to stop AMR. As mentioned above, bacteria can thrive by simply overcoming their local exposure to a drug. We therefore need to change the rules of the game and adjust the delivery process to overwhelm this

While it can introduce complications, systemic administration of antibiotics, in which drugs are most often delivered intravenously, remains the standard protocol. It is highly problematic as it requires higher – technically too-high – doses of antibiotics to enable enough of the drug to reach the designated area after circulating through the bloodstream; most of the administered antibiotic is lost in the bloodstream and therefore only a

small amount reaches the site that needs it most. Finally, the higher doses of antibiotics increase the risk for toxicity and AMR. An additional consideration that hospital administrators and healthcare workers must consider is the impact AMR has on recovery after surgery. During surgery, blood flow is disrupted at the surgical site for an extended period of time. As such, during surgery and the days following, patients are left without effective levels of intra-wound antibiotics to combat bacteria, exposing them to heightened risk. The preferred method is therefore local drug administration. Current localized drug delivery platforms are limited, however, unable to anchor to the local site for the duration of time needed to prevent infection, with only a small fraction of the administered antibiotic dose reaching the wound before being cleared through the kidneys and liver, and then expelled from the body over the course of just a few hours. As a result, even the most experienced surgeons lack the tools necessary to deliver local antibiotics effectively which places patients at risk for the development

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Regulatory & Marketplace of surgical site infection (SSI), despite all means of prophylaxis. While systemic diseases like leukaemia must be treated systemically, in many instances, there really is no need for systemic exposure. A slow growing local tumour in the colon, for example, that has localised and metastasised, is treated locally through the process of removal. There is no need for any chemotherapy or systemic treatment. This simple example illustrates that using systemic treatment, when a localized approach will get the job done, might not offer long term benefits. The situation is similar with the vast majority of wound infection operations, which require only local antibiotic exposure. However, we routinely rely upon systemic drug exposure and potential toxicity or microbiome alterations when resulting in AMR risks with no benefit. The key, therefore, is to identify the large segment of patients requiring only local therapy and provide a local therapeutic option. In the case of SSI prophylaxis and treatment, the surgeon could effectively mitigate the problem with little if any systemic drug exposure. In this scenario, there would be no need to administer to the patient a parenteral or oral antibiotic that could change the patient’s microbiome, and place at risk an untold number of bacterial species for mutations and AMR. Attempts have been made – through antimicrobial stewardship – to advance a local treatment delivery approach in hospitals. However, they have yet to show a favourable outcome, not due to a lack of enthusiasm and support for the concept of local delivery, but rather due to significant limitations in effective formulation and drug delivery. The Potential of Polymer-Lipid based Delivery Systems Understanding the urgency for new local drug administration solutions that enable the local release of standard antibiotics, scientists recently began to develop promising formulaic combinations that harness the qualities of polymer- and lipidbased localised drug delivery systems. Polymer-based delivery systems, trapping medication within polymer structures, are often used to slow down the otherwise-fast release of the entrapped drug, enabling continuous delivery of medication and extended drug release as it anchors directly 22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to the surgical site. The addition of lipids to the polymeric component constructs a highly organised multi-layer matrix that protects the entrapped medication and allows control over the release rate and time-period. Bacterial contamination is prevented throughout the patient’s recovery, ensuring the body rebuilds its own natural defences. As it is a localised solution, the polymerlipid based delivery system will likely halt the creation of any new MDR bacteria and even potentially kill a lot of the existing bacteria, preventing them from propagating in the hospital environment. Whether it will succeed is a matter of development and science/trials, but it’s certainly a space worth watching. The Freedom of Choice The polymer-lipid based delivery system may provide physicians with what they have been desperately searching for: the option to implement effective local therapy for the majority of wound infections while reserving systemic delivery for selected cases. This would clearly change the concept of surgical prophylaxis but would also enhance wound infection management for a significant proportion of patients. Until now antimicrobial stewardship has been limited in its tools and particularly restricted by the reliance on systemic drug administration as the option for all surgical prophylaxis and wound infections. What is most exciting is that with the potential adoption of polymer-lipid multi-layer delivery systems innovation provides

the antimicrobial stewardship team with the option to limit systemic exposure to antibiotics while effectively treating AMR bacteria. This paradigm shift could be highly crucial in addressing the oncoming global health crisis of AMR.

Dr. Anthony Senagore Anthony J. Senagore, M.D., is a colorectal surgeon with a long track record of academic surgery practice and significant experience in healthcare start-up companies and currently serves as Senior Medical Director of PolyPid, Inc. He has served as Professor of Surgery at several prestigious academic medical centers, including University of Texas Medical Branch at Galveston, Central Michigan University College of Medicine, the University of Southern California, Keck School of Medicine, Cleveland Clinic Foundation, & Spectrum Health/ Michigan State University. Dr. Senagore has experience with payment policy and health care economics with service on the AMA/CMA Relative Value Update Committee for 16 years and as Chair of the Practicing Physicians Advisory Committee for the Centers for Medicaid Services. In addition, Dr. Senagore has edited five textbooks in colon and rectal surgery and authored over 230 peerreviewed publications and 25 textbook chapters. Autumn 2021 Volume 13 Issue 3

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 23

Drug Discovery, Development & Delivery

Smart Inhalers: A Digital Step Towards Patient-Centricity

Respiratory infections continue to have the highest incidence rate in Europe. And when asthma is considered, there has been a sharp increase in global cases, morbidity, and mortality rates, as well as being an economic burden over the last 40 years.1 More than 300 million people have asthma worldwide. These figures demonstrate that despite the efforts of the past few years, the reduction of the incidence of asthma has not been achieved yet. Connected devices – such as smart inhalers – offer a great opportunity to increase adherence and improve the quality of life of patients.2

is beneficial. If carefully designed and thoughtfully implemented, digital health has the potential to improve health and care outcomes alike. Health information is fast becoming readily available because of the transfer of digital health data. As a result, higher-quality therapeutic decision-making as well as the mechanism and efficiency quality of health services are improved.5 The demand for teleconsultation platforms in Europe, for example, has multiplied. Research shows that medical video chat tools are used for tens of thousands of consultations a day.6 If people are to live longer and better, they will rely on research and technology. The same combination is currently being used to contain the COVID-19 pandemic.7

provides continuous medical education for both physicians and consumers. Increasing efficiency entails not only lowering costs but also improving the quality of services. As a result, digital health has the potential to increase health care quality by enabling comparisons between various services and encouraging a new relationship between the patient and the health expert. Digital health opens up new possibilities for patient-centred care by allowing medical information and personal electronic records freely accessible to users over the internet. Patient empowerment by using smart devices The rise of digital health matches the current mind-set of most people: patients are no

Increasing life expectancy drives the development of personalised healthcare Since 1960, the average life expectancy has risen by 20 years. And with the world population aging fast, there will be more than one billion senior citizens in the world by 2030.3 As life expectancy continues to rise, a growing number of elderly people will suffer from a variety of both chronic and mental illnesses, and physical disabilities. Depending on the disease, they would require long-term medical attention and care. However, hospital treatment may not be the best option which is when the emphasis starts to shift to at-home treatments. In recent years, home healthcare has been a significant part of the healthcare industry. Technology is setting the stage for some extensive changes in this area. Assistive and monitoring devices as well as mobile laboratories are just a few examples. With these innovations playing such an important role in disease identification, management, and treatment, it is reasonable to assume that they will also aid in improving service delivery and quality of care.4 The future of homecare looks promising, especially in the case of chronic ailments such as heart failure, Alzheimer’s, and COPD. The self-management of health will become more of the norm in the future, driven by an aging population. Digitalisation has the potential to improve health and care outcomes It is clear that the digitalisation of healthcare 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 1 – European Teleconsultation platforms

The fact that digital health is on the rise is unsurprising. Global digital health market revenues in 2026 are expected to account for more than 900 billion EUR. In this context, digital health is defined as both hardware and software applications, Smartphone Apps, telemedicine, and IT systems.8 Considering digital health’s advantages, it is a common belief that in the long term, digital health will increase efficiency and can therefore save costs. Lowering administrative expenditure, eliminating hospital room expenses and avoidable diagnostic or therapeutic intermediations are just a few examples. Digital health already

longer willing to be passive recipients of healthcare services. They want to play a more proactive role in their own healthcare management. Patients may become motivated to take care of themselves more effectively and consistently if they have regular access to their health records. This mindset is reflected by the use of smartphones or smartwatches to e.g., tracking health data and activity, or monitoring behaviour and heart rate. Wearables and smartphone apps for recording, monitoring, and storing specific health data are becoming increasingly popular. According to the forecast, global Autumn 2021 Volume 13 Issue 3

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 25

Drug Discovery, Development & Delivery

Figure 2 – What type of digital healthcare solutions does your company develop or plan to develop?

sales in the mobile health segment could rise to almost 250 billion US dollars in 2025.9 But it is not only about smartphones and watches. It is across the spectrum. Currently, there is a wide range of digital healthcare solutions developed that could offer great opportunities. Smart inhalers are of particular interest and belong to the top-tier for product development and production.10 The cost burden associated with asthma and COPD Poor medication adherence is a major issue in healthcare, especially in the case of chronic diseases. A lack of adherence leads to poor results, which raises the use of health-care services and costs overall. Payers can pass on the financial strain to patients in the form of higher co-payments. The issue of medication adherence is becoming increasingly important in the healthcare industry, resulting in greater costs for the healthcare sector and the pharmaceutical industry. Adherence is highly variable: Between 30–70% of adults and children with asthma do not take their asthma medication as prescribed by their doctor.11 Though the factors of poor adherence are diverse, they could relate to the patient, the healthcare system, the therapy, or the disease itself. A lack of patient adherence is not only an economic burden for the healthcare sector, but also leads to costs for the pharmaceutical industry. The bulk of pharmaceutical profit

loss is due to poor medication adherence.12 Poor patient adherence has a strong impact on pharma businesses, resulting in reduced revenues due to lower prescription intake. The second impact, in terms of brand value depletion, is more long-term. An analysis on chronic diseases revealed that it was possible to quantify the estimate of revenues lost in a specific therapeutic area. It is essential to mention, that the calculation of losses due to poor adherence is based on revenues that could have been earned, not actually earned. The analysis for respiratory agents in the US revealed that the estimate of revenue lost in this therapeutic area is about 46 billion USD. Extrapolated to the global pharmaceutical market, revenue loss is estimated to be more than $560 billion.13 The Smart Inhaler’s 4Ps with Win-Win potential Increasing adherence rates by only 7 percent – e.g., by using smart inhalers that would require e.g., fewer doctor visits and fewer hospital admissions – could translate into a $40 billion pharmaceutical revenue opportunity globally. Most importantly, it will help to improve health outcomes and decrease healthcare spending, giving the pharmaceutical industry enough reasons to continue their development project on smart inhalers helping to save costs and to increase both revenues and patient centricity. The 4P matrix illustrates the potential of smart inhalers.

Table 1 Non adherence related missed opportunities in the US biopharmaceutical market by major therapeutics, 2011; Global Research Report” 26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Precision stands for a more reliable and accurate real-life inhaler technique and adherence information that would be key to support clinical decisions. Penetration can be understood as a remote technology that allows for a better understanding on how patients use their inhalers in real life. Objective data can provide personalised information about a patient’s inhaler medication use – to patients themselves, caregivers, and health care professionals. Finally, the real-life usage data can be used to predict if disease control gets worse and even the likelihood of an exacerbation can get identified. Smart inhalers can help to pave the way to be a win-win situation for users, the pharmaceutical industry, and healthcare providers. Several companies are currently investigating different possibilities to design and manufacture smart inhalers. Some are already commercialised; others are under development. Those companies might have an advantage in using their expertise and existing prototypes for clinical investigations or pilot studies to demonstrate the effectiveness of smart inhalers.

Figure 3 – The 4Ps of Smart Inhalers, Own Illustration

Propeller Health has already illustrated some opportunities for smart inhalers: reduction of hospital admissions, improvement in controller medication adherence, increase in asthma control, and the reduction in rescue inhaler use.14 This could mean that some patients may well be engaged and motivated by the collection of data related to their medication. The feature might then also increase the market share of a drug where the patient has a choice of medication. In turn, this can lead to improved medication adherence and a reduction in revenue lost to the pharma company. If this can be shown to improve clinical outcomes, then the healthcare payer starts to gain a benefit if this reduces higher costs associated with disease complications.15 Flow inhalation measurement technology It is well known that patients often struggle Autumn 2021 Volume 13 Issue 3

Drug Discovery, Development & Delivery REFERENCES 1. 2.

3. 4. 5. 6. 7. Figure 4 Real time recordings of inhalation flow profile: An imaginary patient case; Illustration by Sensirion

to use their inhaler correctly, resulting in inadequate drug delivery.16 According to research, the two most common mistakes made while using an MDI are both related to patient inhalation. The first error is related to the coordination between inhalation and triggering the dose release of the inhaler. The second most significant error is not breathing deeply enough. By monitoring patient inhalation airflow, there is a great potential for technological developments to reduce these common mistakes.17 The patient's ideal inhalation window can be determined using flow inhalation analysis technology. By measuring the inhaled airflow into the inhaler and recording the moment that the medication is dispensed, it is possible to verify if the drug was delivered during the optimal window of the inhalation process.18 The inhalation airflow profile can be used to determine a number of parameters that provide data about a patient's inhalation: • • •

depth and length of inhalation, slow inhalation according to instructions, lung function and its development over time.19

This information can be gained from accurate and measured real-time recordings of the inhalation flow profile, which can

be used to determine whether the patient performed the inhalation correctly. Tracking these metrics over time can be helpful for getting guidance on the efficacy of the drug and the progression of the condition as every inhalation is monitored for its accuracy and correct use. Additionally, it could alert a healthcare professional in case of complications as well as being a good resource for patients to improve their adherence. Summary In the treatment of asthma and COPD, adding a flow sensor to the drug delivery system is a useful asset. It is a method of giving direct guidance to patients, as well as assisting them in monitoring their illness and increasing adherence. Adding a diagnostic unit to the drug delivery device that the patient is already familiar with is a powerful tool in asthma and COPD disease management. It is a solution of guiding the patient and providing direct feedback as well as supporting the patient in controlling the disease and increasing adherence. The information collected could be used to anticipate asthma attacks, aid therapeutic decision-making, and improve healthcare resource allocation.

Figure 5 – The potential of a connected device, Own Illustration wwww.international-pharma.com

8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

Institute for Health Metrics and Evaluation: “Incidence per disease” Jung B, Shears D, “Embedded Connected Metered Dose Inhalers Meeting Requirements for Mass Adoption”. ONdrugDelivery Magazine, Issue 76 (Jun 2017), pp 44-48. The World Bank: “Life expectancy at birth” Keepnews D et al: “Measuring patient-level clinical outcomes of home health care” eHealth Network Guidelines Health Advances blog: “The Changing Fortunes of Telemedicine in Europe – Past, Present, and Future beyond COVID-19” Bestsennyy O et al: “Telehealth: A quartertrillion-dollar post-COVID-19 reality?” Statista: „Market volume for digital health worldwide 202 Statista: „mHealth - Worldwide sales with Mobile Health by 2025 “ Dimensional research “Digital health technology trends. A Survey of Digital Healthcare Decision-Makers, May 2020” Kaplan A et al: „Treatment Adherence in Adolescents with Asthma” Capgemini Consulting: „Estimated Annual Pharmaceutical Revenue Loss Due to Medication Non-Adherence” Capgemini Consulting: „Patient Ad-herence: The Next Frontier in Patient Care” “Propeller Health Asthma Patients Maintain High Medication Adherence When Using Propeller Health to Manage Their Condition” Phillips-Medisize: „Smart Inhalers: The value and the challenge” Alt A: “Flow Measurement in Smart Inhalers for Connected Drug Delivery” Jahedi L et al: „Inhaler Technique in Asthma: How Does It Relate to Patients' Preferences and Attitudes Toward Their Inhalers?” Alt A: “Flow Measurement in Smart Inhalers for Connected Drug Delivery” Alt A: “Flow Measurement in Smart Inhalers for Connected Drug Delivery”

Thorsten Lehmann Thorsten Lehmann is a Business Development Manager. With a background in International Management and an additional degree as a pharmaceutical consultant, his career focuses on the Health Care Industry. Thorsten worked for one of the world’s leading providers of healthcare products and now leads the development of solutions for the smart drug delivery system market at H&T Presspart. Thorsten is multilingual (German, English, French.) INTERNATIONAL PHARMACEUTICAL INDUSTRY 27

Drug Discovery, Development & Delivery

Methods to Reduce the Anxiety of Mental Disorder Medication The unprecedented stresses and strains of the last year or so have led to large numbers of people suffering from temporary psychosis or, at the very least, experiencing some form of diminished mental wellness.1 Imagine the terrifying prospect of having to daily face hallucinations, delusions, and deeply true, deeply isolating, sadness. Combatting such loneliness, anxiety and desperation must be emotionally and physically exhausting. Particularly when there is no apparent end in sight to these feelings. Welcome to the very real, life-debilitating world of someone suffering from schizophrenia. Trying to treat someone in this broken mental state is complex. Will they remember to take a tablet? Will they really accept an injection given the extent of their delusional state? In the words of one sufferer: "Real people with real feelings get schizophrenia. One should never underestimate the depth of their pain, even though the illness itself may diminish their ability to convey it… As one of my own patients told me, 'Whatever this is that I have, I feel like I’m a caterpillar in a cocoon, and I’m never going to get the chance to be a butterfly."2 In this article we will explore the very real benefits alternative dosage forms, such as oral thin films and transdermal therapeutic systems, bring to the treatment of mental disorders, combining high levels of patient acceptance with effective therapeutic benefit. Every day, in pharmaceutical companies across the world, thousands of people are committed to delivering better patient outcomes. Often talked about in depersonalised terms, this ’patient’ is the ultimate beneficiary of all manner of workstreams, projects and clinical trials. But how often do 28 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 1 – Mean rotigotine plasma concentrations after application of rotigotine transdermal patch (2mg/24h) or intravenous infusion of 1.2mg over 12h. Adapted with permission from Cawello et.al.

we give thought to the reality of the people behind these theoretical patients? Beyond our understanding of their conditions, symptoms and clinical requirements, to what extent do we consider their emotional state, their hopes and fears, and their experience of medical care? In the case of mental disorders, this has particular resonance given the variety of barriers that come between patients and successful treatment outcomes. Indeed, the proportion of schizophrenia patients likely to meet the criteria for recovery is estimated to be just 1 in 7. And, while factors such as substance abuse and comorbid psychiatric disorders play their part in influencing this statistic, poor outcomes are most likely to be related to issues around access to treatment, engagement in ongoing care, treatment response, and poor adherence. All these factors are strongly linked to the patient’s personal attitude, circumstances and experiences.3 For the answer to why accessing antipsychotic therapies and maintaining adherence remain such significant contributors to treatment failure, it is worth returning to the importance of seeing a patient as an individual. In real-world healthcare settings, each interaction with a schizophrenic patient is highly personal and highly contextualised. It considers a range of interconnected forces that are specific to a particular person and their mental state

at that given time, which might range from overly excited to actively hostile. Research continues into the wide variety of factors that trigger non-adherence among patients on anti-psychotic drugs. One such factor is the symptom of cognitive impairment, which has been observed to affect most patients with schizophrenia, negatively impacting their ability to register, process and recall information.4 Put simply, this means patients with schizophrenia are often, by default, incompatible with sustained adherence programs. Further contributing factors to nonadherence include the poor levels of insight that patients possess into their own symptoms and their consequences. This lack of awareness often means there is a resulting lack of acceptance of the need to manage symptoms via ongoing treatment. Treatment may also be rejected by patients who are influenced by the perceived stigma of a mental health diagnosis. Others still may fail to adhere to treatment programs for fear of experiencing unwanted side effects or simply to avoid the discomfort of drugs being delivered by injectable. Non-adherence is difficult to accurately detect since healthcare professionals (HCPs) are unable to constantly monitor each patient under their care. This means that HCPs are not necessarily equipped Autumn 2021 Volume 13 Issue 3

Drug Discovery, Development & Delivery with all the facts they need when making judgements about the effectiveness of a given treatment. This potentially leads to decisions about ‘failures’ that can trigger unnecessary changes in medication or inaccurate increases in dosage. For patients, non-adherence can result in any number of consequences, from psychotic relapse and hospitalisation to an increased suicide risk.5 Where patients are unable to follow a treatment schedule, greater onus is placed on caregivers to support adherence through easy-to-administer therapies outside of a medical setting. And, looking at the factors that positively influence adherence, evidence does suggest that the patient’s engagement with their therapy is key. In patients with bipolar disorder for example, studies have found that a collaborative environment, where patients are invested in the management of their own illness, lead to better treatment adherence.6 There is potential for innovative drug delivery mechanisms to be used in the treatment of psychiatric disorders, helping to counter many of the existing factors that lead to non-adherence, reduce the burden on caregivers, and support improved patient outcomes. Transdermal therapeutic systems (TTS) present an increasingly strong case in this context. This category, which has expanded to incorporate a diverse range of patch technologies, features many patient benefits, some of which are amplified in the face of the challenges presented by psychiatric applications.

Non-invasive by design, TTS facilitate the systemic absorption of drug molecules via the skin to give patients and caregivers a simpler, pain-free route to administration. TTS also avoid first-pass hepatic metabolism to enhance the bioavailability of the drug and enable dosing levels to be reduced. With an infusion-like drug release, patients can benefit from reduced dosing frequency, with drug levels controlled by the patch size. Of particular relevance for patients with mental health disorders, TTS deliver more predictable outcomes through the delivery of sustained, stable plasma medication concentration levels, avoiding the peaks and troughs that can be observed with oral formulations. For caregivers, the sight of a patch also provides visual confirmation of compliance. Such attributes have led to the development and approval of a range of psychotropic drugs in transdermal delivery forms. These include Rivastigmine, an acetylcholinesterase inhibitor for the treatment of Alzheimer’s disease and dementia associated with Parkinson’s disease, which has been approved by many regulatory agencies globally, including the US Food & Drug Administration (FDA) and the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK. Further approved therapies delivered via TTS include rotigotine, a dopamine agonist delivered via a once-daily transdermal patch for the treatment of Parkinson’s disease; methylphenidate, a central nervous system (CNS) stimulant for the treatment of ADHD;

Figure 2 – Infusion like drug release of TTS wwww.international-pharma.com

selegiline, a second-generation monoamine oxidase inhibitor (MAOI) for the treatment of depression; as well as blonanserin and asenapine for the treatment of schizophrenia.7 These market references highlight how transdermal technologies have been employed to deliver a sustained dose and support ongoing condition management for patients whose symptoms or situations may compromise adherence. There are times, however, when patients with mental disorders require immediate treatment over sustained dosing. In acute episodes of schizophrenia, for example, patients may be more aggressive and violent because of psychotic symptoms such as delusions and hallucinations, and the feelings of suspicion and hostility that they trigger. Impulsive actions, including aggression, may also be sparked by the patient’s frustration at aspects of their immediate environment.8 In these situations, there is a far greater need for medicines to be fast-acting and to be administered via non-invasive routes. The benefits of oral thin films (OTF) are increasingly being explored in this space, since they provide a platform for rapid API uptake in the bloodstream via oromucosal absorption. As an edible delivery mechanism, OTF do not require the addition of water when being administered and, unlike many oral drug forms, there is very little requirement for active participation on behalf of the patient in terms of chewing or swallowing. The film either dissolves or disintegrates. The simplicity of delivery makes OTF particularly suitable for paediatric and geriatric patient populations, and because they are also able to avoid first-pass hepatic metabolism, bioavailability can be enhanced. A variety of OTF formats are available, with each aligned to a particular plasma concentration profile. This ranges from fastdisintegrating film, which demonstrates rapid onset but is relatively short-acting, to non-disintegrating buccal film, which provides dosing at a more sustained, lower level. Innovative new formats, such as the FOAM OTF developed by LTS, introduce further benefits, which among others, includes the possibility of delivering higher drug loads, while also presenting in a form that is easy to handle, has a soft mouthfeel and disintegrates quickly. INTERNATIONAL PHARMACEUTICAL INDUSTRY 29

Drug Discovery, Development & Delivery REFERENCES 1. 2. 3.

4. Figure 3 – Modulation of plasma profiles depending on OTF type

A OTF solution has seen notable success in the case of Suboxone, a sublingual film formulation of Reckitt Benckiser’s buprenorphine and naloxone treatment for opioid dependence. Launched with a novel marketing approach in the second half of 2010, the film achieved 55% market share in the US by 2012 and today is the preferred dosage form for buprenorphine and naloxone in the US and Australia. Beyond this application, the global market for OTF products encompasses treatments for conditions including Alzheimer’s and Parkinson’s disease. Over time, the potential for OTF to tackle mental health disorders will continue to expand just as it will for the use of TTS in the wake of the FDA’s 2019 approval of asenapine in transdermal patch form to treat schizophrenia. For both these non-invasive drug delivery technologies, API-based innovation will focus on areas such as overcoming solubility challenges and increasing bioavailability for a wider range of drug molecules.

Often, when they are spoken about, patients are framed as passive receivers of treatment,9 reflecting the Latin root of the word ‘patiens’, which means to suffer or bear. However, in the case of mental disorders, the patient can certainly be active rather than passive at the point therapies are administered. Agitation, aggression, forgetfulness, confusion and disorientation are just some of the very real, very human, characteristics that must be acknowledged and appreciated to develop innovative therapies that can be delivered in an optimal way. More personalised therapies for individual patients is a key talking point in our industry today. Taking this truly patient-centric approach to drug delivery ensures therapies will be both actively accepted by the patient in the short-term, while also encouraging the sustained longterm adherence necessary for the enhanced outcomes every individual patient deserves.

5. 6. 7. 8. 9.

https://www.nature.com/articles/d41586-02100175-z The Internal Experience of Schizophrenia, Catherine Harrison, PhD, Dec 2020. Zipursky RB. Why are the outcomes in patients with schizophrenia so poor? J Clin Psychiatry. 2014;75 Suppl 2:20-4. doi: 10.4088/JCP.13065 su1.05. PMID: 24919167. https://pubmed.ncbi. nlm.nih.gov/24919167/ Front. Psychiatry, 05 December 2018 | https:// doi.org/10.3389/fpsyt.2018.00622 https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC7584050/ https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4932152/ https://journals.sagepub.com/doi/pdf/10.1177/ 2045125312458311 https://www.psychiatrictimes.com/view/ aggression-and-impulsivity-schizophrenia https://bmjopen.bmj.com/content/9/3/e025166

Dr. Tanja Kromm Dr. Tanja Kromm studied pharmacy at the University of Mainz, Germany and completed her PhD in biochemistry research in the field of Parkinson’s disease. After several years working in a pharmacy, she joined the quality operations department at LTS where she was responsible for solving quality issues within the scope of deviations and investigation reports. In 2020 Tanja joined the marketing & market services department of LTS as a market analyst. delivering market intelligence and pharmaceutical evaluation on a range of topics.

Dr. Patrick Mohr Dr. Patrick Mohr studied pharmacy at the University of Bonn, Germany. He received his Ph.D. in Medicinal Chemistry from the University of Jena with a thesis focussing on development of newly dopamine receptor ligands as potential novel antipsychotics. In 2006 he joined the R&D department at LTS as project lead for the development of several transdermal therapeutic systems including early phase development up to life cycle management. In 2012 he took over the responsibility of a newly founded area focussing on pharmaceutical development of internal projects based on TTS and OTF technologies.

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World-leading drug delivery device solutions provider Holistic partner Early device strategy to state-of-the-art manufacturing High quality standards

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Drug Discovery, Development & Delivery

Improving Productivity in Discovery Research: Workflow Management Design-Make-Test-Analyse cycle and productivity The Design-Make-Test-Analyse (DMTA) cycle, central to the discovery of new small molecule therapeutics and agrochemicals, has periodically received attention as a metric for improving productivity in research and development. The rationale for improving DMTA is simple: the path to a drug candidate will inevitably involve multiple iterations of design. The faster a project team gets around the cycle, the more iterations can be completed in a set time, or the shorter the time that it will take to complete or close a project. The focus on DMTA stems from the postcombinatorial chemistry analysis of large pharma in the early 2000s. At that time, it had become clear that making thousands of compounds in each cycle was less important than increasing the number of cycles in a project lifetime. Cycle times of 120 days were not uncommon in large companies – reflecting just 6 iterations of DMTA in a typical 2-year project lifetime. This focus on cycle time brought averages down drastically, but further improvements are still possible, and since the process will be repeated many times throughout a project, small gains are amplified to deliver significant enhancements in productivity. Recent advances in computational methods and artificial intelligence (AI) approaches have highlighted other key areas for improvement. However, DMTA remains central to the process of discovering new small molecules. The inclusion of computational approaches has further highlighted the need to streamline communication, particularly through the Design-Make transition, as complex algorithms can often generate highly novel molecules that need expert input from synthetic chemists before the decision is made to embark on synthesis. Communication remains central to DMTA, whatever processes are followed, and provides a key opportunity for technology 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 1 – The DMTA cycle is central to the discovery of new small molecules. The time taken to complete each iteration is a key determinant of productivity.

to improve cycle times. Currently, however, the myriad of communication tools often fragments information rather than centralising it. It is all too common to find, especially where outsourcing is involved, that the list of molecules currently being synthesied, or that have been submitted to biological assays, is contained in disparate Excel and PowerPoint documents that cannot be searched effectively. Impact of outsourcing on DMTA: challenges and opportunities Outsourcing has become a staple of pharmaceutical research and development. Its growth over the last 25 years has been driven by cost reduction, productivity enhancement, and de-risking strategies with an increasing use of specialist providers that have a history of success against challenging targets. The outsource model, whether for synthesis, biological assays or animal studies, presents challenges and opportunities to further increase productivity. Outsourcing: Design In the hypotheses-driven Design phase, the principal aim is to innovate, creating new molecules to address the principal

issues with the current project lead while still being readily synthesisable. It is only occasionally outsourced as a standalone task, more commonly it is part of a greater commitment to outsource the entire DMTA process. The challenges to productivity here are common across internal and outsourced projects: •

• •

Multiple team members having the same idea and hence pushing the same compound forward to synthesis (particularly on larger or cross-site teams due to complexities of communication). Re-design of existing compounds made in the early stage of a project (‘project amnesia’). Design of molecules that computational models predict to be inactive or have unfavourable properties (due to information silos).

Getting the optimal design in each Design phase would minimise the number of DMTA cycles that would be needed in a project. This requires designers to use all available project and computational knowledge to reach the best possible decision or be inspired to take a leap forward. Equally, eliminating undesirable designs early on Autumn 2021 Volume 13 Issue 3

removes downstream losses in productivity through wasted synthesis, testing and analysis of compounds. Taken together the possibilities for productivity improvements from the Design phase are significant. Outsourcing: Make In the Make phase, productivity challenges primarily centre around resource utilisation and communication; factors which are critical to both the outsourcing team and to any commissioned contract research organisation (CRO). It is a waste of valuable resources to have CRO teams working on fruitless synthetic targets, or waiting for meetings to decide upon the next molecule to make. Instead, smooth and fluid communication is required to ensure the commissioned resources are working at optimal productivity, especially as project priorities evolve due to newly generated results. Equally, the CRO has a strong vested interest in ensuring high resource utilisation since contract synthesis is highly sensitive to both costs and customer satisfaction. An ideal CRO has smooth communication tools, and an efficient and effective work force, making it a good partner with a good reputation that will enable customer acquisition. Outsourcing: Test As compounds enter the Test phase, the challenge for increasing productivity is again one of communication, but there are also significant logistical and process-oriented challenges. Here, multiple highly skilled CROs are often employed to address different aspects of molecule testing, from physicochemical analysis to animal studies. Tied to these is sample and data management, with multiple systems or organisations involved in storing the physical sample and the data associated with it. To operate at maximal productivity, the Test phase needs to track multiple physical samples, informing each recipient at each organisation of the required test, and ideally update the Test requester as data is deposited. Further, testing groups and organisations should benefit from a high degree of visibility of the testing pipeline. Foresight on which specific assays are required for the compounds that are nearing completion of synthesis is invaluable to ensure that sufficient reagents and protein are available to conduct the tests and deliver results efficiently. Outsourcing: Analyse In the final phase of DMTA, the knowledge gained from the current iteration of the cycle is assessed to form the root of the subsequent Design phase. Productivity in the Analyse phase is dominated by information wwww.international-pharma.com

Figure 2 – Pharmaceutical research and development often involves a network of individuals, collaborators and contract service providers. Each new partnership presents challenges and opportunities to increase productivity.

delivery – it is paramount to present all the available project information (whether this be in the form of plots, assay results or 3D protein-ligand crystal structures) clearly and concisely to ensure the best possible conclusion and to inform the following design step of the next iteration. Importance of communication to manage CRO and other partnerships The single biggest factor for managing partnerships is effective communication. The separated nature of the relationships introduces significant challenges especially where multiple partners are involved. These challenges could be verbal, with many different native languages, technical (for example the transfer of large amounts of data in a secure manner), or time-zone induced (where companies are more than eight hours apart and finding a common time for verbal communication can be difficult). In turn, this throws the emphasis onto email and other static forms of knowledge transfer to ensure all stakeholders are aligned. Whilst the modern world seems well-equipped for such communication (live documents, video calling and chat software), the reality is that few of these tools understand the complex chemistry needed to record compounds and their associated data effectively.

and priorities are re-aligned to ensure everyone is on the same page. However, this also represents a loss in productivity. Instead of a steady flow of information between the parties, it becomes disjointed – how frequently should meetings be held, or reports written to maximise output while minimising miscommunication and maintaining transparency? Even with frequent updates, conveyed information is distilled and sanitised from the actual practice as it is often difficult to communicate the full history of a particular task in a PowerPoint slide. Further, each meeting or report requires attendees to write and read updates which are then distilled further for management both within the CRO and the commissioning partner. Whether the meeting or report is detailed or superficial, there is a significant productivity burden in the preparation of slides and documents to get the information into a ‘presentable’ format. Lastly, such detailed meetings and reports, while common place, often fall into the trap of discussing detail around one particular update, instead of focusing on strategic planning where the many points

Inevitably, a large amount of the communication in a modern drug discovery project, whether outsourced or not, relies on weekly, bi-weekly or monthly team meetings combined with written (usually monthly) reports. It is here that understandings INTERNATIONAL PHARMACEUTICAL INDUSTRY 33

Drug Discovery, Development & Delivery

Figure 3 – A centralized platform connecting disparate organizations and individuals working across DMTA offers a solution to promote collaborative working.

of view bring additional wisdom to key decisions. Communication problems are most acute as a project nears completion. Preparation of patent materials can involve searching through disparate systems and applications for relevant information on inventors, inventive steps and reduction to practice. For example, a hypothesis could be put forward in email, fleshed out with molecules in PowerPoint and then have synthesis reports spread across ELNs, PowerPoint and Excel. Many of the challenges outlined above also apply to internal research projects. Teams may be split across multiple buildings, sites and time zones causing a similar fracturing to the communication channels. Processes in this scenario can be even more problematic, with large and cumbersome systems limiting the scientist’s freedom to operate. These issues are often one of the reasons an organisation opts to outsource, seeking a more agile environment to progress their research. Improving productivity and communication through centralised workflow management The problem of increasing productivity through corporate agility, while maximising communication, is central to modern research and development management. However, new web-based technologies offer a promising solution, by enabling 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

disparate systems to be tied together, coordinating actions across multiple time zones and triggering automated workflows and updates. A single platform to connect the disparate teams working across DMTA provides many benefits: • •

• •

A centralised location to capture, share and report all project information. Top-level overview of all projects in the company portfolio, including related studies, scientists involved, therapeutic area, milestones, status and projected dates. Real-time dialogue between collaborators to deliver updates. Common terminology and language, mutually agreed definitions and nomenclature to describe project milestones.

Requirements of implementing a centralised system Critical to such an application is the ability to segment information for each stakeholder, enabling each user to see their work in the context of the wider project or not, as is appropriate. To achieve this, detailed security and privacy settings are required so the fluidity and accessibility of a web application are applied equally within both internal and externalised projects, with CRO users accessing just the information that they need. With this in place, each user

updates the system as the work is completed, enabling rapid and live communication of project status. In turn, this allows project meetings to focus on strategic discussions rather than updates. However, chemistry is a specialist discipline with its own language and so requirements go beyond a basic to-do list or Kanban board. Design and analysis tools must understand 2D and 3D structures, and synthesis tracking tools should cover molecules, libraries, synthetic routes, reagents and remakes, for example. Testing needs to be flexible and configurable, to cover the wide range of biological and physicochemical assays that are performed, whilst informing chemists on the status of their requests. A plethora of IT systems underpin any modern drug discovery organisations so any application covering DMTA must be capable of interacting with this network. A central platform for DMTA must, therefore, consume data from these systems, such as data warehouses, inventory management or electronic lab notebooks, and present it back to the users in a coherent way that enables optimal decision making. In summary, the platform must interface with an extended IT landscape to enable the capture of all molecules, their history and the decisions that have been made, and ultimately stored in corporate databases for later consumption. Autumn 2021 Volume 13 Issue 3

Drug Discovery, Development & Delivery Centralised workflow management benefits all project stakeholders A centralised, DMTA management system enables managers to effectively plan, manage and track projects across multiple activities, teams, and departments. Captured data could be used to identify resourcing issues or suboptimal processes with internal or CRO based resources. Equally, individual researchers benefit from a reduced administrative and operational overhead, and by identifying issues with project molecules at an early stage. Potentially the greatest benefit is to reduce the length and increase the effectiveness of meetings by focussing on strategic discussion and project direction. Benefits extend to CROs where resource management is central to an effective business plan. Foresight on upcoming peaks and troughs in demand enables teams to allocate resources accordingly across multiple projects or customers. Precise communication of required compounds, quantities and purities smooths knowledge transfer from clients and thereby increases productivity further. Automatic report generation and a switch to live status

updating further increases productivity and minimises the time scientists and project managers spend on operational tasks. Lastly, a positive customer experience enhances customer satisfaction and ultimately corporate reputation. Conclusion Discovery chemistry has progressed significantly in recent years. Information is abundant, from computational models to scientific and patent literature. Project progression follows diverse plans, from fragment-based approaches to phenotypic screening. Most organisations now outsource some part of their chemical synthesis, and many outsource whole projects. However, the goal remains the same: a safe and effective bioactive substance – be it oraldrug, topical medicine, or agrochemical. The enduring process is the DesignMake-Test-Analyse cycle which provides a cornerstone to consider and improve R&D productivity. Throughout DMTA, the challenge is now one of communication, both between team members and information silos, whether these are within a single organisation or spread across many

specialist CROs. One promising solution for discovery research is to use a central platform to connect all project stakeholders, which also acts as an information repository. Such a platform needs to meet technical requirements to capture the complex scientific data and integrate with internal systems. This would result in significant improvements to R&D productivity by enhancing the effectiveness of scientists and managers across DMTA.

Tim Cheeseright Building on a DPhil in synthetic chemistry and industrial experience in medicinal and computational chemistry, Tim has been delivering cutting edge solutions to drug discovery organisations for 20 years. His drive to streamline processes and shorten development times for chemistry assets led to the founding of Torx Software.

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 35

Drug Discovery, Development & Delivery

Current Trends in Formulation Development and Implications for Drug Delivery Devices The market for parenteral drug device combination products has been evolving over the last 15–20 years, developing innovation both on formulation and device design fronts. This change is driven by a series of factors including: the growth of biologics and biosimilars, predicted to increase at a compound annual growth rate (CAGR) of 23% from 2019 to 2027;1 evolving healthcare systems in need of affordable therapeutic options; the rise in self-administration and an increasing focus on patient and user experience. The key priority in formulation development is to create a cost-effective drug with proven efficacy and safety that can be scaled up for manufacturing. However, more recently the focus has shifted towards patient experience and ease of use. This change is in part driven by the increase in self-treatment outside the acute care setting to treat a variety of chronic conditions via an increasing number of subcutaneous formulations. Here ease of administration becomes critical. Factors such as the ability to reduce administration frequency and provide less painful and quicker injections are also important considerations. Drug delivery devices need to be intuitive to use and should require as few steps as possible for administration; auto-injectors for subcutaneous injection that are automatic, and pressure activated rather than requiring buttons, can help severely ill patients manage their own medication at home without assistance. Speed to market is also an important commercial consideration in drug development which may affect choices around both administration route and delivery device, while managing risk is a critical challenge throughout development: working with novel excipients and custom devices, for example, adds complexity and additional stability and safety studies may be needed. This increase in requirements may delay time to market but is critical 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to provide assurance that the best drug candidate is taken forward and most appropriate delivery device is selected. Propelled by these key drivers, formulation science is seeing some major key trends. These are: 1. The quest for biologic stability Developing novel biologic formulations is fraught with challenges relating to stability, interactions with excipients, the primary container, oxygen and light sensitivity, high extrusion or shear forces. Novel excipients are being introduced to help with biologic stability and to also allow injection via the subcutaneous route. These may in turn permit the administration of larger volumes (>2mL), therefore reducing frequency of delivery. As a result, delivery devices must accommodate larger volumes in bigger syringe sizes: typically, 2.25mL. Having a platform device that can easily accommodate both 1mL and 2.25mL prefilled syringes and a variety of fill volumes is a distinct advantage and allows flexibility throughout development and commercialisation. An excipient which solves one issue, for example viscosity or stability, may, however, cause another, for example interaction with silicon in the glass primary containers. Innovation in this area has seen a lot of recent development, from novel glass coatings to enhance stability to the use of innovative plastic primary containers which aim to minimise protein aggregation in biologics caused by silicon. The shelf life of a drug is typically around 2–3 years so being able to extend this with stability studies post-launch can provide a significant commercial advantage. Alternatively, storage at below room temperature is an option to extend shelf life but this route relies on patients remembering to keep their drug refrigerated and to remove it before use in the case of biologics, where low temperatures increase viscosity making the injection potentially more painful. In addition, there are implications in the supply chain where cold chain conditions may be required for these products.

2. Reduced injection frequency There is a lot of focus on reducing injection frequency to provide increased patient convenience and therefore improve therapy adherence. Novel drug device combination products, including long-acting and extended-release formulations, help drive this. Increasing drug viscosity can also play a part in reducing injection frequency but here there are trade-offs for administration: needle length and gauge as well as potential impacts on pain on injection, increased injection or device hold time that may be inconvenient or even impossible for the patient to manage. In addition to this, there is the constraint posed by suitability and compatibility of the selected drug delivery device. Increased focus on the patient experience, especially for those who self-administer, earlier in the drug development process does help to provide a more patient-centric approach. This can provide benefits ranging from reassurance to comfort, to convenience and is also seeing an acceleration driven by regulatory pressure to improve device usability. 3. Shift to larger volumes In recent years, there has been a move from 1ml up to 2ml, and some exploration of 3mlplus injectate volume for sub-cutaneous delivery to reduce injection frequency. It is likely that Injectate volumes for subcutaneous delivery will continue to increase from 2ml towards 3ml and beyond enabled by the introduction of novel excipients and additives to allow reduced pain on injection. Autoinjectors which have a two phased independent needle insertion and dose delivery can provide an improved and more consistent patient experience during the administration process even for volumes up to 2mL. 4. Diversified drug delivery In addition to a growing range of formulations there are also increasing options available for subcutaneous delivery devices that range from safety devices for pre-filled syringes to disposable and reusable autoinjectors and also wearables. Each of these now has the capability to add connectivity, enabling transfer of key Autumn 2021 Volume 13 Issue 3

Drug Discovery, Development & Delivery

patient data and the ability to measure and monitor therapy compliance. Having more choice in delivery device allows the formulation experts to explore a variety of options: these might be formulation changes in early clinical studies, or the creation of a range of differentiated products which provide tangible patient benefits. With patients growing increasingly informed about their disease and treatment options, these options also provide them with choice around how they wish to manage their condition. In addition, choice of delivery method and device can also help to provide patient confidence and reassurance and may impact compliance to their therapy regimen. There has been much focus and discussion on wearables as they could provide a more convenient and comfortable means to deliver therapies to the patient. However, with the exception of diabetes these have not yet become mainstream and there are challenges within formulation development, especially for biologics, that need to be addressed before this technology really becomes established. 5. Increased functionality Vs ease of use With the rise of patient self-administration, the emergence of connected devices has started to play an increasingly important role in the communication and delivery of therapy, specifically in the role of devices in helping to drive improved patient therapy adherence through better support and HCP monitoring. In parallel, there has been a trend towards more complex devices with additional injection speed and depth features. Although these have been welcomed with enthusiasm, there is also the understanding that complex, connected wwww.international-pharma.com

devices with numerous features and user steps may not be suitable for all patients and may present unnecessary cost. Devices need to be simple and intuitive in order to both minimise user errors and encourage adherence. It’s likely that in the future we may see a move to more streamlined, simpler devices which focus on the functionality that is really needed for effective drug delivery, such as efficient end-of-dose indicators, and avoiding over-engineered or complex features which can be either confusing, or not necessary for safe and effective use. 6. The drive for increased sustainability Sustainability, including environmental awareness is also moving up the agenda in the pharmaceutical industry due in part to increasing pressure from governments, regulators, patients and consumers. This is now starting to drive change in multiple areas, from corporate operations to packaging and device choice and may lead eventually to formulation. Despite talk about green chemistry, the drive for improved efficacy is still the top priority for the formulation teams now increasingly coupled with a focus on risk mitigation relating to manufacturing and waste products. From a drug delivery perspective creating formulations that allow a less frequent dosing schedule also means a reduction in number of disposable delivery device used over time. This has been possible, in part, by the development of higher viscosity formulations however these in turn create their own challenges with respect to patient administration and manufacturing. Viscosity can change over time and with temperature, influencing both injection time and the ability of the device to deliver the

dose effectively, making this an important consideration for device choice. Finally, there are a number of trends currently impacting formulation and therefore drug delivery device design. From sustainability to speed to market, from usability to increased therapy adherence, all these drivers have a key feature in common: providing effective patient outcomes without knock-on effects in terms of cost or user experience. Understanding how the different demands can work in synergy will help shape the future of drug delivery. REFERENCES 1.

Research T. Global Biosimilars Market to Reach ~US$ 21.1 bn by 2027, Role in Reducing Cost of Cancer Treatment Key to Growth: Transparency Market Research

Julie Cotterell Julie Cotterell has over 20 years of sales and marketing experience, including regional, national and global roles. She has a wealth of knowledge on different aspects of drug delivery and the associated devices, and is particularly interested in bringing to market products that can allow patients to be treated as simply and effectively as possible. Before joining Owen Mumford Pharmaceutical Services in 2018, Julie worked for both pharmaceutical and medical device companies, including Baxter, BD and Smith & Nephew. Email: julie.cotterell@owenmumford.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 37

Clinical and Medical Research

Managing the Inherent Complexity and Risk of Precision Medicine Clinical Supply Chains Tailoring medical treatment to the individual characteristics of patients based on genetic, environmental and lifestyle factors is quickly superseding more traditional clinical trial models. And with the benefits on offer, it’s clear to see why. Precision medicine, also referred to as personalised medicine, is helping healthcare providers to better understand the factors that play a role in patients’ health, disease, or conditions. This enables providers to more accurately predict which treatments will be most effective and safe and to avoid prescribing drugs with predictable side effects. Through its ability to improve disease detection, predict susceptibility to disease and preempt disease progression, precision medicine is also helping to shift the emphasis from reactionary to preventative; giving rise to customised disease-prevention strategies. For clinical trial sponsors, precision medicine has the potential to eliminate trial-and-error inefficiencies that inflate healthcare costs and undermine patient care. With the reduced time, cost and failure rate of clinical trials contributing to substantial market growth, precision medicines will undoubtedly play a pivotal role in the future of drug development. Yet, with this increased opportunity, comes increased complexity and risk. To reap the rewards associated with operating precision medicine trials, sponsors must approach with caution and focus firmly on proactive planning that will facilitate supply chain flexibility and viability. Transforming drug development with a precision approach Drug development is moving away from the blockbuster model. Driven by patient centricity, a large number of trials are now conducted under a diversified intermediate model, where the IND is designed for a specific group detailed within inclusion/ 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

exclusion criteria. The model’s objective is to reduce adverse events and instances of little to no benefit and increase the percentage of patients who benefit from treatment. As the market becomes more competitive and sponsors look to achieve the dual objectives of enhancing patient centricity, while driving down R&D costs, a new precision medicine model is emerging. This approach for disease treatment and prevention takes into account individual variability in genes, environment and lifestyle factors for individual patients, enabling targeted intervention. It involves two medical products: a diagnostic tool to identify the genetic mutation and a therapeutic agent to target it. The precision model relies on biomarkers specific to disease subtypes to estimate the disease risk and response to therapy and uses genetic sequencing and mass spectrometry as core technologies. Precision medicine is typically more expensive than traditional therapies, due to the high costs associated with manufacture and the need for companion diagnostic or genetic testing, which requires separate regulatory approval. Likewise, the ambiguous evidence requirements for coverage and reimbursement can make marketing difficult. Despite the associated challenges, the model has the potential to deliver significant benefit to patients and sponsors. For patients, targeted therapies enhance quality of life, facilitate earlier disease detection, in addition to early genomic and epigenomic events in disease development – preventing rapid disease progression, especially for carcinogenesis. Precision medicine trials also reduce risk of adverse events associated with a treatment that may not be useful or effective. The model encourages a proactive rather than reactive approach; delaying or preventing the need to apply more severe treatments that may be associated with suboptimal safety and tolerability. Furthermore, the precision model increases patient stratification – enabling sponsors to identify mutations that

give rise to certain treatments and helping to prevent a ‘trial and error’ approach to prescribing medication to patients. For sponsors, precision medicine reduces the number of patients required for clinical trials, leading to decreased trial timelines and reduced overall R&D costs. The model can facilitate market access, as increasing global demand for precision medicine creates advantage for sponsors when filing for approval for a precision medicine product. Return on investment can also be increased, due in part to the specificity and improved clinical outcomes of precision medicines that command premium pricing relative to conventional treatments. The final benefit relates to a sponsor’s ability to identify new drug targets, with research focused on biomarker identification complementing precision medicines that will inevitably drive identification of novel patient sub-populations. This in turn creates opportunities for pharmaceutical companies to develop novel therapeutics designed for these patients. Embracing the potential of precision medicine Precision medicine is rapidly coming of age, with estimates suggesting its market worth topped $183 Billion in 2020 and is forecast to reach $448 Billion by 2026.1 This is evident by looking at drug development pipelines, which are full of new targeted treatments that offer hope to patients. The FDA also anticipates over 200 INDs applications each year from 2020, building upon the 800+ active cell-based and gene therapies currently on file. By 2025, the FDA anticipates approving 10–20 CGT products per year – rising to 30–60 by 2030. Perhaps partially in response to this, the FDA has taken an active role in creating a positive regulatory environment, with 5 publications issued last year alone. There are several factors driving this growth. In an attempt to cater for the healthcare needs of an ageing population, there has been an increased emphasis on costeffective healthcare, which has given rise to precision medicine. This is due to Autumn 2021 Volume 13 Issue 3

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 39

Clinical and Medical Research its ability to reduce direct and indirect costs associated with cancer and genetic disorders and reduce the costs associated with healthcare plans, as the cost of using precision medicine treatment will be lower than the cost of prescribing treatments that are neither biomarker nor population specific and may be ineffective. The shift in demographic has also moved the focus from tackling infectious diseases to managing long-term conditions. The emphasis on health management and wellness has helped shape a new approach to engaging people before they become patients. Resultingly, the healthcare industry is focusing increasingly on prevention – a key benefit of precision medicine. The popularity of targeted therapies is another contributing factor, with biologics dramatically increasing from 5% of new drug approvals in the 1990s to making up a quarter of today’s pharmaceutical market. Regulation is rapidly evolving to accommodate this surge in growth. In the US, the development of a companion diagnostic is now an intrinsic part of the FDA’s approval of precision medicines, which are deemed safe and/or effective only if the patient has a certain biomarker. Other factors contributing to market growth include significant investment in biomarker and targeted therapy R&D, due to the profit potential and opportunity to uncover new revenue streams. New technology is another driving force, with next generation sequencing underpinning many emerging diagnostic tests. The emergence of value-based healthcare models, that reward value (patient outcomes) over volume is also having a notable impact. A final contributing factor that we cannot ignore is the impact of COVID-19 on the clinical trials’ landscape. The urgency surrounding vaccine development, the disruption to supply chains and R&D pipelines and the increase in public awareness, has had an unprecedented effect. Leading industry commentators have suggested that working under a spotlight, navigating protracted economic uncertainty and embracing technology have been core learnings from a landmark year.

be the opportunity to hit the reset button and leverage learnings to create competitive advantage. Through continued collaboration across the supply chain, greater focus on protocol development with the patient's outcome in mind, prioritisation across the value chain, investment in technologies to support the future way of working, and a shift to portfolios in newer modalities (i.e., cell & gene therapy) sponsors will increase their likelihood of thriving in a post-pandemic era of drug development. Exploring the complexity of advanced therapy supply chains The complexities associated with operating advanced therapy clinical trial supply chains are vast and must be approached with caution in order to avoid negative impact to patients and commercial performance. There are several fundamental issues that risk compromising a sponsor’s ability to compliantly and cost-effectively deliver the right drug, to the right patient at the right time and temperature. Limitations relating to recruitment, forecasting and drug stock can make it difficult for sponsors to effectively match supply with demand. Limited product stability, retest dates and forecasting can also raise the financial stakes for sponsors and demand a right-first-time approach to minimise waste and promote product integrity throughout the supply chain. Pressure to accelerate manufacturing and accommodate personalised packaging and dosing criteria also warrants careful planning and precise execution, as does implementing appropriate handling and optimised shipment protocols to effectively mitigate temperature excursions throughout global cold chains. While challenges such as aggressive timelines, inadequate supply chain visibility and the need for controlled temperature handling are not unique to precision medicine, they can be exacerbated where advanced therapies are concerned. Take for example, autologous therapies that require a rapid, patient-led cycle time

from collection to injection, temperature control, full track and trace of material and multi-site collection and distribution. This requires a carefully considered and robust end-to-end strategy, underpinned by effective technology. Digital supply chain and logistics systems will help sponsors of trials involving advanced therapies to effectively manage the heightened risk by providing real time data exchange between clinicians, manufacturing sites and carriers. Another high-risk area in autologous therapy supply relates to regulation so early regulatory planning is critical. This can be achieved by taking a holistic approach to compliance management and obtaining local regulatory requirements and importation guidelines. Sponsors should ask themselves a series of questions to establish whether ATMPs are defined in legislation, whether there are additional regulatory requirements for gene and cell therapy and tissue engineering and if there are specific safety or legal restrictions for GMOs and viral vectors. If sponsors are planning on conducting trials within the EU, it is also advisable to solicit feedback from a Qualified Person. Allogenic therapies, utilising donor tissues, bring similar supply chain challenges. As with all stem cell therapies, allogenic products must be manufactured under Good Manufacturing Practices. The scale up of manufacturing for allogeneic cells is similar to techniques used to make protein drugs and other large-scale, cell-derived materials. However, there are some nuances to be mindful of. For example, while both therapies use similar technologies common to the growth of cells, the scale is different. Allogeneic therapies are ‘off the shelf’ and used to treat many patients, so more time is available to quality control the product prior to administration. That said, sponsors will need to introduce flexible manufacturing platforms to support growth of living cells for a larger patient pool. Low stability profiles and restricted ‘time out of conditions’ will pose challenges from production through to patient administration, with narrow

For sponsors, the silver lining of a global pandemic that caused untold disruption will 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Clinical and Medical Research temperature storage and processing ranges limiting global patient recruitment before stability protocols expand. And while the cycle time from patient identification to dosing may be longer than autologous trials, allogenic therapy cycles remain shorter than traditional modalities. Proactive planning for flexible and viable supply chains While advanced therapy supply chains are more complex, the heightened risks can be effectively managed if sponsors focus on proactive planning that facilitates ongoing operational flexibility and supply viability. This requires proactive planning across multiple supply chain aspects, from technology through to packaging and labelling design and production strategy. When it comes to technology, the systems sponsors spec and select, including IRT and forecasting systems, will determine their ability to co-ordinate and share real time data with a vendor network and leverage flexibility between distribution pathways – from direct-to-site and direct-to-depot shipments, execution of partial late-stage and full late-stage kit customisation and patient-centric shipping solutions with direct-to-patient distribution. Capable technology will also empower sponsors to create a comprehensive digital supply chain and maintain temperature visibility and control throughout. With proactive planning, sponsors can harness technology to capture end-to-end cold chain data, reduce risk and promote cost-effective, patient centric supply. Several other aspects must be reviewed alongside technology requirements during the protocol development stage. This includes looking at blinding criteria, exploring how best to limit product waste and fulfil real rather than projected patient demand and how product loss – due to excursions in transit or at sites – can be reduced. Identifying the most appropriate randomisation scheme will minimise waste and promote cost savings too. Analysing these factors early will help determine suitable production approaches, such as the feasibility of implementing a Just in Time Manufacturing (JTM) model. By supplying only what is needed, high value, limited yield product can be preserved, and significant cost savings realised. For precision medicines, packaging design must be flexible to meet demand wwww.international-pharma.com

for patient-specific dosing and to maximise supply. Sponsors should look to pool drug product, components and labels where possible. Identifying needs, limitations and available solutions early on will prevent costly rework operations. For example, during early phases, a trial may focus on dose escalation. While volumes per kg are established, flexible carton design can be utilised, as it can minimise the space required at the site by almost 50%, as well as the number of cartons that require opening when preparing a dose for a patient. As trials progress through to the next phase and the correct vial size and draw volume is better understood, smaller or standard kits can be used. When packaging is standardised, stability protocols may still be volatile and require retesting every 3–6 months. If material is pre-packaged in a traditional made-tostock operation, expiration updates will be problematic, with rework introducing additional cost and handling. The latter will increase the risk of temperature excursions. In this scenario, JTM can pay dividends, as single panel labels can be used to get countries up and running far faster and more cost-effectively compared with a traditional approach. Ultimately, precision medicine has incredibly potential to transform the lives of patients and provide a springboard for the drug development sector to advance global human health. With the correct approach, facilitated by thorough and proactive planning, flexible and viable supply chain operations can be crafted that deliver patient-centric and cost-effective operations. REFERENCES 1.

GlobalData’s Drug Sales and Consensus Forecast Database

Natalie Balanovsky Natalie Balanovsky, Manager of Strategic Innovation, started at Almac in 2015. In her time here at Almac she has worked in various groups including Project Services Operations, and now Business Systems. Natalie has held various roles including Global Project Leader and Project Manager of Distribution, her role in Project Services has awarded Natalie the opportunity to partner with sponsors to implement a lean management method to effectively reduce waste and optimize efficiency Natalie went on to apply the lean principles to her role as Just In Time Manufacturing Solutions Manager, part of Almac’s strategic initiative to develop solutions that support our customers need for adaptive, efficient supply chain strategies. As the Manager of Strategic Innovation, Natalie will continue to build upon her contributions and deliver on Almac’s strategic imperative “to drive intelligent, value-based solutions focusing on simplification & acceleration to enhance the customer & patient experience.“ Natalie has over 20 years of professional experience within Project Management, Business Development, GMP Operations, and Quality Compliance. She holds a Bachelor of Science degree in Business from Delaware Valley University and a Master of Business Administration degree from LaSalle University. She is a certified Project Management Professional and a Member of the Delaware Valley Chapter of Project Management Institute.

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Clinical and Medical Research

The Case for a Distributable CDx Model

Precision Medicine The past decade has been an exciting era in healthcare for patients and providers with the increasingly broad adoption of precision medicine in drug development, clinical trials and approvals. The rise of precision medicine means patients have access to targeted, potentially more effective, therapies based on their genetic responses to treatment pathways. At the forefront of this trend is oncology. In oncology alone, by 2019, more than 160 biomarkers were approved for targeted therapy selection by the U.S. Food and Drug Administration (FDA). Further, more than 90 percent of pivotal clinical trials currently underway are to evaluate drugs aimed at specific molecular targets for the treatment of cancer.1 The trend of precision medicine development particularly in oncology is not only happening in the United States, but also across Europe and Asia Pacific regions. In Japan, for example, the Lung Cancer Genomic Screening Project for Individualized Medicine project (LC-SCRUM) was established in 2013 as a National Cancer Screening Program to screen target genes in lung cancer in an effort to advance the development of new molecular targeted drugs and diagnostics. As of August 2020, LC-SCRUM has expanded to more than 200 institutions in Japan and six institutions in Taiwan. LC-SCRUM is now in phase 4 of its program and continues to expand cancer screening in additional Asian countries.2 Other countries have launched their own precision medicine initiatives as well. In the United Kingdom, the 100,000 Genomes Project was launched to better understand rare diseases and cancer with the aim of integrating personalised data into healthcare delivery.3 The World Economic Forum has also established a precision medicine program to encourage collaboration between governments, industry, academia and patient groups to ensure more patients have access to advances in precision medicine on a global scale.4 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The Rise of NGS Companion Diagnostics With the increase in targeted therapies available to patients comes a growing need for companion diagnostics (CDx) to find patients who may benefit from these treatments. Companion diagnostics first emerged more than a decade ago. In 2011, the FDA published draft guidance on CDx development and since then has worked with pharmaceutical companies and diagnostics companies on the development and approval of CDx tests to coincide with new drug launches.5 Next-generation sequencing (NGS) has emerged as an ideal solution for CDx development because it enables testing for multiple biomarkers associated with multiple therapies simultaneously from a single sample. Because current targeted therapies available are often approved to treat advanced stage cancer, tissue samples – typically from a small biopsy or cytology specimens – are often not sufficient to be run through multiple single gene tests. Further, single gene testing can be time consuming. As a result, molecular testing is shifting to multiplex genetic tests and pharmaceutical companies are increasingly partnering with testing companies in early stages of drug development to bring NGS CDx tests to market in parallel with new therapies to increase opportunities to reach patients with targeted, potentially more effective treatment. Over the past five years, more than 20 pharmaceutical companies have announced CDx partnerships with leading NGS companies, including Thermo Fisher Scientific. The FDA has approved several NGS CDx tests to-date. Most approved CDx tests are designed to be run in centralised reference labs, while in contrast, Thermo Fisher’s Oncomine Dx Target Test was designed with a global distribution model in mind to be implemented in any hospital lab. Distributable NGS CDx Model vs. Centralised Lab Service NGS CDx Model To reach as many patients as possible, pharmaceutical companies will typically plan for a phased global launch of a targeted therapy, which requires bringing new

targeted therapies and their accompanying CDx tests through regulatory approvals in key regions including the U.S., the European Union, Japan, Latin America and Asia Pacific countries. In each region, regulatory and reimbursement environments vary greatly, and navigating them can be a challenge as pharmaceutical companies seek to reach as many patients as possible through CDx testing. In the U.S., send-out, or outsourced, testing to centralised reference labs is a well-established model, though there’s a much-needed effort underway to bring testing closer to patients at the community level to enable faster turnaround time and broader access to therapies. In addition, centralised testing is often not feasible in regions outside of the U.S. where the financial or logistical burden of centralised testing is too high. Thus, driving patient testing access for a new drug requires a distributable NGS CDx test that can be easily deployed through local laboratory networks based on countries’ regulations, payor policies and testing environments. Key factors such as sample send-out challenges, turnaround time and reimbursement economics may result in local environments where a distributable NGS CDx model is favorable over reliance on a centralised lab service-based NGS CDx. Sample send-out challenge In Europe, for example, sending samples out of the country to a U.S. centralised lab for CDx testing is generally not an accepted practice. To most efficiently determine patients who may benefit from targeted therapies – and to reach as many patients as possible – a local, distributable CDx testing solution that can be implemented in any hospital in-country is necessary in such scenarios. Turnaround time Shorter turnaround times (TAT) are critical to match patients with appropriate targeted therapies without delaying care, especially for patients with aggressive or late-stage cancers. The median life expectancy for stage IV non-small cell lung cancer (NSCLC) is 16 weeks6 and guidelines recommend a TAT goal of one week, up to a maximum TAT of two weeks.7 Hence, a distributed CDx test Autumn 2021 Volume 13 Issue 3

Clinical and Medical Research offered at a local lab can offer a significant advantage in faster turnaround time for results versus sending patient samples to a centralised lab that, in some cases, may even be located in another country. This may allow physicians to start patients on effective targeted therapies earlier in their care journey. Reimbursement economics Significant progress has been made in the past five years by the U.S. Centers for Medicare and Medicaid Services to expand national coverage to all NGS CDx tests approved by the FDA. However, outside of the U.S., many countries are behind with NGS reimbursement, often with more restricted coverage and substantially lower reimbursement thresholds, which ultimately can result in more of the cost being passed on to patients. By more closely aligning costs with local reimbursement standards, a distributable model allows CDx tests to be much more affordable to patients under local reimbursement payment structures. CDx in Japan: A Case Study for the Distributed NGS CDx Model Japan is one country where a localised CDx model has proven invaluable. Japan has been an early adopter of precision medicine, making it an important market for pharmaceutical companies. More than 20,000 patients with advanced solid tumours have participated in SCRUM-Japan, making it the world’s largest genomic screening program. The project has directly impacted access to new therapeutic drugs and diagnostics in the country, enabling 11 new drugs (13 indications) and seven in-vitro diagnostics approvals. As new drugs and diagnostics are developed, the country has also continued to evolve regulatory guidance for the use of CDx and new, targeted therapies. In Japan, CDx test results are required for clinicians to prescribe therapies for patients. The adoption rate of the CDx test has a direct impact on the number of patients that can be identified for therapies. As of 2021, three NGS CDx tests have been approved by the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, including Oncomine Dx Target Test. Oncomine Dx Target Test, a distributable NGS CDx test, was the first NGS CDx test approved by PMDA in April 2018 as a companion diagnostic for BRAF in NSCLC. In Feb. 2019, PMDA expanded approval for the test as a companion diagnostic for EGFR, wwww.international-pharma.com

ALK, and ROS1 in NSCLC. The test was then approved by the Ministry of Health, Labour and Welfare (MHLW) for reimbursement in June 2019 and has since been widely adopted in leading commercial labs and hospital labs in Japan. By aligning with local reimbursement thresholds, labs can provide CDx testing services, without incurring large out-of-pocket cost for the patients. As of December 2020, more than 30,000 patients have been tested by the Oncomine Dx Target Test in Japan. In contrast, a centralised test recently approved as a companion diagnostic for a MET inhibitor has seen slow uptake in Japan due to hospital CDx reimbursement issues. The out-of-pocket cost of centralised companion diagnostic testing is simply too high for medical institutions, which often can only claim reimbursement for far less than the actual costs of these tests. This prompted the Japan Lung Cancer Society and the Japan Lung Cancer Alliance to jointly issue a new guideline recommending using Thermo Fisher’s Oncomine Dx Target Test to initially screen patients to see if they are positive for MET exon 14 skip, and to use the centralised CDx as a confirmatory test before putting the patients on therapy. Conclusions As pharmaceutical companies determine the best approach for collaborating with a CDx partner, the most important consideration is of course the ability to benefit patients. Local regulations, reimbursement and testing environments have an important impact on identifying patients for treatment. Japan is just one example of a country where a distributable NGS CDx model that fits local reimbursement economics and enables in-country testing is essential to put more patients on targeted therapies. In many regions, a distributable NGS CDx may be far more advantageous than a centralised lab service NGS CDx as a global solution that can be deployed locally, cost effectively and with fast turnaround time to drive the broadest

adoption of targeted therapies and improve patient outcomes. REFERENCES 1. 2. 3.

4. 5. 6.

Albrecht, B., Alfano, S., Keane, H., Yang, G. Delivering innovation: 2020 oncology market outlook, McKinsey (2020) LC-SCRUM ESMO presentation, 2020 National Academies of Sciences, Engineering, and Medicine; Division on Earth and Life Studies; Institute for Laboratory Animal Research. Advancing Disease Modeling in Animal-Based Research in Support of Precision Medicine: Proceedings of a Workshop. National Academies Press (US); 2018 May 30. 2, Existing Precision Medicine Initiatives. https://www.weforum.org/communities/ precision-medicine, visited on 9 July, 2021 Mansfield, E. FDA Perspective on Companion Diagnostics: An Evolving Paradigm. Clin Cancer Res. 20(6), 1453-1457 (2014) DiStasio, M. et al. Molecular Testing Turnaround Time for Non-Small Cell Lung Cancer in Routine Clinical Practice Conforms Feasibility of CAP/ IASLC/AMP Guideline Recommendations: A Single-center Analysis. Clinical Lung Cancer 18(5), 349-356 (2017) Lindeman, N. et al. Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors. Journal of Thoracic Oncology 8(7), 823-859 (2013)

Jane Li Jane Li has been serving as Senior Director, Global Companion Diagnostics Commercialization for Thermo Fisher Scientific’s Clinical Sequencing Division since 2015. Previously, she was Senior Director, Clinical and Pharma Services for the Clinical Sequencing Division. She also held different roles in corporate strategy, business development, and M&A over the 20 years she’s been with Thermo Fisher.

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Technology

Beyond the Pill – Why Reliable Electronics is Key to Healthcare Technology is a driving force in improving and enhancing healthcare, with advanced electronics integral to many medical developments. Today, medical improvements go beyond the pill. Electronic solutions are now imperative to improving the population’s health and wellbeing. Medical electronics is exponentially escalating with the electronics market estimated to be worth USD 6.3 billion in 2021 and projected to reach USD 8.8 billion by 2026, at a CAGR of 6.9%.1 This is due to our ageing population and increased life expectancy. The increasing widescale adoption of electronics in all areas of the healthcare sector is also adding to the growth. Electronics are fundamental to medical devices from simple remote patient monitoring (RPM), like digital scales to sophisticated in-hospital devices, such as ECG monitors and surgical control panels. They are also used within implantables like cardioverter-defibrillator and Medtech devices which assist the dispensing of pharmaceutical products. Let’s also not forget about the increasing mHealth culture. MHealth, or mobile health, is the use of medicine and public health supported by mobile devices. This can include disease and epidemic outbreak tracking to chronic disease management, all of which require electronics to power. This growing demand calls for extremely complex electronics with more functions and increased portability. Printed Circuit Boards Assemblies (PCBAs) must be smaller and lighter but still contain the circuitry required to power these highly technical medical devices. The problem, however, is that the smaller and more densely packed PCBAs are more difficult to produce and to maintain quality. Add to this the need for the rapid escalation in the production and the problem of maintaining consistency increases. Medical device manufacturers must ensure that their products are produced efficiently to meet the required time to market, whilst guaranteeing longterm performance and reliability. 44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Parts come out of a vapour degreaser clean, rinsed and dry to reduce bioburden risk

Contamination Can Cause Failure PCBAs used within medical electronics cannot fail as the result can be catastrophic. Reliability must be the number one consideration when manufacturing these highly technical devices. They call for faultless manufacture and the use of components that will stand the test of time and function consistently without error. However, the increasing use of miniature components with ever-tighter tolerances, makes managing faults problematic and challenging. Quality cleaning is one method to help solve this problem. Contamination on the PCBA is one of the main causes of electronic device failure. The smallest contaminant can form a barrier between electrical contacts and other problems. Contamination comes in many forms from simple dirt, dust or oil from a fingerprint, to rosin or flux residue found on the circuit board. If assemblies are not cleaned it can lead to shorting, delamination, electrochemical migration, parasitic leakage and dendrite growth. Often causing reliability issues and PCBA failure. Improved cleaning directly translates to more effective PCBAs, and therefore to better medical electronics. For this reason, cleaning must be performed correctly and

effectively to guarantee the lifespan of the electronic assembly and ensure reliability. Cleaning Complex Assemblies Many manufacturers understand the importance of cleaning PCBAs but find it increasingly difficult to achieve successfully. The growing demand for miniaturisation requires microelectronic components. The reduction in pitch between conductors collects and traps contaminants making cleaning even more complicated. Low standoff components like MOSFETs are commonplace and input/output counts are increasing as circuit boards become multi-functional. This development in circuit board technology, complexity and high density is a reliability risk. Removing any harmful contaminant and residue from a PCBA is critical. Let’s also not forget that within the medical sector any device has to stand up to strict standards. The processes used in the manufacture of medical electronics must be validated as precise and repeatable. These devices have to pass extremely stringent tests and regulatory requirements. They must be free from contaminant to function consistently and meet the high specifications demands. Quality, consistency and safety are all priority concerns for the patients using Autumn 2021 Volume 13 Issue 3

Technology the devices, the medical staff reliant on the results, and the hospital and product manufacturers who are liable if failure was to occur. Regulations ensure these criteria are met, including the International Organization for Standardization (ISO). There are a number of ISO standards that must be followed, for example, ISO 10993. This evaluates devices within a risk management framework to ensure they are safe, assessing bioburden, pyrogens and sterility to ensure that no harmful material remains on the device, and the device is safe for its intended use. Electrotechnical Commission (IEC) 606011 is another important regulation explicitly designed for medical electrical equipment and systems. It requires that the basic safety and essential performance of the medical device must be maintained. Cleaning is pivotal to help meet these requirements and is also central in meeting the new EU Medical Device Regulations (EU MDR; ref., EU 2017/745). Vapour Degreasing – The Silver Bullet A validated and consistent cleaning regime is critical to the function and longevity of PCBAs. A cleaning method that is helping to ensure the reliability of medical electronic devices is vapour degreasing. It combines exceptional cleaning and also addresses regulatory requirements. When used with modern cleaning fluids, it is the silver bullet to the challenge of cleaning PCBAs. Vapour degreasing is a straightforward process that is effective at removing contaminants. It uses cleaning fluid immersion, combined with vapour rinsing and vapour drying to clean PCBAs down to the submicron range. A vapour degreaser is a closed-loop system that comprises two chambers both containing cleaning fluid. In one chamber, the fluid is heated to a boil, which then generates a vapour cloud that rises to meet cooling coils. These cooling coils cause the vapours to condense and return to their liquid state. This liquid is then channelled back to the second chamber, the rinse chamber. Soiled parts are immersed in the continuously filtered and distilled cleaning fluid inside the vapour degreaser to dissolve or lift the soils from the surface of the parts. As the parts are lifted from the cleaning fluid, they undergo a brief vapour rinse and drying process. The cleaning fluid condenses and drips back into the vapour degreaser to wwww.international-pharma.com

Reliable devices require faultless electronic components

be reused. The vapour degreaser recycles the cleaning fluid many hundreds of times before it needs to be refreshed or replaced. This helps reduce the environmental impact and cost of hazardous waste removal. After a typical cleaning cycle of about 6–20 minutes, the parts come out clean, rinsed, dried, spot-free and ready for the next stage of production. Effective Cleaning Fluid The modern cleaning fluid used within a vapour degreaser is specifically engineered with enough cleaning power to effectively remove contaminate, but also gentle enough to be compatible with commonly-used PCBA materials. It has low viscosity and surface tension ratings, together with high volatility allowing it to clean and rinse in small gaps and areas that other cleaning options cannot easily infiltrate. This ensures that all the surfaces of the PCBA are effectively and critically cleaned, even under tightstand-off components which are abundant in miniaturised electronics.

ensure the cleaning results are reliable and consistent. Crucially, these advanced fluids help reduce the risk of bioburden both on the manufacturing floor and on the finished product. This is a critical requirement when validating medical devices and the manufacturing process used. As vapour degreasing fluids contain no water there is no threat of bacteria growth. When parts are cleaned using a modern cleaning fluid inside a vapour degreaser, the parts leave the machine immediately dry, further eliminating the risk of bioburden and helping to meet the criteria needed for process validation. Safer for the Environment and Workers What makes modern vapour degreasing cleaning fluids even more impressive is that they meet strict global environmental regulations. They have improved HAP (hazardous air pollutant) and human toxicity profiles with higher, better TLVs (Threshold Limit Values) than the legacy solvents.

It also has a low boiling temperature, minimising the risk of damage to delicate PCBA components. And since the cleaning fluid is ultra-pure, it leaves no residue behind. Moreover, most vapour degreasing fluids are very heavy and dense, further aiding in dislodging contaminant from around and under components.

Innovative cleaning formulations are engineered to clean very effectively inside a vapour degreaser without the use of environmentally-harmful fluids that may contribute to groundwater contamination and air quality concerns. Most have a low GWP (Global Warming Potential) and zero ODP (Ozone Depleting Potential).

Modern, non-flammable and sustainable cleaning fluids specifically designed for a vapour degreasing system can make a substantial enhancement to the performance, reliability and longevity of PCBAs. They are lab-tested and certified to

In addition to preserving air quality by producing fewer emissions, the modern sustainable cleaners offer worker safety benefits. First, unlike legacy solvents such as n-propyl bromide (nPB), perchloroethylene (PERC) or trichloroethylene (TCE), modern INTERNATIONAL PHARMACEUTICAL INDUSTRY 45

Technology

Vapour degreaser cleaning fluids are lab-tested and certified to ensure the cleaning results are reliable and consistent

cleaning fluids are compositionally stable and nonflammable. This is an important benefit to environmental health and safety managers since it helps protect their workers from burn injuries in the event of an accident, such as a sudden arc flash. Second, modern sustainable cleaning fluids have very high marks for worker exposure limits. The PEL (Permissible Exposure Limit) or designated time limit that workers should be exposed to a chemical is much higher for modern cleaning fluids. Permissible exposure levels for modern fluids are about 200–250 ppm. Compared with TCE which has a 100-ppm PEL or nPB that is rated at just 0.1 ppm, modern cleaning fluids are significantly better for the safety of exposed workers.

Reliable electronics are Advancing Healthcare In the medical and pharmaceutical worlds, electronic devices help address many health issues. Their importance in monitoring and recording patient symptoms and vital signs, as well as their use in machines like those auto-dispensing the correct medication and dosage are growing in use. Medical device manufacturers must ensure the PCBAs within these critical devices work reliably. However, the complexity and high-density design of PCBAs causes a greater likelihood of cleaning challenges and consistency problems as the requirement for circuit board miniaturisation continues. This must be addressed through high-reliability critical cleaning.

With the medical electronics market set to increase as technology develops, it is vital to incorporate specific cleaning procedures that are easy to validate with long-term cleaning performance. Vapour degreasing and modern cleaning fluids are the solution. They meet the challenge of cleaning today’s complex PCBAs, as well as addressing regulatory requirements and certification conditions specified within medical manufacturing. REFERENCES 1.

https://www.marketsandmarkets.com/MarketReports/medical-electronics-market-104528 355.html

Jay Tourigny Jay Tourigny is Senior Vice President at MicroCare Medical which offers medical device cleaning and lubricating solutions. He has been in the industry more than 30 years. Tourigny holds numerous U.S. patents for cleaning-related products that are used on a daily basis in medical and precision cleaning applications. Web: www.microcare.com.

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Autumn 2021 Volume 13 Issue 3

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 47

Technology

How Technology is Making an Impact in Improving Managed Access Programs In the pharmaceutical industry, it’s critical to deliver medicine quickly to patients that need it most, but lengthy approval times for new treatments is not often something terminally ill patients can wait for. Looking at the big picture, it can take an average of 10 years for a new treatment to go from initial discovery to becoming commercially available in the marketplace. Terminally ill patients do have more direct access to investigational drugs and initial trials thanks to the Right to Try Act. However, the issues around process and approval times for new drugs was further illuminated during the COVID-19 pandemic. Managed Access Programs, like you find with companies such as Novartis, have helped make new treatments more accessible and available to critically or terminally ill patients, but there’s still work to be done in addressing rising patient needs. In the 1970s, the FDA opened these programs for cardiovascular patients in the US. The advent of the HIV crisis in the 80s and 90s, with its high mortality rate and lack of treatment options, the use of managed access programs broadened significantly. For example, drugs like AZT offered a “parallel track” to allow patients who were not in the clinical trial to still have access to these treatments, saving many lives. Almost 4,000 patients were allowed to access the treatment prior to approval over the course of 6 months.

outweighs the risk, and that such access be allowed by local laws and regulators. The lack of an overarching protocol surrounding the use of the pharmaceuticals can result in inappropriate use by physicians, which often leads to the reporting of possible adverse effects which could delay or derail marketing and regulatory approval. The allocation of separate resources to MAPs can impact ongoing clinical trials and delay commercialisation. Another challenge surrounds the ethics of access to managed access programs. Pharmaceutical companies, ostensibly have an obligation to complete clinical trials as quickly as possible in order to ensure that an investigational drug can be made available to a wide swath of patients. However, MAPs raise the question of equitable access. Patients with a larger pool of resources (i.e money, social media access, well connected doctors) can reach out to pharmaceutical companies more quickly than those without but who may meet eligibility requirements. These challenges were highlighted and exacerbated at the advent of the COVID-19 pandemic, when care providers and pharmaceutical companies alike were scrambling to find appropriate treatments for the never-before-seen coronavirus. For example, by mid-March 2020, Novartis was

receiving proposals from different global researchers and institutions looking to conduct trials against COVID-19 with Novartis compounds. Managing this high volume of urgent requests required developing a tailored response mechanism that streamlined the approval and distribution process of products through the MAPs system. We worked with Novartis to launch GEMS, an end-to-end SaaS system for managing MAP requests. This COVID-19 specific workflow, once in place, led to significant reductions in turn-around times for processing and approving requests. It reduced review and approval times from five days to five hours and waived legal conditions to reduce delays that prior to the pandemic could last anywhere from 2 to 10 days. This in turn expedited the drug shipping process which was often occurring within 24 hours from the original receipt of the request. As a result of this implementation, the company was able to process over 1000 requests from individual patients and governments alike, allowing an estimated 2500 patients to access Novartis compounds within a 7–8 week period. The benefit of leveraging SaaS technology for this purpose is that it allows companies to build and configure specific workflows for numerous variables in the managed access process. This flexibility allows pharmaceutical companies to create a single platform that

While the benefits of these programs are obvious and oftentimes lifesaving, there are many issues surrounding how patients access care. For one, differences in national pharmaceutical regulations can make it more difficult for patients to receive medicines. MAPs are generally determined on an individual basis, with requests for developing drugs made by individual physicians and approved based on criteria determined by the pharmaceutical company. These criteria include exhaustion of alternative therapy/ treatment options, ineligibility for or inability to access ongoing clinical trials, sufficient data to ensure the potential benefit of treatment 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2021 Volume 13 Issue 3

Technology financing an IIR requires a wide breadth of knowledge including regulatory oversight and medical writing, expertise in data analysis/ management, and more. A successful pharmaceutical study, be it one initiated by the manufacturer themselves, or independently undertaken by a clinical body requires collaboration and buy in from a variety of participants within and outside any single organisation. The technology used to create GEMS can be used to create a hub that centralises the processes for these research studies, providing a holistic view of the status and progress of these studies and their timetables, allowing for transparency and ease of communication among all participants, mitigating many of the common challenges in this field.

accelerates the process, granting access to drugs and treatments more quickly than before. Clinicians, patients, or anyone else requesting drugs or treatments can easily apply for MAPs through a single application page. Serving as a central hub and single point of access for all requests, this streamlines the process for both the requestor and grantor. At CyberGrants, we’ve built out this process for a bevy of pharmaceutical customers, including Novartis, who cite the flexibility of the platform and reporting capabilities as crucial differentiators when it comes to leveraging technology to support managed access. The ability to speed up pharmaceutical approval processes while maintaining integrity and accountability in the process is critical for public health, a matter clearly

illuminated by the pandemic. The need for effective and efficient processes to address pain points common in other areas of pharmaceutical development and treatment will grow in urgency as countries return to “normal” in the next few years. Similar technologies can be implemented for other programs such as independent medical education, Investigator Initiated Research studies (IIRs)/trials, fellowships, and sponsorships. For example, in the case of clinical trials, clinician participants often express dissatisfaction with a lack of ownership or active participation in the process, whether it be designing the study or analysing the data. To rectify this, clinicians often use IIRs to exert a modicum of control over the research. However, initiating, sustaining, and

The goal of technology is to expedite and redesign familiar endeavors to make them easier to use for as many people as possible. As a result of technology, transparency, speed and collaboration are more critical than ever to innovation and growth within industries – especially the high stakes world of pharmaceuticals. Pharma companies should embrace flexibility as often as possible, not only when dire circumstances require it, to ensure that they’re providing the best care and in turn best outcomes for their customers who need it the most.

Mark Layden Mark has had successful executive leadership tenures with some of the world's top technology brands, such as SAP, Applied Systems, and FICO, including international stints in Germany and France. Mark joined CyberGrants in 2015 and has spearheaded tremendous growth in company revenue, clients, and product development. Mark is a Cum Laude graduate of Harvard University where he played football and acquired an Economics degree. Mark lives in Chicago with his wife and four kids and commutes to Boston. Weekends he's a White Sox fan and weekdays it's the Red Sox. Mark's mission is "to help our customers make extraordinary and incredibly good things happen." Email: cybergrants@pancomm.com

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Technology

Building Common Ground for Collective Intelligence: How Digital Supply Networks Can Provide a New Era of Collaboration for Industry 4.0 In an age of disruption, not having endto-end visibility across increasingly complex global supplier networks, results in a constant state of firefighting mode. In the pharma industry, new ground is gained every day in understanding how digitally connected supply networks can help drive innovation, respond rapidly to disruptions, and ensure business continuity. The journey to digital supply network adoption begins where many organisations are today – suffering from a lack of supply chain visibility – and ends with an opportunity to leverage the power of collective intelligence. In this article, John Bermudez, VP of Product Marketing at TraceLink, explores how organisations can create their own digital supply networks on demand to forever change the way they work with their suppliers and partners. Bermudez also offers a look at how pharma companies can build their own network ecosystems with a digital network platform. Supply chain visibility is critical… but it’s not easy More than half of the companies across the end-to-end pharma supply chain lack the upstream and downstream visibility needed to respond effectively to sudden marketplace disruptions, according to IDC research, that surveyed more than 500 companies on the impact of COVID-19 on the global pharmaceutical industry. Visibility problems threaten efforts to build more agile, responsive, and resilient supply chains that can withstand and quickly recover from disruptions like those caused by the COVID-19 pandemic, the research found. "Visibility and agility are critical components of overall resiliency,” said IDC Program Vice President and Supply Chain Strategies Practice Leader Simon Ellis. “You 50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

simply can't be a resilient supply chain if you don't have those kinds of things.” While companies struggle with visibility remains, demand for goods is stronger than ever In June, the Institute for Supply Management (ISM) monthly index reported the 13th consecutive month of growth across 17 of 18 industries. However, many of these manufacturers are having a hard time keeping pace due to a plethora of supply chain issues, ranging from material shortages to commodity price increases. According to ISM, lead time for production materials reached 88 days in June – the highest figure ever recorded in the history of the report. Record-long raw-material lead times, wide-scale shortages of critical basic materials, rising commodities prices and difficulties in transporting products are continuing to affect all segments of the manufacturing economy. Supply chain issues, material shortages, labour issues, and other obstacles are now beginning to manifest in prices. ISM’s manufacturing price index reached its highest mark in the last 40 years, jumping 4.1% to 92.1% in June. As supply constraints, material costs, and other obstacles begin to impact activity across the sector, it’s critical manufacturers address supply chain friction whenever and wherever they can. Supply chain issue management is a low-hanging fruit in that regard, with multienterprise work management solutions enabling manufacturers to significantly improve the way they work with their supply chain partners. This enables dramatic improvements in supply chain issue resolution and delivery performance. The journey to supply chain success starts with digital supply networks The good news is that there are some steps companies can take today to meet the rising demand for goods and improve supply chain visibility. For starters, supply chain leaders must evolve the mental model

of “supply chain” to encompass the entire supply chain, not just next-in-line upstream or downstream trading partners. Second, digital supply networks and collaborative, multienterprise applications have arrived – and they are fundamentally changing the way that manufacturers work with suppliers. Pioneering companies today are pushing the envelope and building digital supply networks to create an always-on, alwaysconnected, real-time and dynamically adaptive supply chains. By enabling organisations to reach new levels of supply network collaboration, agility, and resilience in the face of disruptions, digital supply networks are poised to power the next stage in the evolution of supplier relationship management across all industries. With a digital supply network, digital network links replace expensive point-topoint integrations, data flows seamlessly across network members, and work processes can be tightly coordinated between network partners. Inventory levels, production and distribution process information, and demand and supply forecasts can be shared across the value chain of suppliers, manufacturers, wholesalers, and points of sale. The five stages of digital supply network adoption Where did these pioneering companies start their journey? How can other companies take the first step towards integrating digital supply networks into their supply chain strategy? The answers to these questions can be found by analysing the various stages of digital supply network adoption. The transformation begins where many organisations are today – suffering from a lack of supply chain visibility and contending with data silos that limit agility. But as the digital journey continues, those silos are gradually knocked down, and companies gain an opportunity to capitalise on the power of collective network intelligence. By adopting digital supply network technology, organisations can expect the process to unfold in the following five phases. Phase 1: Prior to the adoption of a digital supply network, supply chain data is siloed, Autumn 2021 Volume 13 Issue 3

Technology and information flows linearly from one silo to the next. For example, data flowing from an ingredient supplier to manufacturing organisation to distributor, and so on. Visibility is generally limited to the previous or next node in the supply chain – and disruptions can easily occur often without any warning. Phase 2: Once an organisation goes live with a digital supply network, they are immediately able to connect with more companies across their end-to-end supply chains, quickly proliferating their digital network links. As a result, additional supply chain information becomes available for stakeholders making decisions across the lifecycle. Phase 3: During this stage, supply chain data insights start moving in a variety of directions and is distributed among stakeholders. These digital links begin to render informational data silos obsolete and valuable supply chain insights become more freely accessible.

Collective Intelligence: The answer is a digital network creation platform To digitally transform entire industries, organisations need a network platform and a new breed of multienterprise business applications to create digital networks on demand to tackle critical business activities – while also enabling organisations to share collective intelligence freely and securely. One of the most powerful benefits of building networks on a single platform is the collective intelligence that can emerge from collaborative, interoperative networks. Like Waze for traffic intelligence, a digital network platform with a common data model will have massive transformative power. For example, resource planning decisions can be made based on real-time demand data. With extended visibility raw material and supply disruptions can be identified long before they impact production.

Phase 4: Now, the network is becoming the connective tissue that enables organisations to continuously create digital links with supply chain partners and secure information as it flows between stakeholders.

The results? Products will be brought to market with unprecedented safety, security, and efficiency. Collective intelligence gleaned from cross-network analytics will help organisations predict and prevent shortages and disruptions. And entire industries will be digitally transformed.

Phase 5: The final stage. This is when data silos are eliminated and supply chain data flows freely in and out of an interconnected digital core. By this point, supply chain visibility has increased well beyond just the next or previous node, and the ability to identify potential disruptions grows ever stronger.

Last word on pharma’s digital journey Members of the healthcare and supply chain ecosystem know that it cannot fulfill its commitment to patients or society without better operating models with network trading partners. This collaboration is vital to the safety and security of the world’s drug supply.

The power of digital supply networks is clear – but challenges remain While some companies have made it to the fifth phase and have significantly improved visibility across their end-to-end supply chains, there are looming challenges that can prevent supplier management teams from achieving the full potential of digital supply networks.

Fortunately, the foundation for the collaborative digital supply chain infrastructure pharma needs has been built already, through the global, industry-wide requirements to meet track and trace regulations. The digital supply networks that were created to help companies meet these requirements have evolved and organically expanded to provide endto-end supply chain solutions that help companies digitalise their processes, network ecosystems, and ultimately, their supply chains.

While an organisation and its network members can share insights freely and orchestrate processes, silos can still exist between the networks themselves. This makes it difficult to share data and glean insights across all networks in an industry. As a result, preventing shortages and predicting potential disruptions is more difficult, and supply chain optimisation across an entire industry is not possible. wwww.international-pharma.com

Designed for interoperability and collaboration, pharma finally has the collaborative platforms and networks it needs to disrupt disruptions and assure patients safe secure access to affordable medications and healthcare.

John Bermudez John Bermudez is responsible for leading the overall strategy, business planning, and operational execution for TraceLink's Digital Network Platform business. He has over 30 years of experience in management, marketing, product management, engineering, software development, research and SaaS transformation, and is an established leader in supply chain management. Prior to TraceLink, Bermudez led Infor's supply chain management digital transformation and acquisition strategy and held roles as Vice President at Oracle and AMR Research/Gartner, where he co-authored a book on the impact of e-commerce on supply chain management. Bermudez holds an MBA in finance and a Master of Science degree in Operations Research from Rutgers University.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 51

Manufacturing

How to Future-Proof the Manufacture of Sterile Drug Products ChargePoint Technology’s Christian Dunne, Head of Sterile Solutions, explores the latest trends in containment and advises how pharma companies can adapt and thrive in a fast-evolving environment. The aseptic pharmaceutical processing market is growing incredibly quickly – in fact it is projected to develop from $62.2 billion in 2020 to $73.6 billion by 2027.1 This strong and sustained performance is being fuelled by greater demand for sterile drug products. To illustrate, the generic sterile injectable market is predicted to grow at a compound annual growth rate of 11.3% moving from 2020 to 2030 to reach a value of $198.7bn.2 A factor that is driving this growth is the way in which modern therapies have changed their approach to helping patients. There has been a shift towards more targeted therapies, which has resulted in products being produced in smaller batch sizes. This is increasingly true in aseptic processing and that means pharma manufacturers have to consider how to produce these products efficiently and cost-effectively at a smaller scale. This has significant implications for manufacturers, who have to rethink how facilities are designed and re-assess capex spending. As with any significant shift in process, any changes that are implemented need to be ones that are functional in the longterm, especially in today’s rapidly changing environment. This can only be achieved by first assessing the principal challenges facing manufactures involved in aseptic processing. The challenges faced The pharma industry is operating in an increasingly complex environment. The shift towards personalised treatments often means that it is not cost-efficient option for drug developers to build out facilities specific to each treatment, with all of the associated capex spending. In turn, this has led to greater outsourcing of many stages of 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the manufacturing process that has resulted in a more fragmented supply chain. Reliability of the supply chain The changing nature of the supply chain has also led to some problems, notably the reliability of supply. This is now driving by pharma companies to consider diversifying their supply chains through the on-shoring of certain relationships, and the search for new suppliers that are more robust and reliable than existing partners. As a result, manufacturers in the area are exploring ways of differentiating themselves from the competition. They are looking to do this through the expansion of their operational capabilities and building new aseptic lines, including the exploration of new markets. This latter factor is crucial to drug developers, as it makes them less reliant on individual countries or regions, minimising any risk of future disruption. This has become a significant concern, after the impact of the COVID-19 pandemic led to problems in the supply of supplies for sterile manufacturing, such as ingredients for products and materials for packaging. Regulatory Managing customer demand for aseptic processing cannot just be met by expanding existing sterile capacity and maintaining standard operations. The Good Manufacturing Practices (GMP) Annex 1 (sterile products)3 is about to have revisions come into action, after a consultation draft released in 2020.4 The updated Annex 1 contains a number of revisions that will have wide-ranging implications for aseptic processing and containment, particularly in relation to Contamination Control Strategy (CCS) in cleanroom zones. An entire section has been added regarding closed systems, which provides a number of additional factors that pharma manufacturers will need to adhere to in order to ensure their CCS complies with the new Annex 1. This means that pharma manufactures will need to minimise the

number of manual interventions to ensure sterility, as well as being designed for integrity. As a result, a priority will be placed on carrying out thorough risk assessment and the monitoring of integrity, which will require additional methods to be put in place to comply with regulation. Transit between facilities and regions One area that should not be overlooked is the transportation of drug substances which, due to the changing nature of the industry, is becoming more important. For instance, the greater level of outsourcing is greatly influencing increased travel. The contract manufacture of sterile drugs allows pharma companies to reduce the demands for in-house means of producing their products. This is a trend seen across the industry and is expected to continue to grow. This will result in ingredients travelling more, across different facilities and different locations. All the while, sterility will need to be managed. Batch size As mentioned, it is now more common for smaller batches sizes to be needed for new types of products. For instance, ‘precision treatments’ in an area such as oncology will be catered towards the genetic profile of a patient, reducing the number of treatments produced in that particular area. With this comes a change within the manufacturing facilities themselves, where it is more common for a greater number of products to be manufactured in the same facility, with more specific process requirements. This means that equipment, and the facility itself, need to be able handle multiple process lines. The past saw greater investment into large-scale equipment and facilities, while the future may favour greater flexibility. Speed Directly related to the batch size is the speed at which operations are carried out. This can be directly linked to the product itself, where speed to market is becoming ever more important. This is particularly difficult when a processing environment must be sterile at every stage in production. Cost The traditional manner of producing large Autumn 2021 Volume 13 Issue 3

Manufacturing batches is no longer cost-effective for all types of products. It is therefore imperative to find ways of reducing costs or gain efficiencies in the process. This is especially true as more stringent regulation increases demands on manufacturers. Innovation is key The obvious question is then how to increase the output of the end product whilst complying with increasing regulation and mitigate the aforementioned challenges? The answer is that this is happening through the updated offerings of containment technology offered by specialist solution providers. The development and adoption of hybrid Single use (SU) technology, such as SU powder transfer bags and SU passive valves are examples of the way that containment equipment is changing to meet drug developers’ needs. The key advantages of SU equipment in sterile pharmaceutical production are numerous: • • •

•

SU technology can ensure the aseptic integrity of products during logistics, and in the manufacturing facility itself SU equipment is generally easy to use, with only limited training or production line upgrades needed The technology streamlines cleaning and validation procedures, as they are designed to be only used once prior to disposal. This improves integrity and also reduces production downtime Adoption of SU technology can also reduce the cost basis of the process, through the added efficiency gained by avoiding cleaning and washdown Transit between facilities or regions can be simplified through the use of SU bags instead of reusable alternatives

These factors allow firms to ensure optimum product quality, while improving process efficiency and reducing production costs. This is achieved because there is no need for cleaning or washdown procedures between batches. The SU equipment, such as SU bags, can be discarded immediately after use, which significantly streamlines the hygiene procedures required to maintain a sterile environment. This reduces production downtime compared to reusable alternatives. Manufacturers can also use SU bags to reduce the reliance on alternative means of transport, such as plastic or fibre drums, making the entire process more costand time-effective. wwww.international-pharma.com

Added to this improved efficiency means that manufacturers can optimise the output of their lines, which enables them to produce more product without compromising on quality. In this way, the greater efficiency also reduces the cost base for the product created. Innovation within SU technologies A standout example of a piece of SU technology that can support drug developers in ensuring compliance with the developing containment legislation is the split butterfly valve (SBV). This technology provides a solution for the sterile transfer of powders, including drug substance and drug product. SBVs enable the transfer of powders into and out of process equipment during the pharmaceutical manufacturing process. The SBV is comprised of two components: an active half, which is attached to the production line equipment and a passive half that connects to a filling container. The two halves are connected together in order to create a single plate. This allows the product to transfer from the line into the container via the interior of each half. The end result is that the power does not come into contact with the surrounding environment, which ensures aseptic integrity through the process. A new SBV that functions with a disposable version of the passive components have also now been created. The principal benefit of this is to manage the same quality of aseptic processing but also greatly improving the efficiency of the process. The disposable passive half is attached to a SU flexible charge-bag, enabling it to be contained and sterile during the transfer of powders through the manufacturing process, as well as between facilities. Once the disposable passive half has been used, there’s no need for cleaning because it can be disposed of between fillings, improving efficiency. The disposable SBVs are sterilised prior to use and their manufacture takes place within an ISO6 cleanroom environment. The sterilisation commonly takes place through the use of gamma radiation, qualified according to ISO11137. However, X-rays are now increasingly being adopted to reduce the degradation which sometimes occurs during the irradiation process. This sterilisation process, whether by gamma radiation or by X-rays, allows for the SBVs to

be used in aseptic processing environments – ensuring sterile integrity conforming to existing and forthcoming regulation. The future of productivity and sterility SU technology is just one element of measures to improve productivity, efficiency and sterility across the industry. Change is also arriving from other areas, particularly in the realm of improved technology and the use of data. Similar to other manufacturing industries, the potential for the integration of smart monitoring technology is enormous. A growing example of continued innovation in the space is “smart factory” technology, which has huge potential to advance aseptic integrity. The “smart factory” concept allows pharmaceutical production lines to have real-time usage data of their equipment. This can aid drug developers to establish an audit trail quickly and efficiently. For the individuals, such as health and safety teams, and those responsible for compliance, to have access to rich realtime data on the status of equipment installed on the line is invaluable. Through this, everyone involved can manage the validation programmes for the aseptic lines proactively. More than this, the real-time data can be made available remotely to those individuals from a mobile device or through an online dashboard. As a result, health and safety team are able to gauge the usage of valve components at any time. This even allows individuals to monitor processing lines and individual components that are housed in different facilities. The data can also be synchronised via WiFi to a portal, where data are stored in the cloud for production and process managers to analyse remotely and export for further reporting. “Smart factory” technology is therefore able to significantly improve on traditional strategies to assess the health status of valves on the line, by providing a reliable and fully automated means of monitoring the technology. The real-time data generate can then help line operatives to determine where and when maintenance is needed, before a situation arises whereby aseptic integrity or productivity is affected. This allows for INTERNATIONAL PHARMACEUTICAL INDUSTRY 53

Manufacturing larger movements in the industry now, through the adoption of such technology, is one way that manufacturers can prepare themselves now for future challenges and to advance aseptic integrity. REFERENCES 1. 2.

3. 4.

https://www.globenewswire.com/newsrelease/2020/10/27/2114839/0/en/GlobalAseptic-Processing-Industry.html https://www.globenewswire.com/en/newsrelease/2021/02/16/2176372/0/en/GenericSterile-Injectable-Market-to-Garner-Growth11-3-by-2030.html https://ec.europa.eu /health/sites/ default/files/files/gmp/2017_12_pc_annex1_ consultation_document.pdf https://www.honeymangroup.com/training/ articles/annex-1-revision-2020/

Christian Dunne

preventative action to take place proactively, minimising any potential downtime and helping to ensure compliance with the new Annex 1 integrity requirements. An evolving space As the demand for aseptic pharmaceutical processing continues to grow, it is certain that the space will continue to evolve. The trends that are already clear are the continued movement towards fewer manual interventions, as well as the push towards greater integrity and thorough risk assessment. 54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Luckily, there are now a greater number of tools that are being developed specifically to aid manufacturers to develop their processes alongside these changes. One of the benefits of SU technology is that they are a flexible tool that can be seamlessly introduced into current processes. Moreover, the newer “smart” technology is able to go beyond just making the processes more streamlined to also provide a tool to the individuals working directly on the processing lines to be more proactive in maintaining operations. Reacting to the

Christian Dunne is the global product manager at ChargePoint Technology for the sterile containment solutions. For the past 20 years Christian has been creating innovative solutions for the pharmaceutical, biotech, cell therapy and fine chemical industries to overcome high potency containment and aseptic processing challenges. His technical expertise spans high containment isolators, grade A (ISO5) sampling & dispensing facilities, together with R&D and production filling line restricted access barrier systems (RABS) and isolators. For the past six years, Christian has been working with ChargePoint Technology on the advancement of its split butterfly valve technology, designed to handle highly potent/sterile powders and small-scale components, where both product and operator protection are paramount. While working on many aseptic applications, Christian integrated a number of different bio-decontamination systems and consequently has an in-depth understanding of their performance and application. This knowledge was key to the development of the now established ChargePoint AseptiSafe Bio®, used for the transfer of sterile powders in the industry. Christian is an active member of the International Society for Pharmaceutical Engineering (ISPE) and The Pharmaceutical Healthcare Sciences Society (PHSS).

Autumn 2021 Volume 13 Issue 3

1mL & 2.25mL Spring-free passive safety devices for pre-filled syringes

UniSafe® has a fully integrated and secure plunger, which is fixed 2mm away from the stopper The benefits of a secure integrated plunger are: • Plunger rod cannot be pulled out when removing the RNS or the device from packaging, eliminating risk of accidental drug spillage and compromised sterility • The device design helps to address the potential risk of container closure integrity (CCI) • Simple final assembly as the plunger rod does not screw into the stopper • Reduces risk as device cannot be re-used • Maintains sterility in assembly

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 55 OMPS/ipi/ad/ob/0921/07

Manufacturing

Formulation and Process Considerations for Optimising Spray-Dried Solid Dispersions Spray drying active pharmaceutical ingredients (APIs) in solution to overcome solubility hurdles requires part craft and great attention to process variables. In this article, Javier Gurrea, a spray drying manufacturing specialist from Idifarma, explains how expertly applied spray drying technology offers drug innovators a faster route to higherperforming drugs. Although a technically challenging process, spray drying is a mature, well understood technique capable of transforming solutions or suspensions into solid particles. Although this process has been widely used in diverse industrial fields, it has become more and more demanded in pharmaceutical applications for the production of solid dispersions (SDSDs). Pharma leveraging SDDs more than ever Today’s APIs are increasingly insoluble and that is presenting new problems for formulators looking to manage the bioavailability and dosing of their formulas. As a result, a significant number of therapeutics gaining approval recently possessed poor biopharmaceutical properties that had to be managed through advanced processes and formulation strategies. Improving the bioavailability of these new and existing drugs is turning out to be big business for contract development and manufacturing organizations (CDMOs) as pharma’s drug developers look to exploit both accelerated new chemical entity (NCE) and existing drug development pathways. Several of the most popular drugs on the market today have had to manage poor solubility and low bioavailability. That trend isn’t slowing either. Pharma industry analysts estimate that as many as 40% of approved drugs and nearly 90% of the developmental pipeline drugs consist of poorly soluble molecules.1 For developers, changing formula chemistries and identifying different routes of administration are just a few of the ways the industry is seeking to profit 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

from accelerated drug development routes including 505(b)2 New Drug Applications (NDAs). The industry is finding that redeveloping existing formulations can quickly improve the therapeutic value of existing drugs to both payer and patient. Regarding drug bioavailability enhancement, SDSDs have proven to be a highly controllable, flexible manufacturing strategy to improve the solubility of drugs – especially those with low aqueous solubility. Because each product is unique, a deep knowledge of the key aspects of the formulation and the mechanistic understanding of spray drying process is required. Understand your evaporation rate inside and out During spray drying, the heat and mass transfer that takes place determines the characteristics of the particles being formed. This atomisation of the solution is a crucial aspect of the process because it generates fine droplets in order to increase the surface area of the liquid exposed to the drying gas.2 Initial mass transfer is characterised by a constant evaporation rate, equivalent to a pure solvent droplet – because it refers to the evaporation of the solvent on the surface of the droplet. This is followed by the diffusion of the solvent from the core to the particle surface.2 At this moment, the temperature of the particle suddenly increases, and the particle formation rate diminishes due to the higher amount of solvent in the drying gas stream. Consequently, the evaporation rate undergoes a sudden decrease due to the droplet viscosity, which can solidify the surface first, hindering the solvent from leaving the interior of the droplet. It is a key consideration not to be overlooked or dismissed lightly. The evaporation rate is crucial in stabilizing the amorphous form of the drug, and the time the particle is in contact with the hot gas may also have an impact on the stability of the product obtained. In this sense, although the drying capacity of the gas can be increased by raising the process temperatures, it cannot

rise indefinitely to avoid compromising the stability of the solid dispersion. Tetris and the ‘rush hour effect’ It is important not to forget that the drying process takes place in milliseconds and during this brief point in time, different phenomena occur that can and will determine the characteristics of the particle being formed. First, the droplet mass remains constant until the solvent begins to evaporate. Then, the amount of solvent of the droplet goes down and the solute content concentrates on the surface of the particle. As a result of this ‘concentration gradient’ there is a slight diffusion of solutes towards the nucleus of the particle as well. In this case, if the diffusion rate of solutes is not as fast as the decrease in droplet volume, a ‘crust’ can form on the surface of the particle.3 As evaporation of the solvent continues, this outer skin can hinder the evaporation of the solvent from the core of the particle and, depending on the resistance and thickness of the crust formed, the particle can inflate or burst resulting in hollow or porous particle due to the internal pressure. This phenomenon is commonly known as ‘rush hour effect’.4 On the contrary, if the evaporation rate is low, the solute particles have enough time to migrate to the core of the particle during the solvent removal, resulting in denser and smaller particles (‘tetris effect’) (See Figure 1). Fortunately, these phenomena can be explained by a simple equation referring to the Peclet number (Pei) equation which relates the variables that influence the characteristics of the resulting particles (Equation 1).5

• •

𝑃𝑃𝑃𝑃! =

𝑘𝑘 8𝐷𝐷!

k is the evaporation rate Di is the diffusion coefficient of the solute

For a given solution composition, a low evaporation rate (low Pei) results in Autumn 2021 Volume 13 Issue 3

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 57

Manufacturing smaller and denser particles while a very fast evaporation rate (solvents with low boiling point, high Pei) provides particles of more volume, porous, less dense and with an enrichment of solutes on their surface. Additionally, the solvent characteristics can also affect the distribution of the particle components, as can be seen in the equation, that includes the diffusion coefficient of the solute in the solvent. When values of diffusion coefficient are low (corresponding to a higher Pei) there is an enrichment in solutes on the particle surface because the particle components diffuse more slowly than the particle size decrease during the solvent evaporation. In contrast when diffusion coefficients are high (lower Pei) the components will be uniformly distributed along the particle.3,6,7 All things considered, by manipulating the key process inputs of spray drying, the properties impacting the dissolution behaviour such as morphology and particle size, as well as density and flowability (relevant to process quality and throughput goals in downstream processes like tableting or capsule filling) can be modulated. Manage spray drying variables for best results Manufacturers with experience have found that the better technicians are at leveraging a series of critical spray-drying process parameters, the more capable they are of generating desired particle morphologies. Breaking it down, precise particle formation control requires a thorough evaluation of both feed solution variables and process parameters:

Figure 1 – Effect of evaporation rate on transition from droplet to particle

larger particles with a rough surface and high porosity).3,10 •

Polymer content. The evaporation kinetics is influenced by the polymer concentration in the solution, which will result in a given solution viscosity. On the other hand, the miscibility of both components, and the potential to obtain a homogeneous system, is determined by the API-polymer ratio.8

•

Solids content. Typical solids content used in amorphous solid dispersions are within the range of 10% to 30%. This solids content is inversely proportional to the evaporation rate.9 Regarding desired particle size, low-concentrated solutions generally produce small spherical particles (of high hygroscopicity and concentrated solutions often result in

58 INTERNATIONAL PHARMACEUTICAL INDUSTRY

•

Type of gas and flow rate. On the one hand, the type of gas used can influence the particle size. Gases with low density, such as nitrogen, result in smaller particle size.2,16 On the other hand, the higher the gas flow rate, the smaller the particle size obtained during the process, and, in addition, it has been observed that working in open cycle produces higher yields than working in closed cycle.2,17

•

Type of atomizers used. Depending on the design of the atomising system, particles with different properties can be obtained using:

Process parameters •

•

Feed solution variables •

Solution stability. This variable requires close examination, especially when large commercial volumes of solution are prepared, involving a large period of time between its preparation and its drying process, in order to avoid nucleation and crystalline growth.11

low will cause a high level of residual solvent in the product, compromising its stability.15

•

Liquid feeding rate. This parameter dictates the time in which the particles are in the drying chamber, as well as the amount of solvent present in the gas stream and the subsequent outlet temperature observed. It is also directly proportional to the particle size and some authors have described that this feed rate could be inversely proportional to the solubility enhancement of the active ingredient.12 Inlet temperature. Because inlet temperature has been postulated to be directly proportional to the obtained glass-transition temperature (Tg), it is inversely proportional to the crystallinity of the drug.13 High inlet temperatures can generate larger particles and may cause solvent entrapment in its core, resulting in the subsequent destruction of its outer skin while lower inlet temperatures, generate smaller denser particles with a rough surface.3,14 Outlet temperature. Two aspects of outlet temperature should never be overlooked. If the outlet temperature is above the Tg of the product, it can adhere to the walls of the equipment due to the sticky characteristics of the compound, reducing process yield. Similarly, an outlet temperature too

•

Rotary/centrifugal atomisers: These devices use a rotating disk to break the liquid stream into small droplets that are projected towards the walls of the drying chamber thanks to centrifugal force.18

•

Bi-fluid nozzles: This is the most common type of atomiser employed in the pharmaceutical field. In these devices the liquid is put in contact with a gas stream resulting in a disintegration of the liquid into fine droplets. The characteristics of the atomisation will be influenced by the characteristics of the solution or suspension and the gas used (density, viscosity, pressure, etc.).19

•

Pressure nozzles: This type employs hydraulic pressure to break the liquid stream through a nozzle, where a series of spiralshaped inserts break the solution into small droplets. One advantage of these atomisers is that they Autumn 2021 Volume 13 Issue 3

Manufacturing

allow the obtention of larger particles that facilitates the subsequent downstream process without needing to perform a dry granulation step to achieve the optimum flow and density features.20 Programs run better with systematic Quality by Design Although spray drying can be a challenging technology to master it has fast become the preferred way for drug developers to overcome the limitations of APIs with poor aqueous solubility due to its applicability to obtain amorphous solid dispersions or to dry nanosuspensions for instance. In support of quality and reliability in process the industry is increasingly introducing spray drying in a more systematic and empirical way following ICH Q821 guidelines and its primary Quality by Design (QbD) approach. Having a deep knowledge of all the parameters that influence the process and their potential impact on particle formation is the initial and key step in starting a successful drug manufacturing program for tricky, insoluble formulations. The process is sophisticated, and program planning requires a precision approach. REFERENCES 1.

2. 3.

Kalepu S, Nekkanti V. Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharmaceutica Sinica B. 2015; 5(5):442-53. Singh A, Van den Mooter G. Spray drying formulation of amorphous solid dispersions. Adv Drug Deliv Rev. 2016; 100:27–50. Paudel A, Worku ZA, Meeus J, Guns S, Van den

wwww.international-pharma.com

Mooter G. Manufacturing of solid dispersions of poorly water-soluble drugs by spray drying: Formulation and process considerations. Int J Pharm. 2013 Aug 30;453(1):253–84. 4. Pai DA; Vangala VR;, Ng JW;, Tan RBH. Resistant maltodextrin as a shell material for encapsulation of naringin: Production and physicochemical characterization Item Type Article. 2015. 5. Vehring R, Foss WR, Lechuga-Ballesteros D. Particle formation in spray drying. J Aerosol Sci. 2007 Jul;38(7):728–46. 6. Osman A, Goehring L, Patti A, Stitt H, Shokri N. Fundamental Investigation of the Drying of Solid Suspensions. Ind Eng Chem Res. 2017 Sep 20;56(37):10506–13. 7. Lintingre E, Lequeux F, Talini L, Tsapis N. Control of particle morphology in the spray drying of colloidal suspensions. R Soc Chem. 2016;12(36):7435–44. 8. Wang S, Langrish T. A review of process simulations and the use of additives in spray drying. Food Res Int. 2009 Jan;42(1):13–25. 9. Miller, D.A., Gill, M. Spray-drying technology. Formula Poorly Water Soluble Drugs SpringerNew York. 2012; 3:363–442. 10. Littringer EM, Mescher A, Eckhard S, Schröttner H, Langes C FM. Spray Drying of Mannitol as a Drug Carrier – The Impact of Process Parameters on Product Properties. Dry Technol. 2012 Jan;30(1):114–24. 11. Lindfors L, Forssén S, Westergren J, Olsson U. Nucleation and crystal growth in supersaturated solutions of a model drug. J Colloid Interface Sci. 2008 Sep 15;325(2):404–13. 12. Sahoo NG, Abbas A, Judeh Z, Li CM, Yuen K-H. Solubility Enhancement of a Poorly WaterSoluble Anti-Malarial Drug: Experimental Design and Use of a Modified Multifluid Nozzle Pilot Spray Drier. J Pharm Sci. 2009 Jan 1;98(1):281–96. 13. Albers J, Matthée K, Knop K, Kleinebudde P. Evaluation of predictive models for stable solid solution formation. J Pharm Sci. 2011. 14. Dobry DE, Settell DM, Baumann JM, Ray RJ, Graham LJ, Beyerinck RA. A model-based methodology for spray-drying process development. J Pharm Innov. 2009. 15. Thybo P, Hovgaard L, Lindeløv JS, Brask A, Andersen SK. Scaling up the spray drying

16. 17.

18.

19. 20. 21.

process from pilot to production scale using an atomized droplet size criterion. Pharm Res. 2008 Jul 11;25(7):1610–20. Özbilen S. Influence of atomising gas on particle characteristics of Al, Al–1 wt-%Li, Mg, and Sn powders. Powder Metall. 2000 Feb 19;43(2):173–80. Wang A, Lu Y, Zhu R, Li S, Ma X. Effect of process parameters on the performance of spray dried hydroxyapatite microspheres. Powder Technol. 2009 Apr 4;191(1–2):1–6. Huang LX, Kumar K, Mujumdar AS. A comparative study of a spray dryer with rotary disc atomizer and pressure nozzle using computational fluid dynamic simulations. Chem Eng Process Intensif. 2006 Jun 1;45(6):461–70. Masters K (Keith). Spray drying in practice. Charlottenlund: SprayDryConsult; 2002. 464 p. Mujumdar AS. Handbook of industrial drying. CRC/Taylor & Francis; 2007. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Pharmaceutical Development Q8(R2).

Javier Gurrea Javier Gurrea has 5 years of experience in Pharmaceutical Development and GMP Manufacturing. His work is focused on the development and manufacturing of drug products with Spray Drying technology. He has been involved in numerous projects based especially on amorphous solid dispersions, as well as working on other applications of this technology including micro and nanoparticles. Javier has a double degree in Pharmacy and Nutrition from the University of Navarra (Spain).

INTERNATIONAL PHARMACEUTICAL INDUSTRY 59

Manufacturing

From R&D to Production: How the Bioreactor Choice Can Streamline Biologics Scale-Up Transferring a biologic candidate from the research and development phase to commercial production usually requires increasing the working volume of the upstream bioprocess. During scale-up, process performance optimised at small scale needs to be reproduced at larger scale, ideally without much need for process optimisation at large working volumes. This requires reproducing the cells’ growth environment across scales. In this article we discuss why certain bioreactors’ engineering parameters are critical to make this possible and demonstrate, how we scaled-up a cell culture process for mAB production from research to pilot production scale, using single-use bioreactors at all stages. Developing new biologics in a commercially viable manner requires monitoring of development costs and time to market. An integral part of biologics manufacturing is the upstream bioprocess, during which cells are multiplied in bioreactors and allowed to express the protein of interest. Process scale-up strongly determines upstream bioprocess performance. To achieve this goal, streamlined process transfer is implemented to reproduce the product titers and quality which have been optimised in small working volumes at production scale. Can we reproduce the cells’ growth environment at different scales? Various parameters define the cells’ growth environment in a stirred-tank bioreactor, such as the concentration and distribution of nutrients, the dissolved oxygen concentration, and shear stress. These parameters relate to the bioreactor’s capabilities: Gassing devices, gas flow, and culture mixing influence the DO and shear conditions. The culture mixing determines the distribution of nutrients. To streamline scale-up, bioengineers commonly use bioreactors with similar geometries at all scales and keep one or more physicochemical parameters constant between vessels of different sizes, such as the volumetric mass transfer coefficient 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

(kLa), power input per volume, tip speed or mixing time. Keeping one process parameter constant will change others. Therefore, we can only partially reproduce the cells’ growth environment at different scales. The bioengineer must identify the parameters which influence cell growth and productivity most, to decide, which scale-up strategy is the most suitable. In aerobic bioprocesses the key parameters are typically oxygen mass transfer, carbon dioxide removal, mechanical stress, and mixing quality. Scale-up strategies Constant power input per liquid volume (P/V): Keeping the power input per volume constant is probably the most widely applied strategy for scale-up, because the mechanical shear stress, mixing quality, oxygen mass transfer, and carbon dioxide extraction in aerobic cultivations all depend on the specific power input. Calculating P/V requires the bioreactor’s power number. P/V is calculated as follows: P/V = (Np x ρ x N3d5)/V, with Np being the impeller power number (also known as Newton number), ρ: DI water density (kg/m3), N being the agitation speed (rps), d being the impeller outer diameter (m), and V being the full working volume (m3). Np is a dimensionless number associated with different types of impellers and needs to be determined for each vessel type used in the scale-up workflow. Constant tip speed: The impeller tip speed correlates with the velocity of the fluid at the tip of the impeller and therefore is related to the shear force to the cell or biologic. The impeller tip speed equals π x d x N, with d being the impeller outer diameter and N being the agitation speed. The tip speed range of a vessel can therefore be easily calculated from the impeller outer diameter and the agitation speed range, which are known from the vessel specifications. Constant kLa: The kLa determines how much oxygen is transferred to the culture medium. Being able to reproduce the kLa of the small-scale bioreactor at larger scale is a prerequisite to avoid oxygen

being a limiting factor for cell growth. The kLa depends on various parameters, including the gas flow rate, the sparger type, the agitation speed, and properties of the culture medium. Hence, it depends on the operating conditions and keeping constant the kLa across scales is labor intensive: kLa values under many conditions need to be measured and determination of kLa in real-time may be required. The bioreactor kLa can be determined following a protocol recommended by the DECHEMA® expert group for single-use technology in biopharmaceutical manufacturing.1 Constant mixing time: Various parameters, among others the agitation speed and impeller type, influence the mixing time. The mixing time describes, how long it takes to homogeneously distribute liquids, which are added to the culture medium, such as pH agents and feed solutions. The mixing time needs to be experimentally determined. Scaling up from research to production scale using single-use bioreactors Whichever of these scale-up strategies the investigator chooses, two important considerations need to be taken into account. First, the tip speed range, kLa range, and the P/V range, respectively, of the differently sized bioreactors need to overlap to some extent to be kept constant across scale. Second, information on certain vessel engineering parameters is required to define this overlap. Upstream bioprocesses are usually developed at small scale and subsequently scaled-up to large production volumes. Today, single-use bioreactors are often favoured in the development and manufacturing of biologics, due to their advantages with respect to turn-aroundtime and sterility. In a proof of concept study we developed a cell culture scale-up workflow, which uses single-use bioreactors at all stages from bench to pilot production scale. To cover this range, we used two single-use bioreactor product lines: BioBLU® c Single-Use Bioreactors from Eppendorf and Thermo Scientific™ HyPerforma™ 5:1 Single-Use Bioreactors (SUBs). The BioBLU c product line comprises five differently sized vessel types, together covering working Autumn 2021 Volume 13 Issue 3

Manufacturing volumes from 100 mL to 40 L. The Thermo Scientific HyPerforma 5:1 SUB line comprises six differently sized single-use bioreactors, together covering working volumes from 10 L to 2000 L. For our study we used the following selection of the available vessels: • BioBLU 3c Single-Use Bioreactor (3 L working volume), • BioBLU 10 c Single-Use Bioreactor (10 L working volume), • Thermo Scientific HyPerforma 50 L SUB (40 L working volume) • Thermo Scientific HyPerforma 250 L SUB (150 L working volume).

A: BioBLU 3c Single-Use Bioreactor (left) and BioBLU 10c Single-Use Bioreactor.

We controlled the BioBLU c Single-Use Bioreactors with a BioFlo® 320 bioprocess control station (Eppendorf ) and the Thermo Scientific HyPerforma Single-Use Bioreactors with a BioFlo 720 bioprocess control station (Eppendorf) (Figure 1). For the scale-up strategy we selected the option of maintaining a constant

P/V. The power numbers of the BioBLU c Single-Use Bioreactors, which we needed for P/V calculation, we had experimentally determined in an earlier study.2 The power numbers of the Thermo Scientific HyPerforma SUBs were provided by the manufacturer. We aimed at a P/V of 20 W/m3 at all scales. To calculate the corresponding agitation speed at the desired working volumes, we used the Scale Up Assist software feature of the BioFlo 320 and 720 controllers. It is auto-populated with the vessels’ power numbers and impeller diameters and from these values calculates the agitation speed which results in a P/V of 20 W/m3 at a selected working volume. Keeping constant P/V and using the process parameters summarised in Table 1, we scaled-up a CHO cell culture bioprocess for mAB production from 3 L to 10 L in BioBLU Single-Use Bioreactors and further up to 40 L and 150 L in Thermo Scientific HyPerforma SUBs. A detailed description of the materials and methods has been previously reported.3

B: BioFlo 320 bioprocess control station

Table 1 – Overview of process configurations and setpoints for all cell culture runs

C: BioFlo 720 bioprocess control system with 250 L SUB. Figure 1: Bioprocess equipment used in this study. wwww.international-pharma.com

Comparable cell growth and antibody production from 3 L to 150 L The cell growth curves for all four vessel sizes are shown in Figure 2. By using the parameters calculated by the BioFlo 720 Scale Up Assist feature, we could match the growth profiles across all platforms in multiple batch runs. All runs yielded similar IgG production values when they reached completion (Figure 3). INTERNATIONAL PHARMACEUTICAL INDUSTRY 61

Manufacturing

Amanda Suttle

Figure 2: Cell culture comparison of BioBLU Single-Use Bioreactors to SUB system (50 L and 250 L)

Amanda Suttle works in the Eppendorf Applications Lab as a Research Scientist and has been a part of Eppendorf since 2014. She earned her Bachelors of Science degree in Biology from Bay Path University in 2013. Amanda has hands on experience culturing a variety of mammalian cell lines from primary T – cells to suspension CHO cells. Amanda conducted the cell culture scale-up study described in this article.

Ulrike Rasche

Figure 3: Antibody production for scale-up runs

Conclusion In these investigations we performed a proof of concept study for scaling up a mAB production process from bench to pilot-production scale using singleuse bioreactors, based on constant P/V. The BioBLU c Single-Use Bioreactor and Thermo Scientific HyPerforma 5:1 Single-Use Bioreactor product lines were appropriate for our project, because they covered our desired working volume range and all information on the bioreactor parameters required for scale-up strategy design were available. By applying this platform, we were able to replicate cell growth and mAB production at working volumes from 3 L to 150 L. While we did not fully exploit the working volume range covered by the BioBLU c and HyPerforma Single-Use Bioreactor lines, in principle it should be possible to facilitate upstream bioprocess scale-up from 100 mL to 2000 L. REFERENCES 1.

DECHEMA Expert Group Single-Use Technology; Recommendations for process engineering characterization of single-use bioreactors

62 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and mixing systems by using experimental methods (2nd edition); 2020 https://dechema. de/en/papers-path-123212.html Fradin et al. rAAV Production in Suspension CAP GT® Cells in BioBLU® 3c and 10c SingleUse Vessel. Eppendorf Application Note 407. 2018. https://www.eppendorf.com/fileadmin/ knowledgebase/asset/OC-en/619176.pdf Suttle et al. From Shaker to Pilot/Production Bioreactor: How Scale Up Assist Using the BioFlo® 720 Bioreactor Control System Can Help Your Antibody Production Workflow. 2021. https://www.eppendorf.com/fileadmin/ knowledgebase/asset/OC-en/953666.pdf

Ulrike Rasche works as a Scientific Communications Manager at the Eppendorf Bioprocess Center in Juelich, Germany. She earned her doctoral degree in cell biology from the University of Bonn, Germany and conducted postdoctoral research at the Institut Curie in Paris. Ulrike wrote this article.

Ma Sha Ma Sha heads the Eppendorf global applications teams and laboratories in Enfield, USA and Juelich, Germany. Ma received his Ph.D. of Biochemistry from the City University of New York (CUNY) and conducted extensive postdoctoral research at The Rockefeller University and Harvard Medical School. Ma has over 20 years of experiences in life sciences, including experience in biopharma CHO antibody production and scale-up, Vero based Vaccine applications, and fermentation process development. Ma supervised the scaleup study described in this article. Email: bioprocess-experts@eppendorf.com Web: www.eppendorf.com/bioprocess

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Manufacturing

Small-Scale Batch Production for Clinical Gamma Scintigraphy Studies of Pharmaceuticals Evaluation of pharmaceutical dosage forms using clinical gamma scintigraphy in early phase clinical development can provide critical information on drug delivery to the site of action/ absorption and enables visualisation and quantitation of regional transit of drug and dosage forms. Radiolabelling of dosage forms is accomplished by the association of a short lived gamma emitting radioisotope e.g. Technetium-99m (99mTc), with a carefully selected component of the formulation. It is essential that the inclusion of the radioisotope does not appreciably alter the key pharmaceutical properties of the product, and that it acts as an accurate surrogate for the chosen formulation component. This must be demonstrated by performing in vitro assessments, typically standard pharmacopoeial test methods, with additional analysis to quantify the radiolabel. Following successful radiolabelling method development and process validation, a data package is generated including Master Batch Records (MBR) and information for the Investigational Medicinal Product Dossier (IMPD) which forms part of the Clinical Trial Authorisation (CTA) application. A multi-disciplinary team with appropriate experience and expertise is essential in order to perform such studies. Introduction Pharmaceutical gamma scintigraphy is a technique which has been adapted from clinical diagnostic applications to enable the in vivo fate of pharmaceutical dosage forms to be accurately determined in patient populations, or healthy volunteers. It is the gold standard for deposition, retention and transit studies and has been used in many 100’s of clinical trials since the 1970’s. Its application to pharmaceutical products is dependent upon the physicochemical association of a radiolabel with the active pharmaceutical ingredient (API) or some other carefully selected excipient in the 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

product (Taylor et al., 2018, Strugala et al., 2012). Pharmaceutical gamma scintigraphy has applications in defining delivery to and residence of drug delivery systems at the site of action/absorption. It also enables visualisation and quantitation of regional transit of drug and dosage forms. PK analyses may also form part of the study protocols to provide further insight into formulation performance. Thus a greater understanding of the fate and variability of delivery systems administered by the oral, pulmonary, nasal, rectal and vaginal routes may be determined. Pharmaceutical gamma scintigraphy is performed using fully quantifiable and trial-validated procedures and has conventionally been applied to assess inhalation systems since it is the only method that allows an absolute measure of the deposition of drug within the lungs (Newman et al., 2012). The gamma emitting radioisotopes used for this application have short physical half-lives i.e. in the order of hours, and characteristic photon energies in the range of 100–300 keV, e.g. Technetium99m (99mTc, photo peak 140 keV, physical half-life approx. 6h) and Indium – 111 (111In, photo peaks at 173 keV and 245 keV, physical half-life 2.8 days). For clinical diagnostic applications, the physicochemical properties of the radioisotopes are often modified using commercially available ‘kits’ containing appropriate ligands which form functional complexes. For example, stable hydrophilic forms of 99mTc such as 99m Tc-diethylene-triamine-pentaacetate (Technescan, PL 12288/0011) are used for renal scintigraphy, and lipophilic forms such as 99mTc-exametazime (Ceretec, PL 00221/0126) are used for brain scintigraphy or radiolabelling leucocytes. These same kits and others, can be utilised to modify the properties of 99mTc or 111In to optimise association with a particular dosage form or API. The characteristic photon energies and short physical half-lives of these isotopes results in low radiation exposure for diagnostic procedures. Adhering to the principle of as low as reasonably

practicable, research studies are usually conducted with administered radioactivity at much lower amounts than the diagnostic reference levels (ARSAC Notes for guidance, 2021) recommended for similar clinical procedures. This can be achieved as imaging protocols for research studies are optimised for highly selective and specific study endpoints. The availability of a dedicated research gamma camera is essential to this process. Using optimised imaging protocols, cross-over studies can be conducted in healthy volunteers or patient groups whilst ensuring the radiation dose is minimised. For example, a three-way cross-over study to evaluate lung deposition can be performed with a radiation exposure equivalent to 3–4 months’ background radiation, i.e. approx. 0.75 mSv. The average annual UK background radiation exposure is approximately 2.7 mSv (Public Health England) but as with other parts of the world, there are large region to region variations in natural background radiation. Radiolabelling Pharmaceuticals Manufacture of the radiolabelled investigational medicinal product (IMP) must be performed according to the principles of Good Manufacturing Practice (GMP) under a Manufacturing and Import Authorisation for IMP (MIA (IMP)). Holders of manufacturing authorisations require the services of a Qualified Person (QP) who is responsible for certifying that the IMP is manufactured and tested in accordance with the terms of the Clinical Trial Authorisation (CTA) and GMP. The method development data and the validation data will be incorporated into the Investigational Medicinal Product Dossier (IMPD) to be submitted as part of the CTA application to the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK. The key to success is that the formulation characteristics should not be perturbed by the addition of the radiolabel and that the radiolabel must be an accurate surrogate for the desired formulation component. In order to achieve this goal, it is essential that the investigators have a thorough understanding of the formulations under Autumn 2021 Volume 13 Issue 3

Pharma grade cGMP Quats

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Manufacturing test, since it is often necessary to be able to reverse engineer the product to ensure the radiolabelling is successful. Extensive in vitro testing is required to demonstrate that the radiolabelling process has not altered the properties of the original, i.e. reference product, and also to show that the radiolabel is an accurate surrogate for the API or selected formulation component. The initial stage of this process involves methods transfer of key analytical techniques from the Sponsor company to the contract research organisation (CRO). Once the radiolabelling method is finalised, master batch records (MBR) describing the manufacturing steps, including in process control measures and release tests are documented and signed off by the Sponsor. This article describes the key steps in the radiolabelling method development and validation processes in order to successfully manufacture small scale GMP batches of radiolabelled products. While the focus is on inhalation dosage forms the principles for radiolabelling method development and validation are applicable to other pharmaceutical preparations such as oral dosage forms i.e. tablets, capsules etc. Development Phase The target for radiolabel association should be identified, this is usually the API but could under certain circumstances be another component of the formulation that will provide critical information regarding the fate of the dosage form. For example, in the case of a liposomal formulation of the antibiotic amikacin, the physical form of the radiolabel was selected so that it associated with the lipid bilayer and provided information on the fate of the drug carrier (Weers et al., 2009). To investigate delivery from a novel electronic inhaler, a hydrophilic form of the radiolabel i.e. 99mTcDTPA was dissolved in the aqueous phase enabling both the delivered dose and also the deposition pattern within the lungs to be quantified (Nikander et al., 2007). The key formulation performance characteristics of the test product i.e. baseline performance, must be evaluated by the CRO. Formal methods transfer i.e. analytical and product test methods should be performed at this stage. The objective of these experiments is to demonstrate successful methods transfer and to establish 66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the key performance characteristics of the product, e.g. aerodynamic particle size distribution (APSD) for an inhaled product or drug release characteristics for oral dosage forms. To fully characterise the reference product, it is necessary to evaluate samples from a number of batches in order to understand batch to batch variability. The pharmaceutical qualities so determined must remained unchanged following radiolabelling and are used to define the key characteristics that the radiolabel must possess in order to function as a surrogate. The challenges of radiolabelling formulations for inhalation devices range in terms of complexity from the addition of a suitable chemical form of 99mTc into a jet-nebuliser formulation through to the production of small batches of radiolabelled API for use in a dry powder inhaler (DPI). These challenges are overcome by application of our knowledge which has been gleaned by performing radiolabelling studies with a wide array of different formulation and device types. Ultimately, every formulation/device combination is unique and requires a bespoke set of methods applicable for small batch radiolabelling. The on-site release procedures for radioactive products vary depending upon the complexity of the radiolabelling methodology. In some instances, the process may involve incorporation of the radiolabel into a ‘finished’ product i.e. one that has been through certification and batch release by the original manufacturer, e.g. a nebuliser preparation. In contrast, for a DPI the radiolabel must first be exclusively surface associated with the API prior to blending with the carrier, followed by device/ capsule filling. The DPI example offers the greatest challenges since the product is being formulated from its constituent components and this has to be produced, characterised and released on the day that it is to be administered. In all scenarios detailed In-Process Control (IPC) checks and Release/Quality Control tests must be performed. Initial experiments can be conducted in the absence of the radiolabel this is often referred to as ‘cold’ labelling. This strategy can provide an insight into method feasibility without unnecessary radiation exposure to operators. The mass of radiolabel associated with the dosage forms

is very small, in the order of nanograms or less, and so its omission does not diminish the value of cold radiolabelling experiments. During these experiments possible effects of the radiolabelling procedures on formulation performance must be assessed. For example; the effect of varied volumes of the vehicle to facilitate radiolabel incorporation into a nebuliser preparation, or the impact of batch sizes for small scale powder blending for DPIs may be evaluated. It is critical that these procedures do not change the performance of the test product relative to that of the standard reference product. Once this has been established subsequent experiments with the inclusion of radioactivity may be performed in the knowledge that the process itself does not impact product performance. The objective of the next phase of experiments is to demonstrate that the radiolabel acts as an accurate surrogate for the selected formulation component i.e. usually the API. At this stage draft Master Batch Records (MBR) will be prepared to document the key steps of the method to ensure consistent processing at the next stage of development. Preliminary Radiolabelling Phase Once the baseline performance characteristics of the test formulations are established draft acceptance criteria for radiolabel characteristics can be defined. Using the methodology from the ‘cold’ labelling studies preliminary experiments incorporating low levels of radioactivity are performed. The in vitro tests e.g. dissolution/ disintegration tests for oral dosage forms, APSD for inhalers, are repeated following the inclusion of the radiolabel, with additional analysis, using a gamma counter or a gamma camera, as appropriate for the formulation/ delivery system, to quantify the tracer. The objectives of these tests are two-fold i.e. to show consistent performance with the control, unlabelled formulation, and to demonstrate a good correlation between the radiolabel and API (or chosen excipient) in order to confirm that the radiotracer is a suitable surrogate for the selected formulation component. For inhalation products, the International Society for Aerosols in Medicine (ISAM) Regulatory Affairs Networking Group (Devadason et al., 2012) published guidance to advocate the standardisation of radiolabelled product criteria in terms of minimal changes to key characteristics of the Autumn 2021 Volume 13 Issue 3

SCINTIGRAPHICS SCINTIGRAPHICS

PHARMACEUTICAL IMAGING PHARMACEUTICAL IMAGING

Clinical gamma scintigraphy services for pharmaceutical development  Pre-formulation  Device/formulation performance  Accelerated stability testing  Radiolabelling method development & validation  Clinical protocol design, & review  Regulatory submissions  Healthy volunteer & patient populations  Clinical scintigraphy studies for pulmonary, nasal, and oral dosage forms www.scintigraphics.co.uk Cardiff Scintigraphics Ltd., Cardiff Medicentre, Cardiff, CF14 4UJ, UK.

Tel: +44 (0)29 2075 7865 Email: info@scintigraphics.co.uk INTERNATIONAL PHARMACEUTICAL INDUSTRY 67

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Manufacturing reference product e.g. total emitted dose, APSD, and ensuring acceptable correlations between radiolabel and API recovered from impaction tests and delivered dose assessments. Successful outcomes at this stage enables progression to the Validation Phase. However, prior to this step the Master Batch Records (MBR) must be finalised so as to accurately document the manufacturing steps including appropriate IPC checks (Table 1) and Release Tests (Table 2) to ensure the quality and consistency of the final product. An example of the APSD release test data for DPI batches manufactured during the course of a clinical study is shown in Figure 1. The plot shows the relative recovery of the radiolabelled API and the radiolabel (99mTc) from inertial impaction tests using a Next Generation Impactor (NGI). The histogram also shows the recovery of API for the reference unlabelled product. At this stage stability issues should be considered. Generally, because of the short physical half-life of the radioisotopes the dosage forms are administered within hours of completion of the radiolabelling process. However, physical stability should be demonstrated over a period relative to the anticipated clinical dosing procedures. If it is assumed that it will take 4 h to dose all subjects/patients on each dosing day, then the radiolabelled product should be demonstrated to perform as expected over a similar or slightly extended period of time i.e. include a contingency allowance. Validation Phase The final stage of the radiolabelling development process is to progress from the low levels of radioactivity used during the preliminary experiments to the levels that will be required for clinical imaging. The validation phase is performed according to the final MBR and using the same batches of product, excipients and/or devices that will be used on the clinical dosing days. Several validation batches should be prepared to demonstrate the robustness of the process. Most clinical study designs will involve a manufacturing campaign spanning a period of weeks or months depending on the subject population; specific patient groups typically take longer to recruit than healthy volunteers. Thus multiple batches will be manufactured and it is essential that the process is robust so that the chance of batch failure is minimised. 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Cardiff Scintigraphics Limited

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Table 1: Example In-Process Controls for the Manufacture of a Radiolabelled Dry Powder Inhaler Product. In-Process Controls for the Manufacture of a Radiolabelled Dry Powder Inhaler Table 1: Example Stage of Product.IPC Tests Method Batch Limit Preparation/ Stage of Material Preparation/ Prep of 99mTc Material Prep of 99mTc Radiolabelling Test powder with Radiolabelling 99m Tc Test powder with 99m Tc Radiolabelled Test powder Radiolabelled blended with Test powder lactose blended with

lactose

Capsule filling 99m with CapsuleTc filling radiolabelled 99m with Tc Test powder radiolabelled Test powder

IPC Tests 99m

Method

Batch Limit

Tc recovery

Dose Calibrator Not less than or equal to xxx MBq at timeor equal to xxx MBq at Dose Calibrator reference Not less than Dose Calibrator Not less than reference timeor equal to xxx MBq/mL of first Dose Calibrator at Notintended less thantime or equal todose. xxx MBq/mL Dose Calibrator Specific Activity: xx.x – MBq/mg at intended time of firstxx.x dose. intended time xx.x of first doseMBq/mg Dose Calibrator at Specific Activity: – xx.x Dose Calibrator xx.x – xx.x MBq dose at intended time per of first dose Dose Calibrator RSD xx.x <– x% xx.x MBq per dose HPLC xRSD blend uniformity samples for HPLC < x% xxx – xxxuniformity µg per dose HPLC x blend samples for HPLC RSD < x% xxx – xxx µg per dose HPLC Retention RSD < x% time of the main peak from the sample is peak Identification HPLC Retention time ofsolution the main consistent with the retention from the sample solution is time of Test drug substance from consistent with the retentionthe time standard solution. of Test drug substance from the Description of filled Visual Sealed, intact, free from visible standard solution. capsules Assessment powder on outside, free from Description of filled Visual Sealed, intact, free from visiblevisible defects capsules Assessment powder on outside, free from visible Capsule fill weight (of the Gravimetric xx.x – xx.x mg per capsule defects radiolabelled product) Capsule fill weight (of the determination Gravimetric xx.x – xx.x mg per capsule radiolabelled product) 99m determination

99m

Tc recovery Radioactivity of 99mTc for addition to Test powder Tc for Radioactivity of 99m 99m Tc on Radioactivity of addition to Test powder radiolabelled Test 99mpowder Radioactivity of Tc on Blend Uniformity radiolabelled Test(Dose powder Calibrator measurement Blend Uniformity (Dose is non-destructive and the Calibrator measurement same samples will and be used is non-destructive the for HPLC analysis). same samples will be used Identification for HPLC analysis).

Table 2: Example Release Tests for Tc radiolabelled Capsules for a Dry Powder Inhaler Table 1: Example In-Process Controls for the99m Manufacture of a Radiolabelled Dry Powder Inhaler Product. Formulation. Table 2: Example Release Tests for Tc radiolabelled Capsules for a Dry Powder Inhaler Test ItemFormulation. Method Acceptance Criteria Description Test Item Description

Visual Assessment of capsules Method Visual Assessment of capsules

Capsule Radioactivity Capsule Content Radioactivity APSD at release Content

Dose Calibrator

Sealed, intact, free from visible Acceptance Criteria powder on outside, free from Sealed, intact, free from visiblevisible defects powder on outside, free from visible xx.x – xx.x MBq defects

Dose Calibrator

xx.x – xx.x MBq

Gamma Scintigraphy

APSD at release

Gamma Scintigraphy

APSD at release

HPLC

APSD at release

HPLC

Performance Criteria MMAD (µm), Criteria GSD and FPF (%) to Performance comply with release criteria forto MMAD (µm), GSD and FPF (%) reference product. comply with release criteria for Performance Criteria reference product. MMAD (µm), Criteria GSD, FPF (%), FPD (µg Performance or mg) to comply MMAD (µm), GSD,with FPFrelease (%), FPD (µg criteria forcomply reference or mg) to withproduct. release

Table 2: Example Release Tests for 99m Tc radiolabelled Capsules for criteria a Dry Powder Inhaler Formulation. for reference product.

Figure 1: Validation Data Showing Mean % Recovery of 99mTc, radiolabelled API and API from Reference Product. 99mTc recovery was measured using a gamma camera, API was quantified by validated HPLC-UV assay.

Validation batch results must comply with all IPC and Release Test specifications, the data generated, along with the preliminary radiolabelling results, will be included in the IMPD. The IMPD contains chemical and pharmaceutical quality information about the Investigational Medicinal Product (IMP). For scintigraphy studies the following

information related to the radiolabelling process should be provided: • • • • •

Radiolabel Other Excipients Manufacturing Process Development Manufacturing Process Validation Analytical Method Validation Autumn 2021 Volume 13 Issue 3

Manufacturing • •

Representative Batch Analysis Data Stability Data

This information can be incorporated into the existing IMPD or alternatively submitted as a standalone abbreviated radiolabelling IMPD making reference to appropriate sections of the standard document. Clinical Phase Once the radiolabelling method is successfully validated and the full regulatory review and approval process is complete the clinical phase of the study may begin. On a manufacturing day the 99mTc is eluted from a generator early in the morning and quality control (QC) tests are performed to ensure compliance with appropriate Pharmacopoeial and manufacturer specifications. The radiolabelled product is then manufactured in accordance with the approved MBR. The Production Manager and Quality Assurance Pharmacist perform a QC check of the completed MBR and IPC/Release Test results. In addition to information captured on the MBR, QC checks of all analytical data e.g. inertial impaction results, HPLC data relating to content uniformity of DPI blends and

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associated system suitability results for HPLC performance. Following the QC checks batch certification and release is conducted by the QP. Dosing and imaging typically commences as soon as possible after the product is released due to the short physical half-lives of the radioisotopes. Figure 2 (B) shows lung deposition in a healthy volunteer following dosing from a DPI product. Figure 2 (A) shows the corresponding ventilation image achieved by the subject inhaling a short-lived radioactive gas i.e. Krypton81m (physical half-life approx. 13s), which enables the ventilated regions of the lung to be determined and thus drug deposition and distribution to be accurately assessed. Additionally, transmission scans of each subject are routinely acquired in order to measure regional tissue attenuation to ensure accurate quantitation of radioactivity. In the case of GI studies suitably radiolabelled drinks may be administered to outline anatomical features e.g. stomach, or colon. Conclusions Gamma scintigraphy enables non-invasive

determination of the biological fate of pharmaceutical dosage forms administered to healthy volunteers and/or patients. Effective radiolabelling of the pharmaceutical is achieved following detailed characterisation of the test product, followed by meticulous method development and validation in order to demonstrate a robust, reproducible and accurate process. Successful outcomes are dependent upon the CRO having the necessary technical expertise and experience of dosage form evaluation and development. Scintigraphy studies can provide information that will facilitate informed decisions to ensure optimal device/formulation selection thereby streamlining the product development process and saving costs in terms of time and finance. Information from scintigraphy studies can be used to support product licence applications for a range of pharmaceuticals. For example, in the case of anti-reflux agents i.e. alginate containing liquids, tablets and powders, scintigraphy has been used to demonstrate efficacy in terms of the

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Manufacturing

Figure 2: A: Anterior images in a healthy subject showing; A: Krypton-81m gas lung ventilation and B: deposition from a 99mTc radiolabelled DPI, radioactivity in the stomach (following oropharyngeal deposition) can be seen below the left lung. Also shown are the regions of interest defining the lung margins (white and green) and the regions used to define the outer (blue) and inner (red) lung regions (right lung only).

formation of alginate rafts floating on the stomach contents (Hampson et al., 2010) as documented in the following summary of product characteristics documents; Gaviscon Double Action Liquid PL 00063/ 0156, Gaviscon instants oral powder cool mint/Fresh tropical, PL 00063/0173, 0367). For orally inhaled products (OIP) containing new APIs establishing lung deposition

70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

via imaging can enable the selection of optimal device/formulation variables to be taken forward to clinical studies to assess therapeutic efficacy. Evaluating lung distribution can be important if specific airways are to be targeted e.g. conducting or peripheral airways. Imaging studies can be combined with PK sampling to provide a greater understanding of the relationship between regional lung deposition, and

drug effects and absorption (Taylor et al., 2018). Equipped with this knowledge the development process may be streamlined with associated cost savings. The value of imaging studies is also recognised in the EMEA guidance (CPMP/ EWP/4151/00 Rev. 1, 2009) on the stepwise approach to establishing equivalence between OIP products. Pulmonary deposition from

Autumn 2021 Volume 13 Issue 3

Manufacturing Deposition Study of Glycopyrronium/ Formoterol Metered Dose Inhaler Formulated Using Co-suspension Delivery Technology. Eur J Pharm Sci 2018; 111: 450-457. https://doi. org/10.1016/j.ejps.2017.10.026 13. UKPAR Gaviscon Double Action Liquid PL 00063/0156, 14. Weers J, Metzheiser B, Taylor G, Warren S, Meers P, Perkins WR. A Gamma Scintigraphy Study to Investigate Lung Deposition and Clearance of Inhaled Amikacin-Loaded Liposomes in Healthy Male Volunteers. J Aerosol Med Pulm Drug Del 2009; 22: 131-138. https://doi. org/10.1089/jamp.2008.0693.

Glyn Taylor

imaging studies can provide supportive data for the design of PK and/or clinical studies to assess therapeutic efficacy. REFERENCES 1.

Administration of Radioactive Substances Advisory Committee. Notes for guidance ARSAC notes for guidance: good clinical practice in nuclear medicine. Feb 2021 (https:// www.gov.uk/government/publications/arsacnotes-for-guidance) Devadason SG, Chan HK, Haeussermann S, Kietzig C, Kuehl PJ, Newman S, Sommerer K, Taylor G. Validation of Radiolabeling of Drug Formulations for Aerosol Deposition Assessment of Orally Inhaled Products. J Aerosol Med Pulm Drug Del 2012; 25, S1: S6-S9. https://doi.org/10.1089/jamp.2012.1Su3 Guideline on the Requirements for Clinical Documentation for Orally Inhaled Products (OIP) including the Requirements for Demonstration of Therapeutic Equivalence between Two Inhaled Products for Use in the Treatment of Asthma and Chronic Obstructive Pulmonary Disease (COPD) in Adults and for Use in the Treatment of Asthma in Children and Adolescents CPMP/EWP/4151/00 Rev. 1 European Medicines Agency 2009 Hampson F, Jolliffe, I, Bakhtyari A, Taylor G, Sykes J, Johnstone L, Dettmar P. AlginateAntacid Combinations: Raft Formation and Gastric Retention Studies. Drug Dev Ind Pharm 2010; 36: 614-623. https://doi. org/10.3109/03639040903388290 MHRA PAR; Gaviscon instants oral powder cool

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mint/Fresh tropical, PL 00063/0173, 0367 Newman S, Bennett WD, Biddiscombe M, Devadason SG, Dolovich MB, Fleming J, Haeussermann S, Kietzig C, Kuehl PJ, Laube BL, Sommerer K, Taylor G, Usmani OS, Zeman KL. Standardization of Techniques for Using Planar (2D) Imaging for Aerosol Deposition Assessment of Orally Inhaled Products. J Aerosol Med Pulm Drug Del 2012; 25, S1: S10-S28. https://doi.org/10.1089/jamp.2012.1Su4 7. Nikander K, Prince I, Coughlin S, Warren S, Taylor G. Mode of Breathing – Tidal or Slow and Deep – Through the I-Neb Adaptive Aerosol Delivery (AAD) System Affects Lung Deposition of 99mTc-DTPA. J Aerosol Med Pulm Drug Del 2010; 23, S1: S37-S43. https://doi.org/10.1089/ jamp.2009.0786 8. Public Health England, Radiation Protection Services, Ionising radiation and you. https:// www.phe-protectionservices.org.uk/radiationandyou/ 9. SPC Ceretec https://products.mhra.gov.uk/ search/?search=exametazime&page=1&doc= Spc&rerouteType=0 10. SPC DTPA https://products.mhra.gov.uk/ search/?search=dtpa&page= 1&doc=Spc& rerouteType=0 11. Strugala V, Dettmar PW, Thomas ECM. Evaluation of an Innovative Over-the-Counter Treatment for Symptoms of Reflux Disease: Quick-Dissolving Alginate Granules. ISRN Pharmaceutics 2012, Article ID 950162 https:// doi.org/10.5402/2012/950162 12. Taylor G, Warren S, Dwivedi S, Sommerville M, Mello L, Orevillo C., Maes A, Martin UJ, Usmani OS, Gamma Scintigraphic Pulmonary 6.

Prof Glyn Taylor is Chief Scientific Officer and a Founding Director of Cardiff Scintigraphics, and Emeritus Professor of Drug Delivery. He has more than 30 years of experience with pharmaceutical scintigraphy studies, collaborating with small and large Pharma, device companies and other groups. He has authored or coauthored more than 200 research articles, in the areas of gamma scintigraphy, pharmacokinetics and drug delivery; and 21 students have graduated with PhD degrees under his supervision. Email: info@scintigraphics.co.uk

Simon Warren Dr. Simon Warren is the Research Director at Scintigraphics and has over 27 years’ experience in the conduct of pharmaceutical scintigraphy studies. He has been responsible for radiolabelling method development and validation programs for a wide range of inhalation delivery systems and oral dosage forms. Dr Warren is also the co-inventor of several patents describing novel formulation and manufacturing methods for pressurised metered dose inhalers using propellants with low global warming potential. Web: scintigraphics.co.uk

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Manufacturing

New DPI Data Insights Shaping Future of Global Healthcare Needs Innovative inhalation therapies and drug delivery are legacies of the COVID-19 pandemic, as pharma and biopharma formulators address growing demands for new healthcare solutions. Lactose-based dry powder inhaler (DPI) formulations are the most significant form of inhaled treatment for respiratory conditions such as COPD and asthma. Now, they also being used to treat COVID-19, leading to an increase in demand for lactose-based excipients. Most DPI formulations consist of a micronized active ingredient blended with larger excipient particles, which enhance flow, reduce aggregation and aid in dispersion. However, the complexity of the formulations required means it can be difficult to understand the impact of individual compounds on the final results. A multidisciplinary study by DFE Pharma, Hosokawa Micron and Harro Höfliger aims to help manufacturers save time and money in the development process by testing various formulations of magnesium stearate-coated lactose in the blending and filling process. This ‘magic triangle’ collaboration, linking global expertise, is part of the new global approach shaping new theories and data to address global healthcare needs. Formulation specialist DFE Pharma provided different qualities and concentrations of fine lactose to powder processing technology manufacturer Hosokawa Micron. Baseline levels are established by blending these fine lactose samples without the addition of magnesium stearate. The different lactose particles are then coated with magnesium to allow comparison of impact on filling and blending properties. The multidisciplinary research extends the findings of previous studies to explore the influence of the different qualities and 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

concentrations of graded powders on the capsule-filling and dosing process. Its next phase includes the addition of an active ingredient. By sharing their data-driven insights, the research team is helping generic players stay ahead of the curve and tap into the growing DPI market. Qualities and combinations of coarse and fine lactose A dry powder inhaler is a device designed to allow an aerosolized powder to be inhaled into the lungs. It is a replacement for aerosols containing a drug substance suspended in a propellant. In DPI formulations, the powder properties are very important in relation to the blending with the Active Pharmaceutical Ingredient (API), the filling of the device and the deposition of the API into the lungs. Most DPI formulations are based on carrier principles. A drug is blended with the lactose which helps improve the handling and the dosing of the API into a device. The lactose will also help to deagglomerate the cohesive particles so individual particles can be inhaled and enter the lung. The lactose allows the right flowability of the formulation for release from the device. A formulation strategy always starts with the drug. With asthma and COPD drugs, they have been micronized to make them small enough to be inhaled. These very small particles in very low doses require a working agent to become processable and delivered into a device. Normally, a pharmaceutical company will have already decided which type of device and filling technology it is going to use. The right lactose grade can then be selected. Formulators can then test the lactose and blending process and then test the formulation – how is it filled, how is the performance, how is the active getting out of the device and into the lungs?

Previous studies into fine lactose particles, fine particle fraction and dosing have shown if you increase the lactose fine particles you increase the fine particle fraction. These lactose fine particles can be obtained from various fine lactose grades. To better understand how these different lactose grades can be used, the DFE Pharma, Hosokawa Micron and Harro Höfliger study selects different fines to test their impact on flow. Coarse grade Lactohale® (LH) 206 and fine grade Lactohale 210, 230 and 300 are blended with a Nauta blender. Particle size distribution and flow properties are measured by Schulze tester and FT4 Rheometer. LH206:LH210 are tested at concentrations of 90:10, 80:20 and 70:30. The same concentrations are run for LH206:LH230. In the case of LH206:LH300 slightly lower concentrations are used – 97.5:2.5, 92.5:7.5 and 87.5:12.5 – because LH300 is a micronized grade of lactose and too many fines can create issues in formulation. Lactose particle size specification in LH206 is D50 of 75–95 while in the fine grades of 201, 230 and 300 the D50 is 14–19, 7–11 and <5 respectively. While D10, D50 and D90s are important parameters for DPIs, there are other important factors which can play a role with respect to fine particle fraction and flow properties. These are Q4.5 which are particles below 4.5µm and Q30 which are particles below 30µm. There is a correlation between Q4.5 and fine particle fraction and Q30 with flow properties. Looking at the impact of the addition of fines on Q4.5 and Q30, there is a clear linear increase of particles in all cases – as the fines concentration increases there is an increase in particles. Autumn 2021 Volume 13 Issue 3

MEDICAL

TPE FOR MEDICAL APPLICATIONS More details about our medical compounds: » www.kraiburg-tpe.com/en/medical » Phone: +49 8638 9810-0

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 73

Manufacturing However, there is a stronger impact of LH300 on Q4.5 than Q30 suggesting, if you want to focus on fine particle fraction, LH300 may be able to modulate fine particle fraction to a greater extent.

However, when using a blister-based device and working with a fairly flexible powder, for example a mixture of sieved and milkgrade lactose, drum-filling technology can be used.

Selecting the right type of blender for DPI formulations There is always a need to match the mixing technology and its operational parameters to the specific application, including DPI applications.

Capsule-based devices are versatile and can be used for both fair flow powder and cohesive powder using either a drum filler or the dosator filling system.

In general, for free-flowing materials, a gentle mixing technology is selected while for cohesive materials a more intensive mixing technology is needed. Free-flowing materials can be mixed in a connective manner by rearranging the particle matrix. Binding forces between the particle are generally weak so a simple gentle mixing will be sufficient for cohesive powders. Where binding forces are strong, these forces need to be broken and rearranged and this requires energy input. This requires a more intensive mixer. A Nauta mixer is used for the prevalence in this study. The mixer can be fixed on top of and directly fit in into a tablet press. The product is charged on the top of the conical vessel and the convective agitation is realised by the combination of the movement of an obit arm and a screw.

Membrane filling is suitable for dosing volumes from 20mm³–1,000mm³ with a dosing range of 10–500mg. This device features a powder hopper with nozzles attached. Empty pockets come and go towards the dosing station and a vacuum pulls the powder down into the pocket from the nozzle achieving 100% filling to the membrane. The main advantages are very limited powder spillage on the sealing area and limited powder dust generation during filling. The membrane filling system is a volumetric dosing system wherein pocket size decides the dosing volume.

from 12 o’clock to three, six and nine o’clock. There are two important parameters in drum filling – vacuum pressure and blowout. Vacuum pressure pulls the powder in. Blowout ejects the powder into the capsule after the six o’clock position and cleans the drum of powder retention at the nine o’clock position. The advantages of are being able to fill a wide range of powders based on flowability, the ability to fill extremely low quantities and high accuracy. Dosator filling is suitable for dosing volumes from 20mm³–1,000mm³ with a dosing range of 10–500mg. Although this is another volumetricbased dosing system, in this case the dosing volume is dependent on the height between the dosator pin, the dosator sleeve and the powder bed.

Drum filling is suitable for dosing volumes from 1mm³–100mm³ with a dosing range of 0.5–50mg.

A cleaning station applies a vacuum to the pins meaning the cleaning cycle can be decided based on powder properties. The dosator system allows easy adjustment of volume, and thus dosing quantity, and a wide dosing range.

Drum filling again is a volumetricbased dosing system. In this case a drum has a powder hopper with a stirrer inside. The drum moves in a clockwise manner

When comparing membrane, drum and dosator filling, the focus is on mean fill weight and relative standard deviation (RSD).

The mixing screw is mounted on the top of the arm, a few millimetres from the top wall or from the wall of the vessel to create some clearance and then the screw conveys the powder upwards along the axis of the mixer. Radial mixing is achieved by the shape of the cone and the arm ensures a tangential mixer. The speeds used are typically small – between 0.5–2m/s. Filling technology options and parameter affects There are two main devices for DPI – blisterbased and capsule – which are the focus of this study. When using a blister-based device and working with cohesive powders like milk-grade lactose then the ideal filling technology is a membrane filler. 74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2021 Volume 13 Issue 3

Manufacturing Looking at the impact of the addition of fines on powder flow, there are three important flow properties where researchers found a correlation with the Q30 as well as the filling. An increase in fines leads to a percentage increase in compressibility and permeability but in flow function there is an inverse relation – flow function decreases as fines increase meaning the powder is becoming more cohesive. In membrane filling, high RSDs are observed with low fines concentration powders. In drum filling, consistent lower RSDs are observed across all batches. In dosator, consistent lower RSDs are observed except for batches with high fines – LH300 at 12.5%. An overall comparison shows significant differences in the mean fill weight are observed in the membrane filler – powder characteristics have a high influence on the filling results. In contrast, drum filling displays a low spread on mean fill weight. High RSDs are observed in the membrane filler and the dosator with LH300 while there is a low spread of RSDs in drum filling. The joint explores the connection between the PSD, the flow properties and the filling systems. In membrane filling systems there is a very good correlation between Q30 and percentage compressibility and compressibility and mean flow rate suggesting compressibility plays an important role in deciding mean fill weight in the case of membrane filling systems. If particles are modulated below 30 micron the mean fill weight can also be modulated. There is also a very good correlation between Q30 and permeability. When it comes to permeability versus RSD, when there is a very low permeability there is a high RSD so a certain amount of permeability is needed in powder to have good RSDs with respect to membrane filling systems. In the drum filling system, there is again a very good correlation between Q30 and flow function and flow function and mean fill. RSD for drum filling systems is consistently around 2% so there is not a clear correlation. However, it is observed that with very high permeability you may end up with slightly higher RSDs. wwww.international-pharma.com

With the dosator system, for RSDs no clear correlations are observed for any flow parameters. However, a relationship is observed with regards to RSD and particles below Q4.5 wherein a very high concentration of particles below Q4.5 may result in high RSDs.

coating used to coat the lactose formulation and analysis of the flow properties and filling.

This could be because of the high concentrations of LH300 or micronized lactose, there could be electrostatics or because of the cohesivity there could be sticking to the dosator pins which could lead to high variability and could also lead to inconsistency in the powder bank.

The results will give generic players a head start in the development process and allow them to tap into this rapidly growing market.

If you are using a dosator filling system concentrations of fines become very important. Summary of phase one findings Phase one of the study focuses on understanding the impact of the addition of fines on flow properties and filling consistency using different filling techniques. As fines concentration increases, cohesivity increases for all different grades of lactose. However, different fine grades have different impacts on Q4.5 and on the flow of powders. A strong relationship between lactose Q30, flow properties and filling is demonstrated. The drum filler shows the lowest variations in terms of fill weight and RSD. It is a robust system for a wide range of powders concerning flowability and flow function showed good correlation to mean fill weight. Powder characteristics have a strong influence on the filling results of the membrane filler with percentage compressibility showing good correlation to mean fill weight. Permeability should be higher than 6 mbar at 15Kpa to ensure low RSD values which can be controlled by Lactose Q30. Dosator filling results in good filling consistency with respect to RSD. However, high RSD was observed with LH206 and LH300 due to the high concentration of fines. Findings from phases two and three of the study will be presented later this year. Phase two will present and publish information on the magnesium stearate

Phase three will share the results of adding the API and analysis of the stability of the formulation.

This multidisciplinary study is an example of how collaborative working between expert players can benefit the wider pharmaceutical industry, helping generic players stay ahead of the curve and meet the healthcare needs of the day.

Harry Peters Harry Peters is a specialist in the use of lactose in pharmaceutical applications for more than 10 years. In the last six years at DFE Pharma he has further specialised in the dry powder inhalation field. He is Senior Research Specialist, R&D Inhalation, having started working as R&D manager and product application specialist for inhalation grade lactose. He advises formulators of dry powder inhalers about the use of inhalation grade lactose. Together with customers, special lactose grades are developed to optimise the filling and performance of the devices and formulations. Together with universities and industry, new characterisation techniques are explored to further understand lactose in dry power formulations.

Dr. Mohit Mehta Dr. Mohit Mehta is Director DPI Consulting at Harro Hofliger, Germany.

Dr. IR. Kay Imole Olukayode I. Imole (Kay) currently works as a process technologist in the research and development department of Hosokawa Micron B.V.

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Manufacturing

Aseptic Processing and Cleanroom Technology

Robert Lee, President, and James S. Drob, Director of Manufacturing Operations, from the CDMO Division of Lubrizol Life Science Health (LLS Health) discuss the importance of cleanroom technology being fit for purpose in aseptic processing and how changing R&D pipelines have led to a rise in the number of companies outsourcing their sterile product manufacturing to CDMOs. The cleanroom technology market is a growing segment of the manufacturing industry that is expected to expand from a value of $3.87bn in 2019 to $5.04bn by 2025.1 One of the main drivers of this growth is an increase in sterile drug products, such as injectable biologics and ophthalmic formulations. Market data shows that over half of clinical stage projects are injectables, and programs for eye diseases have doubled in the past five years alone.2 This pipeline will continue to drive demand for sterile cleanrooms and aseptic manufacturing services well into the future. More than just cleanroom technology, producing drug products in a sterile environment requires a unified organisational effort. This includes having well-trained personnel, robust quality infrastructure, and the proper manufacturing equipment and processes to ensure a consistent product. The complexity of establishing and maintaining all these elements often leads pharma companies to outsource their aseptic processing requirements. This is especially true for small or virtual companies who can more efficiently progress into clinical and commercial production with the right CDMO partner. Challenges in maintaining a cleanroom environment Ensuring sterility is extremely challenging, and careful planning is needed at every stage of processing to negate the serious risk that contamination poses. Injectable and ophthalmic drug products present an increased risk of infection or harm due to the way that they bypass the body’s natural defences. Because of this, regulatory 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

requirements around aseptic processing are strict and constantly evolving. Operator responsibility All individuals operating in a cleanroom environment need to be suitably trained, well-disciplined, and very careful. The objective of the aseptic manufacturing process is to eliminate any opportunities for contamination, and this begins with the operators. After all, contamination arrives most often from the humans involved in the process. To this end, a gowning qualification to ensure proper gowning techniques must be carried out and forms part of a well-orchestrated routine to minimise contamination risk from the moment operators enter a cleanroom environment. A risk assessment should take place while defining the optimal manufacturing process for each project. As a project progresses from R&D into clinical and commercial production, the process may change, and new assessments may be needed. For example, many products start with manual hand-filling of small batches of clinical trial material before moving onto semiautomated and then fully automated highspeed filling lines to support registration batches and commercial supply. These stages have different steps, equipment, and may even take place in different cleanroom environments, which must be factored into the risk assessment. The risk of cross-contamination Cleanrooms require a controlled environment, and multi-product facilities that work with several different client APIs have processes in place to eliminate the risk of cross-contamination. Environmental Monitoring (EM) activities, including the regular collection, evaluation, and interpretation of data regarding the air, surfaces, and personnel in the cleanrooms, are essential. The risk of cross-contamination can be managed and simplified by using disposable pre-sterilised components. The use of single-use technology avoids the need for cleaning validation, which must be carried out when using stainless steel or reusable equipment and adds time and cost to any project.

Achieving sterility: The differences between aseptic processing and terminal sterilisation There are four routes of administration that require sterility: injection, ophthalmic, inhaled, and otic. Producing drug products for these routes of administration requires either terminal sterilization or aseptic processing. Terminal sterilisation involves manufacturing and packaging the product in a cleanroom environment, then subjecting the drug product and its packaging to a sterilization process, such as heat, steam, chemical, or irradiation. For some drug products, such as biologics or certain active pharmaceutical ingredients (APIs), terminal sterilization is not possible, often due to the sensitivity of the product or its formulation components. If it is proven that terminal sterilisation cannot be applied to a drug product, then aseptic processing is an option. Aseptic processing utilises pre-sterilised components for the drug product, container, and closure system. The product must also be packaged in a sterile environment. Aseptic processing must occur within an ISO 5 (Grade A) cleanroom, while terminal sterilisation typically occurs in a minimum of an ISO 7 (Grade C) space. Techniques to demonstrate sterility Aseptic processing is one of the most challenging pharmaceutical processes, and manufacturers need to follow strict processes to demonstrate sterility. Validation of any new aseptic process is essential, and three consecutive media fills or aseptic process simulations (APS) are needed to ensure that a process is truly sterile. Media fills are performed to show sterility assurance across the totality of the process, which means trained personnel, equipment, packaging components, and all manufacturing steps. Any issue during an APS means the entire process may need to be re-validated, costing time and money. A good CDMO performs media fills proactively and maintains validated fills that allow client projects to progress more efficiently Autumn 2021 Volume 13 Issue 3

Manufacturing During media fills, sterility is challenge by exposing a microbiological growth medium to product contact surfaces, such as equipment, container closure systems, critical environments, and process manipulations. This is done to ensure that after incubation, quality personnel can more easily detect microbial contamination during processing. The results of this exposure are then interpreted to gauge whether there is potential for the drug product to be contaminated during actual operations. As previously mentioned, carrying out extensive non-viable and viable EM of the facility is fundamental to ensuring sterility, with close attention paid to the critical areas of operation. EM for viable particles includes methods for isolating bacteria, yeast, and mold in the facility, which involves monitoring the air, members of staff, and surfaces for any microbial contamination. For personnel, this process will involve being plated after critical steps, such as aseptic connections, and upon exiting the cleanrooms. The changing face of aseptic processing There is a common perception that there is a sterile manufacturing capacity shortage in the pharmaceutical industry. While sterile filling lines exist for many marketed products, these lines are often inaccessible for new drug developers or not appropriate for the products that are coming to market today. Much of the existing cleanroom capacity remains geared towards highvolume production and is most suited to manufacturing the blockbuster products of old. In contrast, many of the products coming through the R&D pipeline are lower volume biologics and precision medicines aimed at meeting the needs of complex and sometimes rare diseases. This is driving the demand for greater flexibility in aseptic processing facilities, including the ability to handle smaller batch sizes with speed and manage product changeovers swiftly. This is leading to the adoption of singleuse technologies that remove the need for time consuming validation between product batches. Most biologics are considered complex and introduce unique challenges when it comes to setting up and managing cleanroom environments. Because they cannot be terminally sterilised, most biologic drug products require an aseptic wwww.international-pharma.com

process. Equipment trains for biologics often incorporate formulation steps such as mixing/blending or filtration prior to an aseptic fill. Having ample processing space in the cleanrooms is critical for these activities. When performing aseptic filling into primary packaging, considerations related to temperature, shear, and oxidation must also be taken into account. And finally, aseptic lyophilization, which is carried out in an ISO 5 (Class A) environment, introduces its own set of challenges. With a shortage of flexible, smaller batch manufacturing capacity in the sector, CDMOs have made substantial investments in recent years to meet this need. For example, modular facilities are on the rise which allow greater flexibility by containing movable equipment and equipment trains. LLS Health is addressing this need in our FDA-inspected commercial manufacturing facility, which builds upon our decades of experience as a development and clinical manufacturing partner. Our facility was designed to have no minimum batch sizes and features modular, ISO 7 processing space and utilities to accommodate a wide range of formulation steps. We also offer aseptic filling of vials and bottles along with lyophilization in an ISO 5 cleanroom environment. This facility was designed with the next generation of pharmaceutical products in mind – including ophthalmic products, biologics, and the growing field of precision medicine. Summary In short, there are many challenges that need to be overcome to ensure therapies that need to be are sterile, safe, and scalable. For the growing injectable and ophthalmic product pipelines, demonstrating sterility is an important task that needs careful attention. As complex products and aseptic filling become more common, flexible cleanroom space will continue to be in demand. CDMOs with trusted teams and media fill strategies, such as LLS Health, will enable companies and products of all sizes to get to market and usher in the next generation of healthcare. REFERENCES 1.

https://www.marketintelligencedata.com/ reports/80653/cleanroom-technologymarket-growth-trends-and-forecast-20202025?Mode=ICH_03 PharmaCircle 2020 Global Drug Delivery and Formulation Report

Rob Lee Dr. Lee is responsible for product and business development along with providing strategic direction. Before joining LLS Health, Rob held senior management positions at Novavax, Inc., Lyotropic Therapeutics, Inc., and Imcor Pharmaceutical Co. He holds BSs in Biology and Chemistry from the University of Washington and a PhD in Physical Bioorganic Chemistry from the University of California, Santa Barbara. Rob has published more than three dozen articles and five book chapters plus holds 11 issued patents and 15 provisional or PCT patent applications. He has over 30 years of experience in pharmaceutical research and development of both therapeutic drugs and diagnostic imaging agents. Rob maintains strong academic ties, including an appointment as Adjunct Associate Professor of Pharmaceutical Chemistry at the University of Kansas in the early 1990s, serving as a reviewer for both the International Journal of Pharmaceutics and Journal of Pharmaceutical Sciences, and serving on the Editorial Board for the Journal MOJ Bioequivalence & Bioavailability, The Scientific Pages of Nanotechnology, and The Journal of Analytical and Pharmaceutical Research.

Jason Steele Jason works with LLS Health's CDMO clients to design projects that meet their needs, leveraging his experience providing agile, costeffective solutions that emphasize our customer-centric approach. His initial focus has been on building relationships with LLS's aseptic manufacturing clients and working with customers with the end goal in mind – getting to market. Jason had over 10 years of pharmaceutical experience with a focus in sterile drug product manufacturing.

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Smart Packaging for Smart Devices: Designing a Good User Experience As the use of health apps among the general population continues to grow1, medical device developers are beginning to look to companion apps to tackle the challenge of poor adherence, improve patient experience and ultimately improve healthcare outcomes. These apps are typically paired with a physical device, allowing users to track their symptoms and dose history, access key information and generally provide support as they manage their condition. While the benefits of companion apps may seem clear, convincing users to engage with them can however be challenging. As medical devices become smarter and incorporate new connected technology, users are required to not only learn how to use the physical device, but also to download and pair it and sign up to sharing their data. The fact that connectivity may be an add-on to an existing platform device, which can function both with and without it, only increases the challenge of engaging users with the full digital experience. Apps themselves can be an effective tool in onboarding a patient to a new therapy, however you first need to help your user to download and engage with them. Fortunately, designers have options to utilise different elements of the product ecosystem to prompt and encourage desired user behaviours. One of the first of these elements that a patient will interact with is packaging.

wider product ecosystem, including printed information, physical product design and digital assets. Each of these elements can be used as an effective tool for encouraging desired behaviours in users, especially when used in combination. To begin planning how to use these system elements effectively, a useful first step is mapping the user journey. Mapping the journey – defining the challenges that need solving A journey map is arguably the most valuable exercise to undertake at the start of any design program, allowing us to map out how a user will typically interact with our product. The aim is to gain an understanding of the entire user journey through the eyes of the user, considering the challenges they might face, as well as their behaviours and motivations. The exercise also helps to identify any knowledge gaps which may need further research to fill. Such a process doesn’t have to be complicated. Essentially, the aim is simply to understand at an appropriate level of detail what goes on when a user interacts with the product, their common or existing behaviours, typically from the moment they are supplied with the system kit to the moment they dispose of it. By analysing each step in the process, we can identify ‘pain points’ – moments in time where an interaction might cause confusion, discomfort or anxiety – where a user might struggle physically or cognitively

to complete a task. These pain points can then be aggregated into what are referred to as ‘design challenges’, which help us to see more clearly where each element of our system may enable us to address a challenge, encourage a correct behaviour and provide an optimal user experience. It can also be used to identify the best opportunities to signpost users towards our digital solution. Smart system design Designing an effective onboarding experience requires a combination of good UX design practice and behavioural design principles. There are a number of behaviour change models that can be applied to inform design decisions. The Fogg behavioural model is a good starting point, which is formed from the basis that three things must happen simultaneously for a behaviour to occur: Motivation, Ability and Prompt (B=MAP).2 The user must be sufficiently motivated to adopt a desired behaviour, have the ability to do so and receive a prompt. The use of behavioural design in digital applications is already well established, and there are learnings we can take from digital UX/UI design that can be mapped onto the physical elements of our system. For example, ‘progressive disclosure’ refers to the approach of gradually revealing important information to digital users, to avoid overwhelming them or missing key

Packaging provides us with a golden opportunity to introduce users to a new device. As the first physical touchpoint they will have with a product, it can be used to convey key information and prompts to help users set up and use their device safely and effectively. As we begin to introduce new connected technology to devices, packaging also offers an opportunity to guide users towards companion apps and can be viewed as the first step in digitally onboarding them. For packaging to be used most effectively, we must consider it as part of a 78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 1 Autumn 2021 Volume 13 Issue 3

Packaging benefit of physical, printed materials is that they are less likely to be competing with these same distractions. While many of today’s users may have a preference for digital media, studies have shown that people may remember more key points when reading on printed material rather than digital.3

Figure 2

concepts. ‘Tunnelling’ and ‘chunking’ use a predetermined sequence of steps to encourage a desired outcome. The focus here is getting the user to complete one task or goal rather than many, alongside breaking down information into small, memorable parts to avoid overloading them. Similar design approaches can also be adopted in the design of packaging and printed information. If we look at Figure 1 for example, the packaging for this auto injector has been designed in a way to simplify the unboxing experience, with key information provided on each flap that the user must physically open to see (progressive disclosure). The aim here is to not overwhelm the user with information all at once, instead ensuring they work through each step in the correct order.

As mentioned previously, packaging and print are often the first point of contact your user will have with your device, offering a useful opportunity to begin onboarding them and guide them through set up. While smartphone apps are well suited to help users set up their devices, your user is however at risk of losing attention owing to other notifications and distractions. The

IFUs Printed Instructions For Use (IFU) are a regulatory requirement for medical devices and need to adhere to strict rules on the critical information they convey about both the device and the drug. Typically made up of a single sheet or booklet, printed IFUs have a larger visible viewing area than a single app screen, meaning we are able to show users much more content in a single view, but the information is static. This allows the patient to see the full set-up process they will need to undertake. Unlike an onboarding process through a smartphone app, the patient can also easily refer back to previous steps as needed, giving them more control over the information they see. While these are all potential benefits, there is however also a risk of overwhelming the patient with too much information, which

Similarly, when designing printed patient information such as Instructions For Use (IFU) we can break up content by chunking user steps. For example, when using a single sheet of print, folds in the paper can be used as natural breaks to guide the user through different stages and separate each step (see Figure 1). Print vs digital As people react differently to different media, it’s important to offer users a combination of ways to access key information, across both print and digital. There are of course pros and cons to each of these media, however the key for both is to make the experience as frictionless and simple for the user as possible. wwww.international-pharma.com

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Figure 4

could result in them missing important device set-up steps or content. IFUs need to contain a lot of information, including potential side effects and contraindications. This essential information, by nature, often has to focus on telling people what not to do, rather than just focusing on how to set up their device. As designers, we need to balance these requirements whilst still ensuring we create instructions that are easy to follow.

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We need to choose the best format for an IFU, whether that’s a booklet, concertina, gate fold etc, considering the information that needs to be communicated and focusing on the placement within the pack, the user and environment of use. We must establish a clear hierarchy of information on a page to aid navigation and reduce visual clutter, by clustering information and making careful use of typography, colour and white space.

Type form is an essential way of guiding your user across the page. For IFUs and printed materials, draft guidance from the FDA recommends a minimum font size of 10 points and suggest a sans-serif font such as Arial or Verdana,4 however limiting yourself to these fonts can be quite restrictive. For example, fonts that use open counters (the open space in letters such as an ‘o’), an established lowercase height and minimal stroke contrast can all help the

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Packaging user distinguish between different letter forms more easily. The arrangement of text across the page, as shown in Figure 3, can also make the text much more readable and accessible. The brain handles images better than text, so a combination of images and text to tell a story is also very powerful when designing an IFU. Careful consideration must be given to the placement of images in relation to text and to the style of the imagery. Creating illustrations from the users’ viewpoint can help to aid orientation whilst the considered use of colour and line weight draws attention to relevant features. Smart packaging for digital onboarding While packaging can be used as an interactive tool to guide users through their device set up, digital solutions offer further opportunities to assist with onboarding and competency. In this case, the core focus of the packaging may need to switch to signposting users to your companion app as quickly as possible. The introduction of new technologies such as App Clips and fast pairing has made this process a lot easier. App Clips offer a basic version of an app that can be accessed without the need to search for and download the full product. The idea behind this is to convince users of the benefits of

the app before they commit to it. A key part of the App Clip experience is how you discover it. Having a QR code, or possibly even an NFC tag on the packaging that a phone can be tapped against, can help to remove the barrier of forcing the user to search for the app on the app store.

REFERENCES

If we look at Figure 4, a self-testing kit, a QR code has been used to signpost the user to a companion app, which the packaging clearly states will be needed to complete the test. Here the main aim of the packaging is to guide the user as quickly as possible to the companion app, which will instead provide instructions on how to use the product. In this instance, the packaging makes it clear that the only way to access the instructions for how to use the test is via the app.

Smart design for the future While society appears to be on the fast track towards a more connected future, it is safe to say there will still be a crucial role for packaging and print to play in the world of smart devices. Through careful consideration of our product ecosystem, we can optimise user experience across both physical and digital elements. Using behavioural design theories and applying UX design principles, we can help lower the barrier to adoption of new technologies, whilst ultimately enabling new tools to support patient adherence.

1. 2.

https://behaviormodel.org/ Lauren M. Singer & Patricia A. Alexander (2017) Reading Across Mediums: Effects of Reading Digital and Print Texts on Comprehension and Calibration, The Journal of Experimental Education, 85:1, 155-172, DOI: 10.1080/00220973.2016.1143794 https://www.fda.gov/regulatory-information/ search-fda-guidance-documents/instructionsuse-patient-labeling-human-prescriptiondrug-and-biological-products-and-drugdevice

Paul Greenhalgh Paul Greenhalgh has 20 years’ experience in the development of medical devices. Since joining Team Consulting in 2001 he has worked with some of the largest pharma companies and most innovative MedTech start-ups, developing groundbreaking solutions to improve the way healthcare is delivered. Paul is driven to design products that provide the level of UX we’ve come to expect, all the while working within the tight constraints of a highly regulated industry. He has a degree in Product Design from Central St Martins, London, UK.

Ben Cox As Head of Digital Design, Ben works with a cross-functional group of designers, researchers and engineers to craft engaging and intuitive interfaces, and optimise the user experience of medical devices. With a background in human factors and user-centred design, Ben focuses on UX/UI from product vision to implementation. Previously, Ben worked in several design consultancies, as a clinical scientist and design engineer in the NHS, and has conducted extensive research for DePuy Johnson & Johnson. He has a BEng degree from Cardiff University and an MSc and PhD in Biomedical Engineering from the University of Leeds. wwww.international-pharma.com

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Innovative User-Friendly Child-Resistant Packaging Solutions Abstract In the European Union (EU), poisoning is the fifth leading cause of unintentional death for children and adolescents, with one of the most commonly cited causes being medicinal drugs.1 Despite increased efforts over the last fifty years to improve parental education in childproofing homes and developments in child-resistant packaging that have steadily decreased the number of cases, accidental poisoning remains a considerable risk in the home. This article will explore how the pharmaceutical industry faces this global medical challenge, evaluating existing and future pharma packaging trends. Introduction Unintentional poisoning is a relatively widespread medical emergency, with children at the highest risk of accidental intoxications that could prove fatal.2 Cases often occur within the home when young children are exploring their surroundings and gain access to improperly stored harmful substances such as cleaning chemicals, fuels, alcohol, tobacco and, most frequently, medication. In the United States (US) and Europe, over-the-counter (OTC) and prescription medications are the leading causes of child poisoning, with analgesics being particularly common. As well as the risk to life, unintentional child poisoning has a significant socio-economic impact, with medical costs and long-lasting disability. Figure 1 shows the global burden of unintentional childhood injuries, including poisoning. Pharmaceutical companies are therefore being increasingly called upon by patients and stakeholders to recognise the importance of child-resistant closures (CRCs) in medical packaging. When developing child-resistant packaging for pharmaceuticals, one of the greatest challenges is creating a closure design that prevents children from gaining access to harmful substances while maintaining usability by adults – particularly seniors. A growing trend of home care (intensified by the Covid-19 pandemic) as well as an 82 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 1: Burden of disease (deaths and disability-adjusted life years, DALYs) attributable to the environment globally – unintentional injuries in children ages 0–4 years, 2012. Notes: a This includes injuries from mechanical forces (tools, sports equipment, agricultural machinery), explosions, off-road transportation accidents, animal bites, venom, poisonous plants, ionizing radiation, electric currents, suffocation, natural forces (storms, extreme temperatures, earthquakes), and medical care complications. Reproduced from ref.3 in accordance with the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons. org/licenses/by-nc-sa/3.0/igo).

increasingly aging population, is directing the focus of child-resistant packaging towards the accessibility needs of older patients. Packaging suppliers must work with pharma companies to create life-saving

solutions that address this current tradeoff. Types of child-resistant packaging Since its introduction, child-resistant

Figure 2: Different types of child-resistant packaging (a) re-closable push & turn (b) re-closable squeeze & turn [need to add], and (c) non-re-closable peel & push, where back paper/plastic film is peeled back before tablet is pushed through aluminum foil. Autumn 2021 Volume 13 Issue 3

Packaging packaging has developed and matured into an accepted, effective product in the UK, EU, US, Canada and Australia and is gaining rapid acceptance in the Asia Pacific (APAC) region.4 The global pharmaceutical packaging market was valued at $71 billion in 2018 and is projected to grow at a CAGR of nearly 6% during 2019–2029.5 As well as an upward trend in contract manufacturing, an increasing focus on child-resistant packaging is driving this market growth. Child-resistant packaging is either made out of a material that is difficult to open or relies on a particular method to open it. There is a variety of mechanisms for CRCs on medical packaging which are categorised primarily into re-closable (bottles) or nonre-closable (blister packs), these include: Re-closable • Push & turn caps • Squeeze & turn caps Non-re-closable • Peel & push The screw-on cap is the most well-known re-closable packaging design and can only be opened by pushing down and turning simultaneously, while the most frequently used non-reclosable design is blister packaging, containing individually wrapped pills or tablets (see figure 2). Although the overall aim of each type of packaging is to protect children from ingesting the contents, the strategies can vary. For example, the aim of most bottle CRCs is to stop the child opening the packaging altogether, but if the cap is left off then the CRC fails to work. Another focus taken by some designs is on limiting the dose a child is exposed to if the container is opened, such as liquid flow limiters that only allow one dose to be dispensed. Blister packs offer both ease of patient use and child resistance as they have dose guards that act as more of a secondary barrier that the user must peel away to then push the oral dose through the packaging. Testing/certification Patient compliance influences the pharmaceutical packaging market, as it continues to be a top priority for packaging solutions, along with regulatory standards. Both are therefore important considerations in designing and manufacturing child-resistant packaging. According to the World Health Organization (WHO), “packaging must not only increase compliance through its wwww.international-pharma.com

design but must also protect the patient and indicate the integrity of the product”.6 Comprehensive regulations are in place to ensure that packaging, regardless of its CRC mechanism, complies with safety standards and meets the necessary legal requirements to identify as child-resistant. To obtain certification, pharma companies must submit their packaging for testing by an authorised body. For packaging to be classed as child-resistant, it must meet one of the following standards: •

•

International Organization for Standardization (ISO) 8317 (2015): Child-resistant packaging – Requirements and testing procedures for recloseable packages ISO 14375 (2018): Child-resistant nonrecloseable packaging for pharmaceutical products – Requirements and testing US 16 CFR § 1700.20: Testing procedure for special (Child-resistant) packaging.

An example of the testing procedure as part of ISO 8317, ISO 14375 and US 16 CFR § 1700.20 includes a panel test with 42–51 month old children and 50–70 year old adults. The packaging should be difficult for the children to open while presenting limited problems for the adults. These adults must be able to open the package twice within allocated test periods, and at least 80% of children should be unable to open during specified test periods. As well as this standardised testing procedure, the ISO has published an internationally agreed standard test procedure for re-closable child-resistant packaging.7 A certificate is issued by an ISO 17065 accredited organisation to offer clarity about the packaging’s quality and provide legal protection to manufacturers, market participants, consumers and officials. These standards must be adhered to for pharmaceutical and healthcare companies to claim packaging to be child resistant but are only required by law in some countries, including Austria, England, Scotland, Wales Hungary, Iceland, Israel, Italy, Poland, Spain, and Sweden (Figure 3). Whether mandatory or not, child resistance certifications must cover the full packaging solution, including both the container and the closure. Though many pharmaceutical containers are produced with CRCs, it cannot be assumed that one

combination will pass testing just because another previously has. If a container is changed or even slightly modified, the entire packaging must be re-certified. The time and cost associated with certification can be significant, so drug manufacturers can streamline the process by partnering with packaging manufacturers that can not only supply innovative, high quality packaging, but also provide the required certification. In the early 1990s, the need for more user-friendly child-resistant packaging was recognised by the Consumer Product Safety Commission (CPSC) in the US, leading to the current protocol that trials adults between the ages of 50 and 70 who do not have “obvious or overt physical or mental disabilities”.8 Although the current procedure does attempt to ensure older patients can access their medication, it can be criticised for lacking acknowledgement of vulnerable and disabled patients who are more likely to struggle with adhering to treatment regimes in the first place.9 By not recognising these patients in testing protocols, child-resistant packaging can remain too difficult for them to open and possibly result in them leaving the closures off their medication, increasing the risk of child-poisoning. Creating innovative, truly child resistant senior-friendly (CRSF) packaging is crucial to supporting a more patient-centered, rather than productcentred treatment approach. A strong relationship between drug manufacturers and packaging suppliers, as well as with healthcare providers and patients, will help facilitate this. Why big pharma is changing R&D strategies to focus on child-resistant packaging Large pharmaceutical companies are now driving awareness and innovation in childresistant packaging, creating new advanced designs every year and redesigning their previous portfolios to meet patient needs for CRSF packaging. They have moved from a simple compliant strategy dictated by legislation to developing CRSF packaging solutions that improve and protect their patients' children’s lives. For example, GSK’s existing portfolio is being transitioned into CRSF packaging with 40 internal and external contract manufacturing sites now producing CRSF packaging for GSK brands. As of 2020, 200 million packs from the existing portfolio were supplied in CRSF packaging. Pharma companies looking to implement a more robust CRSF packaging strategy should consider the following: INTERNATIONAL PHARMACEUTICAL INDUSTRY 83

Packaging •

• • •

Not all drug products will be suitable for development in CRSF packaging. Pharma companies should identify which products should be moved to CRSF packaging. Product shelf life/stability requirements. Changes to packaging registered details Markets being supplied: Possible need for patient/care giver education.

Review of recent research The volume of research into improving child-resistant packaging for medications, as well as modernising the testing criteria for CRSF packaging, has increased significantly in recent years. The following three studies demonstrate the variety of approaches being taken to improve the effectiveness of child-resistant packaging: 1. Multi-step mechanisms: Researchers designed and validated the performance of a novel child-resistant packaging system for oral solid dosage forms, with a unique stepwise mechanism that showed considerable effectiveness in preventing children from opening the package.10 The features include (i) re-closable packaging that involves a box container installed “click lock” on either side of the system, (ii) an outer packaging box of 8 cm width, which is too large for the palm width of children under 5 years of age, making it difficult to open, and (iii) a unique irritating sounding buzzer that either motivates the child to cease their attempt, or alerting an adult to the attempt. Only 6% of children succeeded in opening the packaging, while 94% of children failed to open it within 5 minutes. On the other hand, 96% of adults succeeded within 5 minutes, indicating that the mechanism does not significantly hinder patient access to medication. 2. Visual distractors: As well as new designs for manual CRC mechanisms, research is also being carried out to investigate other elements of packaging that could prevent or restrict child access. For example, visual distractors have been shown to effectively delay young children (24–41 months) from opening medicines, in which time adults could be more likely to notice and prevent ingestion. In this study, the visual distracter consisted of a lenticular graphic characterised by a stereoscopic, 3D perspective that 84 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 3: Map depicting the poisoning prevention scores of 31 countries in Europe, from 0-5 stars, with 5 being the highest score, based on criteria determined by the 2012 Child Safety Report Card.11

yielded the illusion of movement and depth, changing colours from yellow to red when the vial was moved.12 While it was recognised that visual distractors could potentially attract children to a container they might have otherwise ignored, the approach and consideration of targeting children’s early stage processing (i.e. perception) rather than relying on late stages of information processing is an area that could be explored further. 3. ‘Smart’ packaging: As packaging technology becomes more advanced, smart containers could become more commonplace in the market. Preliminary results from a recent study indicate that smart pill bottles can be used to reliably detect children trying to open pill bottles and, by emitting an aural alarm, reduce risk of child-poisoning events.13 In this study, a prototype bottle could sense an adult opening the container with 98.16% sensitivity, and a child with 96.67% sensitivity. The following two studies indicate how some elements of child-resistant packaging testing criteria are being called into question, and whether these should be updated to reflect a wider demographic: 1. A global divide: Some researchers have raised the question over whether different geographical regions should be covered by the same global testing criteria for child-resistant

packaging. For example, there is currently no regulation mandating the use of child-resistant packaging in Japan, but the consistently high levels of reported child drug accidents in the country have led to considerations over whether packaging that meets U.S. requirements is suitable for Japanese children. Researchers investigated paediatric characteristics such as literacy ability and finger function in Japanese subjects and examined the usefulness of childresistant packaging technologies used in the U.S. when given to children in Japan.14 Results suggested that the differences in the language, culture, and preschool education between Japan and the U.S. have a significant influence on paediatric characteristics. 2. Improving understanding: As previously mentioned, the criteria for ensuring adults can open child-resistant packaging stipulates that participants in testing must be able-bodied. Therefore, the existing test protocols for evaluation and validation of this type of package do not consider users with special needs, such as wheelchair users and people with limited range of hand movements, who are the most affected by the process of opening. Some studies have focused on better understanding the restricted movements of elderly or disabled users using devices such as movement restriction gloves, creating awareness in the hope of influencing these test protocols, as Autumn 2021 Volume 13 Issue 3

Packaging well as informing ergonomic packaging design.15 Conclusion Over the last fifty years there has been a gradual development in awareness of the risks of unintentional child-poisoning and while the incidence of poisoning events has decreased steadily over the last decade, the need for safe, compliant child-resistant packaging is receiving increasing attention. This attention has highlighted the demand to improve the safety of pharmaceutical packaging that maintains compliance with patients, particularly seniors. Child-resistant packaging that is truly senior-friendly undergoes innovation every year, and this development will be accelerated by strong relationships between drug manufacturers and packaging suppliers. Partnering with packaging manufacturers that can offer certified advanced solutions for CRSF packaging means that pharmaceutical companies can guarantee their products meet relevant regulatory requirements. Beyond the legal requirements, childresistant packaging makes a profound impact on pharmaceutical companies’ larger goal to improve the health of people. If there is danger to the health of children, child-resistant packaging should be used and tested to establish that it works satisfactorily; as the last barrier between the child and the packaged content, it has an important part to play in solving the problem of unintentional child poisoning.

REFERENCES 1.

MacKay M and Vincenten J. Child Safety Report Card 2012: Europe Summary for 31 Countries. Birmingham: European Child Safety Alliance, Eurosafe; 2012 2. Nistor N, Frăsinariu O, Rugină A, et al. (2019) ‘Poisoning in the Pediatric Intensive Care Unit’ in Karcioglu O, Arslan B, editors, Poisoning in the Modern World - New Tricks for an Old Dog? 1st ed. IntechOpen 3. Inheriting a sustainable world? Atlas on children’s health and the environment. Geneva: World Health Organization; 2017. Licence: CC BY-NC-SA 3.0 IGO 4. Wilkins S. Pharmaceutical packaging:childresistant, easy opening, sustainable, European Pharmaceutical Review, 2019. https://www. europeanpharmaceuticalreview.com article/ 84257/pharmaceutical-packaging/ 5. Pharmaceutical Packaging Market: Global Industry Analysis 2014-2018 and opportunity Assessment 2019-2029, Future Market Insights, April 2019. https://www.futuremarketinsights. com/reports/pharmaceutical-packaging-market 6. Annex 9 – Guidelines on packaging for pharmaceutical products, WHO Technical Report Series, No. 902, 2002, https://www. who.int/medicines/areas/quality_safety/ quality_assurance/ 7. ISO 8317:2015 – Child-resistant packaging — Requirements and testing procedures for reclosable packages, ISO, 2015. https://www. iso.org/standard/61650.html 8. US CPSC. 16 CFR Part 1700 – Requirements for the Special Packaging of Household Substances (Final Rule). Washington, DC: US Consumer Products Safety Commission, 1995. 9. Bix L, de la Fuente J, Pimple KD, et al. (2009) Is the test of senior friendly ⁄child-resistant packaging ethical? Health Expectations, 12: 430–437. 10. Chen R, Bello NM, Becker MW, Bix L (2018)

11.

12.

13.

14.

15.

Chasing red herrings: Can visual distracters extend the time children take to open childresistant vials? PLoS ONE 13(12): e0207738 MacKay M and Vincenten J. Child Safety Report Card 2012: Europe Summary for 31 Countries. Birmingham: European Child Safety Alliance, Eurosafe; 2012. Talukder BMSB, Jovanov E, Schwebel DC, et al. A New Method to Prevent Unintentional Child Poisoning, 2018 40th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), Honolulu, HI, 2018: 5142-5145. Mizoguchi M, Miura G and Ojimac F. Study of Child-resistant Packaging Technologies to Prevent Children from Accidental Ingestion of Drugs in Japan, Yakugaku Zasshi, 2018; 138, 1103-1110. Mizoguchi M, Miura G and Ojimac F. Study of Child-resistant Packaging Technologies to Prevent Children from Accidental Ingestion of Drugs in Japan, Yakugaku Zasshi, 2018; 138, 1103-1110. Bonfima GHC, Silvaa DC, Alvesa AL, et al. Hand movement restriction at the opening of childresistant packaging: case study, Product: Management & Development, 2016; 14(2): 141-151.

Najet Mebarki Najet Mebarki has been Senior Product Marketing Manager for oral products at SGD Pharma, since 2018. She has 15 years of experience in BtoB marketing within the packaging sector, in international companies and multicultural environments. Her role is to translate market insights into business value by developing the most suitable product & service offering. Most recently, Najet developed Ensiemo, a CRC packaging solution dedicated to the CBD oil market. Email: najet.mebarki@sgdgroup.com

Dr. Rolf Abelmann Dr. Rolf Abelmann is Managing Director of IVM Childsafe GmbH. Having joined in 2003 as head of testing while completing his doctorate with the University of Göttingen in 2005 he took on his current position in 2006. Email: r.abelmann@ivm-childsafe.com

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Addressing Value-based Care Needs with Parenteral Packaging Three Key Considerations to Boost Quality of Care and Outcomes Amid Demographic Shifts According to the World Health Organization (WHO), the pace of the population aging is faster today than ever before. From 2015 to 2050, the number of people aged over 60 is predicted to increase from 12 percent to 22 percent, creating challenges for countries around the world to ensure both health and social systems are capable of dealing with what the WHO refers to as a demographic shift. To put this into perspective, the figures show that in 2050 the number of people over 60 will reach two billion globally – with the majority living in low to middle income countries – and with healthcare budgets largely decreasing.1 As more people are diagnosed with chronic health conditions and costs continue to rise, it has never been more important to maintain the highest level of care using all available tools and resources, including parenteral packaging. A more holistic approach could be the solution, and many believe that valuebased healthcare is the answer. In 2020,

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for example, value in health was identified as a priority area for the G20 nations, and the establishment of a knowledge sharing platform was welcomed by WHO Director General Dr. Tedros Adhanom Ghebreyesus. The overarching theory is that by monitoring the complete journey of a patient as they progress through a healthcare system, value can be measured through assessing the entire cost of that patient’s care, the quality of that care, and the ultimate outcome. Of course, when looking at the bigger picture – as value-based healthcare demands – value can be added from a wide range of sources, and manufacturing is a key factor to achieve the intended outcome. Thus, it is essential for device manufacturers and drug developers looking to better address the shift to value-based care to work with component manufacturers that can add value directly, through thoughtful design, material selection, and qualitydriven manufacturing processes. Here, we look at three key areas of consideration in parenteral packaging selection that can support a value-based care approach to drug delivery.

1. Avoid Overengineering: Add Value, Not Cost One key aspect of value-based care is reducing the cost of patient care. During the development of a device or treatment, overengineering can inflate cost, making it difficult to adapt to a value-based healthcare industry. To avoid this challenge, manufacturers can work closely with suppliers to recommend optimal solutions that deliver the best possible cost per unit, provided there is transparency from the outset on both sides. Understanding expectations is fundamental, and time must be taken in the earliest stages to ensure the solution offered does not deliver elements that are surplus to requirements. For example, in pre-filled syringes, cartridges and vials, it is possible to recommend a coated stopper in every instance where a stopper is required. The risks posed to formulation integrity by extractables and leachables often necessitate protective coatings. Components that use proprietary fluoropolymer spray coating can prevent any unwanted drug interactions by providing barrier properties

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WHERE PASSION BECOMES ACTION. Whatever we do, wherever we are, we have a common purpose – utilise our strength and innovation to maximise partner value and improve patient outcomes.

WE CARE. WE CREATE. WE DELIVER. wwww.international-pharma.com ltslohmann.de/en

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Packaging and even eliminate the closure as a source of silicone oil-based subvisible particles. However, this is not always required. If the drug is stable with an uncoated stopper, a 100 percent coated solution is not necessary to protect formulation integrity. There are highly efficacious uncoated compounds which offer good stability even with biological drugs. However, it is important to note that 100 percent coated solutions should still be used for the packaging of drugs that could be compromised by extractables and leachables. Components that are only partially coated in areas exposed to the drug are still packaged and transported in bags where coated and non-coated areas can rub and potentially displace rubber particulates on the coated surfaces. It is imperative for drug manufacturers and packagers to work closely with suppliers to fully understand the pros and cons of both options based on the sensitivities of the formulation. If we translate this to a real-world example, a serious initiative to make the drug Insulin more affordable looked to the entire process to reduce its cost. There were no development elements as the patent had expired, but manufacturers collaborated with components suppliers to find safe, cost-effective options to drive savings, including the use of uncoated stoppers and plungers where perhaps coated options had been used historically. When coupled with the fact that processes had been optimised over the many years of the drug’s production, this ultimately made the drug more accessible to patients who had historically found the cost prohibitive. This approach to adding value as opposed to cost is particularly important to the treatment of chronic diseases, which continue to put pressure on both patients and the economy as a whole. A report published by the Milken Institute in 20181 showed that when lost economic productivity was included, the total costs of the varying types of chronic disease in the US was equivalent to almost one-fifth of the American economy. 2. Agility is Critical: Adapting to an Ever-Evolving Industry As the healthcare patient and industry needs shift, device and drug manufacturers looking to fulfil those needs must adapt. Drug delivery devices must increasingly enhance convenience for patients – whether that means using pre-filled syringes in medical settings to save time or equipping 88 INTERNATIONAL PHARMACEUTICAL INDUSTRY

patients with wearables that deliver timed doses – partnering with suppliers that can move seamlessly between designing unique components and scaling up for production is critical to success. An agile supplier can advise as to the best possible components, as well as to ensure that the design can accommodate those components without causing an issue in production or beyond. Most components can be adapted to suit by simply changing the mould and die setup, while most standard compounds have a wide range in processability which makes it possible to provide the requested design in a compound which is best compatible with the drug. In general, standard portfolio products will apply to the largest part of the market and can add the most value in terms of cost. However, where a customer is convinced that patient care can be improved exponentially through the deployment of customised components, to have a supplier with the capabilities to develop and produce such components is a distinct advantage. In most cases, these customised projects concern components for a specific device. Once key benefits are defined, it is essential to partner with a supplier that can identify the ideal solution that also takes into account compatibility, functionality, producibility, and supply chain. 3. Customisation is often the catalyst for greater long-term value In the value-based care model, positive outcomes are a high priority, but the patient experience is also a crucial element. Customisation plays a key role in the patient experience, especially as consumers call for greater personalised healthcare experiences.2 At times, custom components are added to a supplier’s portfolio when they address a broad industry need, making them more cost effective through standard production activities. However, not all suppliers are capable of taking on such a feat, which is often influenced while working with drug delivery device manufacturers to help add value to patients in a number of areas. Many medical devices, for example, are designed to enable patients to stay at home, to have fewer appointments and fewer visits to the hospital. This not only makes the experience a better one for the patient, but also reduces the amount of time clinicians spend with their patients – adding value on many levels.

One such device is the on-body injector, which enables a drug to be administered to a patient via the device from the comfort of their own home. The needle is protected and can be safely disposed of and doctors have the ability to monitor the data captured via the device in terms of how long it took, when the dose was administered, and a range of other statistics. Recognising the need for the similar size diameter cartridges for devices of this nature, some drug delivery component manufacturers were able to better address these needs. Expert manufacturing partners are essential to the value-based care model Customisation, agility to respond to changing market needs, and designing parenteral packaging components that are not overengineered for the application are all important ways that suppliers can support the value-based care initiatives of drug manufacturers. Each of these approaches aim to enhance the overall experience of patients – often, without adding significant cost – to encourage adherence, improve accessibility, and drive more positive treatment outcomes. REFERENCES 1. 2. 3.

https://www.who.int/news-room/fact-sheets/ detail/ageing-and-health https://milkeninstitute.org/reports/costschronic-disease-us https://www.businesswire.com/news/home/ 20200218005006/en/75-of-U.S.-ConsumersWish-Their-Healthcare-Experiences-Were-MorePersonalized-Redpoint-Global-Survey-Reveals

Carina Van Eester Carina Van Eester is Global Platform Leader, Prefilled Syringes & Cartridges at Datwyler Sealing Solutions. She has a Master's degree in Chemical Engineering and has been working in the pharma industry for 15 years as a packaging engineer. After several years of experience in Technical Key Account Management and Validation, Ms Van Eester's current position as Global Platform Leader for Prefilled Syringes and Cartridges includes managing strategic initiatives related to Datwyler's components for various applications. Email: carina.vaneester@datwyler.com Autumn 2021 Volume 13 Issue 3

Corporate Profile

Smaller Carbon Footprint from Plastic Pharma Containers In the public debate about how to reduce the carbon footprint of packaging, it’s often said that glass would be a significantly eco-friendlier material than plastic in pharma packaging. However, a comparative life cycle analysis of containers made from glass, aluminium and plastic gives a different result. How does a plastic pharmaceutical container fare in comparison with an equivalent container made from glass or aluminium in terms of its carbon footprint? To get some clarity on this issue, Nolato Cerbo in Trollhättan commissioned an independent party to conduct a comparative life cycle analysis. A Cradle-to-grave Analysis The cradle-to-grave analysis examined a 200 ml container with an annual production of 5 million in glass, aluminium and three different types of plastic, also factoring in the environmental impact of an 800 km journey from Nolato’s plant to the customer. The analysis found that the glass containers contributed 930 tons of CO2 per year, aluminium containers 575 tons of CO2, plastic containers made from fossil raw materials 447 tons of CO2, the plastic containers made from bio-based

raw materials 337 tons CO2 and the plastic containers made from recycled plastic 300 tons of CO2. So, a plastic container made from recycled plastic had a carbon footprint that was just 30% of that of the glass container. Halving the Carbon Footprint The results of the analysis were then used to simulate the environmental impact of replacing the annual production of 40 million units of a 30 ml glass container with an equivalent plastic container. The simulation showed that changing from a glass container to a plastic one made from fossil raw materials would halve the carbon footprint. If the container were instead made of bio-based material, such as plastic made from sugarcane residue,

the carbon footprint would shrink by an additional one-third of that of the glass container. By using green electricity, which Nolato does wherever possible, including in Sweden, it would avoid an additional 180 tons of carbon dioxide. So, all in all, there’s the potential to cut the carbon footprint by over 1,600 tons of CO2 a year! “This is really interesting,” says Glenn Svedberg, Managing Director of Nolato Cerbo. “These analyses show that we already have the opportunity to opt for environmentally sustainable alternatives that would significantly reduce our carbon footprint.” Bio-based Plastic Already Available Nolato can already supply pharmaceutical packaging made from food-grade, biobased raw material from sugarcane residue, but unfortunately yet, for regulatory traceability reasons, we are not permitted to use recycled plastic in the containers. “The thing that mainly differentiates pharmaceutical-grade from food-grade plastic is the extent of regulatory documentation and testing, and a twoyear guarantee that the composition will remain the same,” says Glenn Svedberg. “Currently, the version of our most popular standard packaging that has been validated for bioplastic has 100% bioplastic in the container and around 80% in the lid. We’re in the process of carrying out tests to achieve an even higher percentage of bio-based material in the lid as well.

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Logistics & Supply Chain Management

Minimising Vaccine Wastage with Advanced Refrigerator and Freezer Technologies A leading cause of vaccine wastage is exposure to inappropriate temperatures during cold chain storage. A new international standard will help healthcare providers to select highperformance refrigerators and freezers with the precise temperature control necessary to protect the quality and integrity of the vaccines stored inside. Introduction The COVID-19 pandemic has catalysed an unprecedented acceleration in vaccine research and development. In less than a year from the identification of the novel viral pathogen, the first vaccines against SARS-CoV-2 gained emergency approval from regulators in several countries after demonstrating high efficacy in clinical trials. The use of innovative vaccine platforms, such as novel mRNA technologies, has played a huge part in this remarkable success story. While the development of COVID-19 vaccines brings hope of a way out of this global crisis, success also hinges on their efficient and rapid rollout to the world’s population. The new vaccine technologies bring new challenges to this already daunting task, not least with managing the vaccine cold chain. Comprised of cold rooms, freezers, refrigerators and transportation boxes, the complex global network contains many components that must keep products at an appropriate temperature on their journey from the manufacturing line to the patient. Despite intense global efforts to ramp up COVID-19 vaccine production and distribution, many of these doses are still not reaching people’s arms, with hundreds of thousands of vaccines being wasted. The US’ Centers for Disease Control (CDC) alone recorded 182,874 wasted COVID-19 vaccine doses as of late March 2021. More broadly, the World Health Organisation (WHO) estimates up to 50% of all vaccine doses are wasted each year.1 A leading cause of vaccine wastage is exposure to inappropriate temperatures during the cold chain. Establishing the proper cold storage infrastructure needed to help mitigate 90 INTERNATIONAL PHARMACEUTICAL INDUSTRY

vaccine wastage will be an important part of tackling the current pandemic, as well as facilitating the rapid and efficient delivery of future vaccination programmes. Recently, NSF International (formerly the National Sanitation Foundation) introduced a new international standard, which will make it easier for healthcare providers to choose high-performance vaccine storage units that are certified to stay within required temperature ranges to reduce the risk of vaccine wastage. The challenges of managing the vaccine cold chain All vaccines are biological products, and many will need to be kept at carefully controlled temperatures from the moment they are produced until administered. Any deviations from validated temperature ranges can lead to the degradation of a vaccine’s active ingredients and a loss of effectiveness. Each vaccine will have specific cold storage requirements that must be adhered to on its journey to patients. Traditional vaccines contain a diseasespecific antigen or weakened forms of the pathogen designed to trigger an immune response. But the first-ever RNA vaccines, which work by introducing an mRNA sequence encoding a specific disease antigen into the body wrapped in fat droplets, were among the first COVID-19 vaccines to receive regulatory approval. Once inside cells, our bodies make the viral antigen – it is this foreign protein that triggers the immune response.

creates avoidable delays in getting effective vaccines to people, which is of critical importance as the world tries to overcome the effects of the current pandemic. Even worse, any undetected exposures run the risk of unknowingly delivering ineffective vaccines to patients – inadvertently putting lives at risk. While there are many different elements involved in managing the integrity of the vaccine cold chain, healthcare providers need to know which refrigerators and freezer equipment are suitable for vaccine storage, providing peace of mind for the quality and effectiveness of the precious products inside. The clear need for high-quality vaccine storage equipment, which has been heightened due to the additional pressure from the current pandemic, has led to the development of a unique class of specialised, high-performance refrigerators and freezers with more precise and sophisticated temperature control features than their typical household or commercialgrade counterparts. Inadequate standards for vaccine storage equipment Not only has the COVID-19 pandemic thrust the vaccine cold chain into the spotlight, but it has also exposed some potential insufficiencies.

While these next-generation RNA vaccines offer game-changing advantages over traditional vaccines, including a good safety profile and their ease of manufacturing, they also bring new challenges, such as the need for long-term storage at low temperatures. For example, Moderna’s RNA vaccine must be kept in a freezer at around -20oC, while the Pfizer-BioNTech vaccine requires storage at ultra-low temperatures of around -70oC.

Until now, few official standards existed for vaccine storage equipment in clinics, pharmacies and other vaccination sites. For instance, the US CDC provides annual guidelines – the Vaccine Handling and Storage Toolkit – that highlights best practice for measuring cabinet temperature and handling vaccines.2 However, it stops short of detailing temperature performance, design and documentation requirements for a vaccine refrigerator and freezer to prevent product loss.

Exposure to an incorrect temperature – either too hot or too cold – at any point in the cold chain can render a vaccine ineffective. The entire batch must be discarded, resulting in loss of time, resources and potentially public confidence. This also

A simple but important metric used to assess refrigeration performance is temperature uniformity, which involves measuring the maximum temperature difference within a unit at any specific moment in time. This can provide valuable Autumn 2021 Volume 13 Issue 3

Logistics & Supply Chain Management information about temperature performance in all parts of the useable spaces within the cabinets. Current CDC guidelines stipulate measuring cabinet temperature using a single data logger with a weighted probe. However, these measurements will depend on the location of the probe and frequency of readings – meaning temperature fluctuations may be missed, putting vaccines at risk. It is also important to consider how a refrigeration storage unit will typically be used in a vaccine clinic, hospital or pharmacy. There are many other factors, such as how often, and how long, the doors are opened, which might impact on performance. Additional tests that mirror typical realworld usage are also needed to assess how these might affect the performance of the storage unit, and inevitably the vaccines stored inside it. A new international standard to minimise vaccine wastage These additional considerations, coupled with challenges faced by vaccine providers in selecting the right vaccine storage equipment, led NSF International (formerly the National Sanitation Foundation) to create a new standard. It aims to minimise wastage by keeping the cold chain within the validated range of a specific vaccine to ensure its effectiveness, and ultimately protect the public. The NSF brought together a multi-institution committee, including re-presentatives from the CDC, state health department immunisation programmes, non-profit organisations and vaccine storage equipment manufacturers, to define a set of performance standards for specialised vaccine refrigerators and freezers. The group created the new standard, NSF 456-Vaccine Storage, based on the analysis of data from real-life usage within clinics, pharmacies and vaccination sites.3 The new NSF standard details requirements for the performance and safety, as well as labelling of vaccine storage units. For example, it dictates the use of weighted probes that more accurately simulate vaccine vials to evaluate the performance of a unit using a test method designed to mirror typical usage. This assessment includes long and short door-opening sessions as well as closed-door sessions, empty and loaded cabinets, and provides information about where to place the probes. While the standard is currently voluntary, collecting these additional data will help evaluate how the typical use of vaccines in a clinic, hospital wwww.international-pharma.com

or pharmacy will impact the performance of a storage unit, and inevitability the effectiveness of the vaccines within.

of a new era of vaccines for controlling, eliminating and potentially eradicating a host of diseases.

The NSF standard also details specific requirements around the design of units intended for vaccine storage and accompanying documentation. For example, these must be labelled to indicate the usable internal space where vaccines can be stored.

But these vaccines will only be effective if they are able to reach the people who need protection. The current global crisis has highlighted some of the challenges around the rapid and efficient delivery of a largescale vaccination programme; ensuring the integrity of the cold chain is a key step to mitigate the risk of product wastage through unintended exposure to freezing or incorrect temperatures.

Choosing high-performance vaccine storage equipment Even within the specialist vaccine class of refrigerators and freezers that are available from manufacturers today, there are huge variations in product performance, functionality and design intent. Many of these products may not meet the new standard recently developed by the NSF. Previously, specialised vaccine storage refrigerators and freezers were assessed against applicable safety standards used to evaluate and mitigate the risk of electrical shock, casualty or fire hazards. While these are all important points to consider for helping ensure a higher level of safety, such tests do not examine performance, functionality or design intent. Of these, product performance is the most important aspect for protecting vaccines from critical temperature fluctuations that might render them ineffective. The new NSF standard supports providers to identify a unique class of advanced, highperformance refrigerator and freezer designed with the priority of protecting critical products sensitive to temperature variation. These units offer precise temperature controls to ensure uninterrupted storage conditions throughout the internal chambers; helping to reduce the risk of product wastage and ensure the effectiveness of the products stored inside. While the world currently focuses on the rapid deployment of COVID-19 vaccines to mitigate the immediate effects of the current pandemic, the introduction of this new NSF standard will also support longer-term public health goals. Creating a sustainable and efficient cold chain will bring benefits for future vaccination programmes by reducing product wastage; saving costs for healthcare providers and potentially improving access to life-saving vaccines. Creating a sustainable vaccine cold chain The COVID-19 pandemic has catalysed a transformation in the field of vaccines. Huge advances in technologies offer the promise

Many specialist refrigeration or freezer products currently on the market for vaccine storage may not meet the new NSF standard. Choosing certified, fit for purpose coldstorage equipment is crucial for ensuring vaccines are stored within their correct temperature ranges. The new NSF standard is a welcome step forward and will help providers differentiate cold storage equipment that is truly suitable for vaccine storage. This will help reduce product wastage and ensure the effectiveness of vaccines – ultimately protecting the public. REFERENCES 1.

World Health Organisation. (‎2005)‎. Monitoring vaccine wastage at country level: guidelines for programme managers. World Health Organisation. https://apps.who.int/iris/handle/ 10665/68463 2. The U.S. Centers from Disease Control and Prevention Vaccine Storage and Handling Toolkit 3. NSF 456–Vaccine Storage (2021), https:// standards.nsf.org/kwspub/public/stds

Chase Heibel Chase Heibel is the Global Product Manager covering the high performance laboratory and freezer portfolio. He has been with Thermo Fisher Scientific for nine years where he has held multiple roles supporting the scientific and medical cold chains. Based in California, where he received his degree from the University of California, he has supported the scientific instruments and equipment industry for 14 years. Email: chase.heibel@thermofisher.com

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Logistics & Supply Chain Management

How to Approach an NLG Solution in the Pharmaceutical Industry NLG is a section within AI technology that develops solutions to automatically generate natural language – or language spoken and written by humans. NLG platforms can create highquality texts depending on the solution, based solely on Machine Learning (ML) or on the insights gained from data. Use cases for NLG are continuing to expand as more and more companies work to leverage their data. The thinking on NLG is evolving, too. In 2015 Gartner argued that NLG was "the last mile in Business Intelligence" and would succeed as plugins describing graphs in plain language. In contrast, Gartner has a larger vision today, saying, "NLG is useful wherever there is a need to generate text or spoken content from data."

arduous and time-consuming process can potentially delay life-saving medications from coming to market sooner and cost pharmaceutical companies millions. A capacity challenge also exists. Writing a CSR report typically takes several months to complete, limiting the number of CSRs a team of medical writers can produce annually. Some pharmaceutical companies have tried using templates to overcome the manual writing process challenge. However, the templates are too complex and rigid for the different scenarios the CSR encompasses.

Content automation driven by NLG technology connects to the clinical study database and instantly generates HIPAAcompliant, auditable reports that quickly meet regulatory requirements. Centralised control of NLG projects reduces the risk of errors and makes it easy to implement guidelines in all required places. NLG software tools enable you to automate the data-driven sections (instead of producing the whole document). First, you create the first draft leaving the more creative analysis and connections for the medical writers. As a result, AI-powered

As the use cases for NLG multiply and companies begin to deploy it en masse, a framework to evaluate NLG vendors is needed to cut through the rhetoric to determine which vendor is best suited for your use case. There are some additional aspects that to consider internally. Internal preparations are required when introducing such a new technology, as new technology affects both the data requirements and the internal content-creating processes. Clinical Study Reports – An NLG Use Case in the Pharmaceutical Industry Given the pharmaceutical sector's high demand for regulatory documentation, several suitable options for implementing content generation are available. In this context, clinical study reports (CSR) are good examples of the potential and benefits of automation. The most challenging phase of bringing a drug to market is the human drug trial, during which time clinicians must write a CSR that describes the pharmacological impacts and trial outcomes. Typically, medical writing teams gather data from the human drug trials and then manually compile the report. However, this outdated, 92 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Table 1 – Clinical study report scheduling: Cumulative participant dataa from eight EMWA conferences 2008 to 2013b

Pharma companies have started to look for NLG software to see if it can write portions of the CSR. The cost and the overhead of development and deployment were too high in the early years. Today, the situation has changed. New scalable NLG tools that cost a fraction of their older counterparts and are built from the ground up are secure, easy to use and scalable.

content generation software allows pharmaceutical companies to generate regulatory Clinical Study Reports (CSRs) on medications up to 40% faster by automating 30% of CSR writing. Criteria to Evaluate NLG Solutions 1. Data-to-Text Versus Machine Learning The headlines around NLG mostly describe Autumn 2021 Volume 13 Issue 3

Logistics & Supply Chain Management the unique ability of the new large language models to create text from a line of reference to a specific author, that sounds exactly like the original, or to write a text on a particular topic on its own. In fact, in the field of these models that can generate language via Machine Learning, a vast amount of progress has been made in recent years. What these language models can do is essentially predict the next word depending on learned linguistic patterns. The results often sound remarkably coherent, and grammatically, they are correct to a high degree. A purely Machine Learning-driven NLG is what I call a "black box" technology, which means that advanced algorithms analyse the data and reach a conclusion that the user doesn't understand and which the software can't explain in the written text. There is no way to incorporate your data into these models. In contrast, the texts of the data-to-text solutions utilise the imported data. The statements in these texts derive from the data. The first milestone for choosing the right solution is to ask about Machine Learning. Although solutions with the ML approach are the most recent stage in technology, they are still in an experimental phase. For documentation purposes, where controllability is a significant factor, a pure Machine Learning approach is entirely unsuitable. The most advanced NLG solutions employ a hybrid approach. They use Machine Learning to suggest data analysis rules, which a human user approves of or rejects. This hybrid approach speeds up development time and also ensures the written text is fully traceable. Traceability is critical to show why the data analysis advice was given, and so the software can explain why as well. 2. Ability to Scale You aren't buying technology for your business as it is right now; you're buying for the future as well. If the tech works for you the way you hope it will, you will want to scale it up. That means going from a few users to a thousand or more, depending on your business. The worst possible outcome would be to find a great use case and technology – only to discover after deployment that the technology cannot scale to meet your business needs. 3. Is the NLG Software Self-Service? Self-service has become a sort of buzzword wwww.international-pharma.com

with lots of companies saying "we offer a self-service" solution, but you need to understand what they mean by this. Eventually, you will want to be able to build and edit applications yourself. It isn't scalable to rely on a third-party software company or one of its partners to build all of your applications. It would be best if you managed these projects yourself to deploy the tool across the organisation. There is also a cost element here. If you have to call a third party every time you need to change an application, the costs will skyrocket. Ask the NLG vendor for a free trial of their software. You likely won't progress too far in that free trial without training. If the NLG vendor can't even offer you a free trial, then you should disqualify them. And, even if you don't plan on creating or maintaining the tool yourself, self-service access to all layers of the NLG setup is vital to avoid lock-in with single partners. If partners get different access levels, a business decision on switching to another managed service provider will be impossible to execute. 4. Multiple Users Eventually, you will need multiple users to work on the same primary application, so the number of users working simultaneously in the application is critical if you want to scale up. For example, you will have a scientist inputting rules relating to the research results for one section and a technical writer working on the text in the next paragraph. Multiple concurrent users are critical in all modern enterprise software. Surprisingly, this feature is not widely available among NLG "self-service" vendors, implying the need for publishing/versioning workflows. You should be able to define a continuous delivery and -testing architecture for your application. 5. Numbers of Reports Run at the Same Time How many reports have you run at the same time? Again, this is a scale question. You need to understand at what point the software becomes overloaded and slows down. Look for specific numbers here, not vague statements. They should be able to say on such a server that the software has run up to X amount of reports simultaneously, or you can test it with a certain number of requests per second. 6. Service Level Agreement Service Level Agreements (SLAs) are also an essential factor in assessing the scalability of an application. Promises on availability and reliability should be available as Service Level Agreements for business applications.

While you might not want to pay extra until it achieves business criticality, the vendor should have standardised documentation and contracts available. Publicly shared application status pages with a history of past incidents are a de-facto standard in the SaaS world and should be available. 7. Security Security is the number one concern of pharmaceutical companies, but it isn't always front and centre in the NLG space. According to the Gartner Market Survey, most NLG vendors offer cloud, on-premise or hybrid solutions. Gartner, however, does not discuss vendor security approaches. Security is of the utmost importance in two of the largest markets for NLG: Financial Services and Pharmaceuticals. If your NLG vendor's software is non-compliant - or worse, open to hacking - you will expose highly sensitive data that could cost your company huge sums of money in fines. Some NLG vendors lack any security processes and attempt to bypass this by pushing for on-premise installation. Onpremise deployment doesn't equal security, so it's imperative to check certifications and partnerships with leading cloud providers along with on-premise ability. 8. Input Data and Integration The point of NLG projects is to put your business's data to work for you, or at the very least to automate away data-driven writing. You must understand what types of data an NLG software requires and in what format. It is critical because some NLG vendors need a very static input, which can create a tremendous amount of work on your side before the NLG project can even get started. Ask to see how the software connects to a dataset. If the vendor can't show you how it connects to a dataset, then you should disqualify that vendor. Integration doesn't just mean connecting to your data; you also need to think about where you would like the narrative generated and what integration might entail. Again, if there is an integration cost, who pays for it, and how long will it take? 9. Multiple Languages The Pharmaceutical industry is global in many cases. Medical writers must write reports in multiple languages due to English being the dominant language of business. If an NLG vendor only works in one language, you should disqualify them. Multilingual ability is critical for your long-term use of NLG if you work in a large enterprise. While many providers offer multiple languages, INTERNATIONAL PHARMACEUTICAL INDUSTRY 93

Logistics & Supply Chain Management they are not always immediately available. For this, you have to check if they already have grammar rules for relevant languages encoded in their software. 10. What Internal Work Do You Need to Do Before Choosing An AI Vendor? The truth is there are quite a few steps you need to take internally. A good AI vendor will bring these points up early in the conversations with you about their technology. It is not a comprehensive list, of course, since different AI use cases require different steps, but it should spark ideas of internal steps you need to take. 11. NLG Solutions Require Configuration The truth is Natural Language Generation requires configuration for each use case you have in mind. There is no magic 'plugand-play' NLG. Some vendors will sell preconfigured applications, but those still require configuration. Suppose you want those applications to use your business's means of analysis or your business's language and way of writing? In that case, these off-theshelf applications will need to be rebuilt and reconfigured. 12. NLG Projects Require Integration You will need your NLG application integrated into your tech stack. There will also be work to do to connect your data sets to the NLG software. Some NLG vendors are much more advanced than others when it comes to connecting to data. 13. Identify Internal Stakeholders and Initiate Change Management Process AI and ML projects often cut across departments involving more than the line of business with the use case in mind. Every department will have different concerns and questions. Ahead of speaking with vendors, it is best to talk with all stakeholders to understand what their hopes and concerns are around the project. You can use those conversations to build a list of questions and a matrix to evaluate vendors. Finally, even if you are using self-service tools, you might need specific certifications or some of their staff to sign specific agreements. Specific certifications vary greatly depending on the use case and even by company, so it is best to do your homework before talking to a vendor. Many people imagine AI as something very different from what it truly is. If you expect your teams to use AI every day, you will need to go through a change 94 INTERNATIONAL PHARMACEUTICAL INDUSTRY

management process to ensure the tech's adoption and alleviate any concerns. 14. Check the Data Quality The importance of data quality is critical. Let's say you want to automate the CSR. If so, you need all of the clinical data in a structured format. Sometimes, companies believe they have this data, but they find the data isn't as structured as they thought when digging into their internal processes. For this reason, it is best to understand the quality of your data very early on so you can ask the AI vendors you are vetting if your data will work or not. If not, you will have to work with conventional data wrangling tools to build coherent databases. 15. Check Patient Confidentiality Issues Frequently the data you are using for your AI projects is incredibly confidential. Even with the most confidential data, there are ways to avoid breaches. For example, you could anonymise the data or work with a stateless solution, meaning it doesn't keep a copy of the data. Summary Conclusion Globally, NLG is the logical next step in the digitalization of the enterprise. Companies have invested in data collection, storage and visualisations. Still, the next big change will focus on data-driven decision-making across the company and the elimination of human-conducted repetitive tasks. NLG

addresses these two new challenges since it can simultaneously automate repetitive writing tasks and empower everyone in an organisation to make data-driven decisions. After all, with NLG, all employees need to do is click, read – and then act. Source https://journal.emwa.org/regulatory-writingbasics/effective-authoring-of-clinicalstudy-reports-a-companion-guide/

Robert Weissgraeber Robert Weissgraeber is the Managing Director and CTO of AX Semantics, where he heads up product development and engineering. Robert is an in-demand speaker and an author on topics including agile software development and Natural Language Generation (NLG) technologies and a member of the Forbes Technology Council. He was previously Chief Product Officer at aexea and studied Chemistry at the Johannes Gutenberg University and did a research stint at Cornell University. Email: robert.weissgraeber@ax-semantics.com

Autumn 2021 Volume 13 Issue 3

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YOUR SECURE SUPPLIER FOR TAMPER EVIDENT SEALING WITH SUSTAINABLE PRODUCTS The PAPER-based security seal with VOID technology is now available!

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• Works on almost all cardboard surfaces • Underlying text and printed codes remain legible • Compliant with FMD safety requirement • Serialisation of each individual product • 'One package - one material' - this way you improve the recycling process and make a positive contribution to the recycling management • Paper seals are produced from renewable raw materials

Our seals are easy to understand multifunctional security locks against tampering and counterfeiting. They are used and tested on pharmaceutical packaging worldwide.

Visit us at Pharmapack Paris, October 13 & 14, 2021 Hall 7.2, Booth E24

Autumn 2021 Volume 13 Issue 3

98 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2021 Volume 13 Issue 3