Pharma Focus Asia - Issue 46 by Ochre Media Pvt. Ltd.

ISSUE 46

2022

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IMCD A global leader in

speciality chemicals and ingredients

PAUL MIMNAGH

Business Group Director Pharmaceuticals, Asia Pacific

Driven by Data A roadmap to biopharma’s digital future 2022 Trends in Pharma Marketing

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Indian Pharma Innovation paves the way for growth The Indian pharma industry has played a crucial role in supporting the global battle against the COVID-19 pandemic by supplying essential drugs and vaccines. The country’s pharma export figures at US$24.44 billion in FY21 are a testimony to the industry’s contribution in serving patient needs across the globe. India currently stands third in pharmaceutical production by volume and 14th by value, ably supported by lesser production costs, abundant skilled workforce and robust R&D infrastructure. India supplies over 40 per cent of generics to the biggest pharma market, the US, 25 per cent of prescription drugs to the UK, and catering to over 60 per cent of the global vaccine demand. It is no surprise that the pandemic has pushed several industries toward innovation and more for the life sciences industry, which is the epicentre of improving and saving lives. At the Global Innovation Summit 2021 for Pharma, held in November 2021, leaders unanimously indicated that the Indian pharma industry is headed to be a global leader propelled by innovation, partnerships, and improving regulatory support. Moving beyond generic drugs to build successful innovative products is driving investment growth and prioritisation. As we have witnessed in the last couple of years, COVID-19 created unprecedented challenges. The global life sciences and healthcare industry rose to the occasion to develop vaccines and drugs in a very short span. Building a culture of innovation primarily depends on strengthening collaboration between industry and academia, creating world-class facilities for researchers and scientists to come up with future-focused drug development. Backed by a strong formulation development capability and its strong presence in the leading

markets such as North America and Europe, India has clocked US$41 billion in revenue for the year 2021. Experts believe this figure is expected to touch US$130 billion by 2030. This depends on how well the industry builds on its R&D capabilities and the implementation of digital technologies that heralded a change in the healthcare continuum. The industry is focused on creating an innovation ecosystem with government support to develop innovation hubs, simplifying regulatory and compliance procedures, providing essential funding and driving initiatives that incentivise innovation. Companies will be looking to embrace digital technologies at scale transforming their businesses, driving efficiencies, improving agility to support the global healthcare needs. From depending on imports in the past to becoming a leading exporter, it has been a long journey the journey for Indian pharma on the global roadmap. The future of Indian pharma depends on the industry’s ability to accelerate innovation, focus on smart manufacturing leveraging the technology advancements and forging ahead to be the global life sciences hub. Hope you enjoy reading the articles covered in this issue. Please provide your valuable feedback to prasanthi@ochre-media.com.

Prasanthi Sadhu Editor

CONTENTS STRATEGY 06 2022 Trends in Pharma Marketing Arnold Leung, Founder & CEO, Appnovation

COVID-19 Where are we heading in 2022? Kenneth Lundstrom, PanTherapeutics

COVER STORY

IMCD A global leader in speciality chemicals and ingredients

Bright Future for Asia M&A Motonori Araki, Partner, Tokyo Todd Liao, Partner, Shanghai Joo Khin Ng, Partner, Singapore Billy Wong, Partner, Hong Kong Nancy Yamaguchi, Partner, San Francisco Morgan, Lewis & Bockius’s Global Life Sciences Industry Group

CLINICAL TRIALS 24 The Aggregate Safety Assessment Plan A valuable tool for clinical trial safety planning Barbara A Hendrickson, Immunology Therapeutic Area Head, Pharmacovigilance and Patient Safety, AbbVie

Paul Mimnagh Business Group Director, Pharmaceuticals, Asia Pacific

50 Mathematical Modelling of Gene Expression A toolbox for treatment design targeting modulation of gene networks dynamics Alexandre Ferreira Ramos, School of Arts, Sciences and Humanities University of São Paulo, São Paulo Guilherme Giovanini, School of Arts, Sciences and Humanities University of São Paulo, São Paulo

MANUFACTURING 35 St.Gallen OPEX Benchmarking for Pharmaceutical Manufacturing Sites Measure yourself against the best but do it right Grothkopp, M., Pirrone, L., Friedli, T University of St.Gallen

40 Vaccines Against SARS-CoV-2 Current situation and future perspectives Ger Rijkers, Science Department, University College Roosevelt, Microvida Laboratory for Medical Microbiology and Immunology, St Elizabeth Hospital

44 Proposome, an Efficient and Safe Topical Formulation Himanshu Kathuria, Department of Pharmacy, National University of Singapore Lifeng Kang, School of Pharmacy, Faculty of Medicine and Health, University of Sydney

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INFORMATION TECHNOLOGY 54 Driven by Data A roadmap to biopharma’s digital future James Choi, Executive Vice President and Chief Information & Marketing Officer and head of Global Public Relations and Process Improvement, Samsung Biologics

RESEARCH INSIGHTS 58 Vaccine Equity A fundamental imperative in the fight against COVID-19

SPECIAL FEATURE 13, 49 Books

Advisory Board

EDITOR Prasanthi Sadhu Alan S Louie Research Director, Life Sciences IDC Health Insights, USA

EDITORIAL TEAM Grace Jones Rohith Nuguri Swetha M

Christopher-Paul Milne Director, Research and Research Associate Professor Tufts Center for the Study of Drug Development, US

ART DIRECTOR M Abdul Hannan PRODUCT MANAGER Jeff Kenney Monica James

Douglas Meyer Associate Director, Clinical Drug Supply Biogen, USA

SENIOR PRODUCT ASSOCIATES Ben Johnson David Nelson John Milton Peter Thomas Sussane Vincent

Frank Jaeger Regional Sales Manager, AbbVie, US

PRODUCT ASSOCIATE Veronica Wilson

Georg C Terstappen Head, Platform Technologies & Science China and PTS Neurosciences TA Portfolio Leader GSK's R&D Centre, Shanghai, China

CIRCULATION TEAM Sam Smith SUBSCRIPTIONS IN-CHARGE Vijay Kumar Gaddam

Kenneth I Kaitin Professor of Medicine and Director Tufts Center for the Study of Drug Development Tufts University School of Medicine, US

Laurence Flint Pediatrician and Independent Consultant Greater New York City

HEAD-OPERATIONS S V Nageswara Rao

A member of

In Association with

Confederation of Indian Industry

Neil J Campbell Chairman, CEO and Founder Celios Corporation, USA Phil Kaminsky Professor, Executive Associate Dean, College of Engineering, Ph.D. Northwestern University, Industrial Engineering and the Management Sciences, USA

Rustom Mody Senior Vice President and R&D Head Lupin Ltd., (Biotech Division), India Sanjoy Ray Director, Scientific Data & Strategy and Chief Scientific Officer, Computer Sciences Merck Sharp & Dohme, US

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Magazine Subscribe Stella Stergiopoulos Research Fellow Tufts University School of Medicine, USA 4

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EXECUTIVES SPECIAL ISSUE 56 APRIL 2022

A special issue designed to focus on a theme or a sector trend. This issue is aimed at facilitating the industry leaders share perspectives and insights with our readers on key issues impacting and influencing the industry. The issue would also cover a few articles on trending topics in the healthcare industry.

If interested in contributing, please reach out to prasanthi@ochre-media.com or gracejones@ochre-media.com

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STRATEGY

2022 TRENDS IN PHARMA MARKETING The pandemic has prompted pharmaceutical companies and healthcare providers to rethink the way their businesses operate, including how the use of technologies and digital solutions can improve the customer experience. This article explores the top trends in 2022 to help devise the best digital strategies for pharmaceutical brands to stay competitive. Arnold Leung, Founder & CEO, Appnovation

t’s been nearly two years since the outbreak of COVID-19 began and we’re still in the midst of enormous disruptions to the world’s economies, businesses, education, and people’s lives. The pharmaceutical industry has been particularly disrupted. Previously, pharma companies suffered from a bad reputation. But following the emergence of the pandemic, they were thrown into the spotlight, suddenly having an important voice on the health of the world. Leaders in the pharma space were on the

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STRATEGY

to support early diagnosis and alternative treatments. However, this needs to be paired with a framework for managing data, and the privacy and security implications that come with it. Yet, for those who are unwilling to take the first step and make the shift, they will eventually lose customers, profit and market share.

TREND 1: Patient-centricity

front cover of every newspaper and magazine not because of scandal, but because of the lifesaving treatments they created. Media were hungry for their opinions on the best way to secure the health of the population amidst the global pandemic. Patients used to be unaware of who manufactured the drugs that they take. Now, they are able to refer to pharmaceutical brands by name. This gives them a new and unique opportunity to engage directly with the patients whose lives they impact, something pharma brands have been challenged with previously. How pharmaceutical brands do this is the basis for the following 2022 Trends in Pharma Marketing. Thanks to their important role in securing our health amidst the pandemic, digitisation strategies are no longer nice to haves for pharma companies, but must haves. In 2022, pharma brands must take the lead in understanding their customers better, including their current needs and future expectations of healthcare services, in order to create a meaningful and beneficial health journey for their patients. Here are three biggest digital pharma trends for 2022.

In the past, a seamless digital experience was considered the benchmark, but now it has become table stakes. With increasing digital disruption across a variety of industries, companies are revamping their existing businesses and operating models in order to stay competitive amidst the digital revolution. However, the ability to pivot with speed and accuracy to changing market dynamics without compromising experience isn’t just a function of technology alone. It requires every individual in the organisation to embrace agile practices and be inclined to test and learn. Pharma industries are no different. Pharmaceutical companies need to take note when marketing their drugs – patients today require a more diversified approach to addressing their health problems. Mobile technologies, social media, the cloud, wearables and the Internet of Things (IoT) are just some of the realities that are disrupting healthcare today – and is the key to enabling a patient-centric approach. What’s more? Investment in technologies to leverage the power of big data is now a prerequisite. That is indeed the only way to collect and appropriately utilise valuable insights from the vast and unmanageable pools of data currently out there in the health IT ecosystem. In fact, some healthcare systems are already integrating datasets across the consumer or patient journey — from arrival at a hospital to check-ups, hospitalisation, treatment and hospital discharge — in order to enhance holistic care and management, not only reducing the need for long hospital stays but also

TREND 2: Personalisation in healthcare solutions It is undeniable that the convergence of digital technologies is helping us lead longer, healthier and more empowered lifestyles. In Asia, in particular, the increasing awareness around health and wellness is giving rise to a diligent, discerning type of consumer class – one that is demanding more participatory, personalised and innovative approaches to healthcare. Apart from this, it is evidenced that the pandemic has accelerated the need for healthcare to be delivered anytime, anywhere and ‘digital first’. The region has also seen strong growth in innovative technologies such as telemedicine, digital therapeutics and remote monitoring over the past few years. For instance, Ping An Good Doctor, a Chinese healthcare services platform, and MyDoc, a telemedicine platform headquartered in Singapore, have more than doubled their active users since 2020; China has repurposed an artificial intelligence model that was used to detect cancer to help isolate and diagnose potential COVID19 patients in under 10 seconds. In reality, the entire healthcare ecosystem was already ripe for change. Even before the pandemic, the market was beginning to expect more from healthcare providers. Patients want to be more involved in decision-making, demanding transparency and personalisation – something they’ve grown accustomed to in industries like retail. Unarguably, there has never been a more important time to focus on health. Consumers in Asia are increasingly embracing the use of sensors,

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STRATEGY

wearables, smart devices that continuously track everything from vital signs, sleep patterns, caloric intake and activity levels to provide a rich, real-time behavioural personal profile. Healthcare providers and organisations that are able to seize the opportunities to recognise, engage and reward consumers throughout their journeys will be able to drive improved outcomes and larger benefits from strengthened relationships. On the other hand, with a rapidly ageing population and rising lifestylerelated chronic diseases such as diabetes, obesity and hypertension1, Asia-Pacific will represent more than 40 per cent of the growth in global healthcare spending over the next decade. Meanwhile, consumers are expecting more from healthcare players: more innovation, collaboration and solutions from healthcare providers for lowering costs and solving complex healthcare challenges.2 Research has found that 77 per cent of consumers have very clear expectations on personalised preventive care from primary healthcare providers. The shift towards personalisation is evident, along with concerns about access to care and rising costs, healthcare providers and pharma brands are left with no choice but to catch up as soon as possible. In addition, studies reveal that the region is home to a burgeoning techsavvy, middle class that is wellnessoriented and outcome-driven whereas the Asian consumer is both demanding and driving a seismic shift on how healthcare is to be delivered and experienced. This will ultimately create opportunities for new entrants from other industries to democratise, decentralise and deliver health in new meaningful ways to consumers across the value chain. Advances in medical science, data and technology combined with reduced cost of genomic sequencing technolo1 https://www.bain.com/contentassets/a1d1395b809d424a8db679657f95b19d/bain_report_asia-pacific_ front_line_of_healthcare.pdf 2 https://www.bain.com/contentassets/a1d1395b809d424a8db679657f95b19d/bain_report_asia-pacific_ front_line_of_healthcare.pdf

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gies has also given rise to the delivery of personalised healthcare and precision medicine tailored to individual genetic, behavioural and environmental information. Singapore for example, is ranked as the highest performer in the region for personalised healthcare readiness, as ranked by Personalised Health Index, developed by Roche and Copenhagen Institute for Future Studies. In a nutshell, the convergence of these prevailing trends has altogether created an environment for highly proactive, personalised and preventative healthcare solutions.

TREND 3: Changing relationships between healthcare providers and patients Healthcare has traditionally conjured up the image of a ‘patient’ – passive and dependent on their physician for treatment of their disease. In the more recent years, this view has shifted dramatically to that of a ‘consumer’ — one that is proactive, independent, highly discerning of wait times, costs, quality and seeks to proactively manage their health. The rise of this highly informed, empowered consumer class has fundamentally altered the physician-patient relationship. Armed with data from a variety of sources, consumers are expecting more involvement, more choices and control over decision making and seek to be engaged as partners and collaborators in their health journey. The pandemic in addition, has heightened consumer awareness and accelerated their desire to take ownership in managing their health, lifestyle and wellness. In addition, Asia-Pacific is home to 60 per cent of the world’s population and is the fastest-growing digital economy. It is poised to become the world’s largest consumer market in the coming decade. Also, studies foresee a major paradigm shift in the healthcare industry in the years to come.3 By 2025, APAC is expected to account for 60 per 3 https://www.brookings.edu/wp-content/uploads/2017/02/ global_20170228_global-middle-class.pdf

cent of the global middle class, up from 46 per cent in 2015. The increase in numbers and the fact that it is also the fastest-growing digital economy paints a clear picture of this consumer group. They will be savvier, know more, have more power and will demand both quality and value-for-money in general. From healthcare providers, they will expect easy access to information, seek consultations, diagnoses and treatments that prioritise their lifestyle,4 preferences and needs. For instance, consumers expect to increase their use of digital health services significantly in the next five years, such as telemedicine, selfdiagnosis app, online pharmacy, health/ life insurance app, etc. A study revealed that, thirty years from now,5 85 per cent of the two billion people who will be over the age of 60 will expect to be more involved and empowered in decisions that manage their health. However, most of the pharmaceutical industry is not yet prepared for how they’ll deliver value in a digitalfirst world driven by preventative care. Unfortunately, the traditional pharma marketing playbook isn’t in tune with today’s way of thinking. Without a forward-thinking strategy that’s designed to meet the needs of a new world of patient-centric and outcome-based personalised care, the road ahead could only get tougher. While trusted clinician relationships will remain central to the ideal healthcare experience, engaging consumers and patients on their terms, and on channels and touchpoints of their choice as they go through their healthcare journey will become the critical differentiator in an increasingly competitive market. Organisations that holistically map their consumer’s end-to-end healthcare journeys as they connect the dots between their lifestyle, technology, wellness and 4 https://www.bain.com/contentassets/a1d1395b809d424a8db679657f95b19d/bain_report_asia-pacific_ front_line_of_healthcare.pdf 5 https://extranet.who.int/agefriendlyworld/wp-content/ uploads/2014/06/WHo-Global-report-on-falls-preventionin-older-age.pdf

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companies who come out on top will be the ones who find innovative and holistic ways to build trust and loyalty by providing meaningful value to custom-

ers through their personal health care experiences. And they’ll be miles ahead of their competition who lag in embracing accessible digital solutions.

Arnold is the founder and CEO of Appnovation, a global digital consultancy. Arnold started Appnovation in 2007 in Vancouver after his graduation from the University of British Columbia’s Sauder School of Business. Since then, he has been leading the company’s strategic vision and business growth across 16 offices around the world, including US, Canada, Europe, Singapore and HK.

AUTHOR BIO

quality of life to deliver tailored engagement and interactions will win the heart and minds of these consumers.6 With 50 per cent of physicians and consumers ready to adopt innovative technologies in the next 5 years, healthcare organisations and providers in Asia need to improve and innovate the ways in which they are delivering value to consumers of the future. These innovative technologies include personalisation, remote monitoring, telehealth, AI and predictive analytics that can offer opportunities to improve the relationship between consumer and healthcare provider, whereas the real value will be driven through seamless integration and orchestration of the end-to-end experience and solidified through trusted consumer-clinician relationships. Healthcare organisations that can deliver this, through smart technology utilisation will benefit not just from increased patient outcomes, loyalty and satisfaction, but also see increased efficiencies and improvements in operating models. In fact, healthcare organisations in Asia Pacific are already transforming themselves into scaling, innovation hubs and adopting Agile and Design Thinking methods to rapidly deliver solutions for evolving consumer needs and behaviours across the value chain. Pharma companies on the other hand are recognising the opportunity to collaborate with consumers and their health providers as valuable partners in their personal health journeys, while adopting technology, user experience design and data analytics which are able to provide a solid foundation for building personalised long-term connections with patients and health providers. The goal, undoubtedly, is to foster and enable patient education and preventative care. No matter which tactics are used, the pharmaceutical 6 https://www.bain.com/contentassets/a1d1395b809d424a8db679657f95b19d/bain_report_asiapacific_front_line_of_healthcare.pdf

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Responsible Growth

Sustainability highlights at Aragen Sustainability today is an important agenda for most organisations globally. Across the board, organisations are increasingly realising that sustainability is a critical parameter to define competitiveness and gain the trust and confidence of all stakeholders. So, what is sustainability? It means meeting our present needs in such a way that we don’t compromise on the future generation’s ability to meet theirs. For an organisation, it is an approach for creating long-term value for stakeholders from an economic, social and ecological perspective. Aragen is a trusted R&D and manufacturing partner to the global life sciences industry. Our purpose – ‘in every molecule, is the possibility for better health’ inspires thousands of our employees to transform ideas into solutions for better health; be it for humans, animals, or plants. Since its inception 20 years ago, Aragen, formerly known as GVK Bio, has continuously expanded its service offerings. Today we are a leading R&D and manufacturing solutions provider serving

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• Submitted letter of intent to the Science Based Targets initiative (SBTi) • Signatory to the GRI South Asia Charter on Sustainability Imperatives • Bronze medal from EcoVadis, the world’s largest and most trusted provider of business sustainability ratings • 9.7 million man-hours of operations without loss-time injury • 6074 MT reduction in CO2 emissions due to renewable energy consumption • 11.16% of the total energy consumption is from renewable sources (green energy) • 223 MT hazardous waste disposed in an environment-friendly manner • 3886 MT hazardous waste recycled • 32489 KL fresh water conserved

clients in the pharmaceutical, biotechnology, nutrition, agrochemicals, animal health, consumer goods and specialty chemicals sectors. While we provide innovative scientific solutions to our customers, we are also committed to doing it in a safe and sustainable manner to minimise the potential impact on the environment and ensuring health and safety of our stakeholders. Sustainable development is an integral part of Aragen’s long term business strategy. By integrating environment, health, safety and sustainability management into one unified program, we strengthen the foundation for compliance, consistency, and continuous improvement. At Aragen, sustainability is not an isolated responsibility but a collective commitment across the organisation. We have imbibed it into every aspect of our operations – following principles of green chemistry in labs and manufacturing facilities, sustainable sourcing, green supply chain, employee wellness and health, community engagement, following good governance practices, ensuring compliance with regulatory requirements, and integrating best global EHSS practices. By continuously reducing carbon footprint, recycling and reusing resources, increasing use of renewable energy, minimising waste generation, and responsible waste elimination, we aim to create a better and healthier tomorrow while helping our clients develop better and more effective products faster. Our teams continuously adopt and implement global best practices in water and energy conservation, wastewater treatment and creating a safe workplace. Continuous process improvement initiatives and adopting operational excellence tools and techniques have helped us reduce overall waste generated across our operations. During FY21, we disposed 240 MT of hazardous waste in an environment-friendly manner and recycled 3945 MT waste. Use of different types of electrodes such as graphite SK-50, glassy carbon, platinum-plated and RVC helps in conducting oxidation and reduction reactions without generating metal waste. Using carbon dioxide as an eluent, our scientists minimise the use of solvents which reduces the consumption of electricity. Use of flow technology enables high temperature and high-pressure operations in a safe manner, improving process efficiency and yield and providing better control on impurities. Not just in our operating facilities but even in our supply chain and logistics operations we are implementing principles of sustainability. Being a member of the Global Pharmaceutical Industry Principles for Responsible Supply Chain Management (PSCI Principles), we voluntarily support and endorse

Aragen’s SDG focus areas: • • • • • •

Good health and well-being Gender equality Decent work and economic growth Responsible consumption and production Climate action Partnerships for the goals

our key suppliers and service providers to align with PSCI Principles. We have integrated and applied the PSCI principles in our business processes within the context of our core value “Safety and Compliance Always” and EHS Policy. Aragen has implemented ISO 50001:2018 certified Energy Management System and has defined short and long-term targets for improving energy efficiency and increasing use of renewable energy in operations. A three-tier team, with cross functional representations and headed by Plant, Production, and Engineering heads, has been constituted to implement various activities and oversee the progress on these targets. Over the past few years, we have steadily increased the use of renewable energy in our total energy consumption. Our total renewable energy consumption is 11% of total energy consumed, an increase of 6 % since FY2018-19. We have also achieved a reduction of 6,074 MT CO2e reduction in green house gas (GHG) emissions by implementing various green initiatives. Our operations are heavily dependent on water consumption. At the same time, we are also conscious of the need to conserve this precious natural resource. Aragen is committed to reducing freshwater consumption to the extent possible by increasing

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the proportion of recycled water usage. Some of the measures to reduce water consumption include installation of efficient water fixtures to reduce wastage/ leakage, facility design based on flowrate, stormwater collection tanks, enhanced steam condensate recovery systems, CTI certified and VFD installed cooling towers. Through these and other recycling and reuse initiatives, we have conserved 32,489 KL fresh water. Aragen operates zero-liquid discharge water treatment plants to reduce the company’s carbon footprint and increase operational sustainability. Aragen has submitted its letter of intent to the Science Based Targets initiative (SBTi) and is part of a growing list of organizations that are committed to setting emission reduction targets in line with the Paris Agreement to limit global warming. It is also a signatory to the GRI South Asia Charter on Sustainability Imperatives, a framework that helps to realise the 17 Sustainable Development Goals (SDGs) defined by the United Nation. We have identified six SDGs as our focus areas and have planned several initiatives to work towards these goals. These are good health and well-being, gender equality, decent work and economic growth, responsible consumption and production, and climate action. Our CSR activities are aligned to these SDGs and focus on education, community support, helping the differently abled, providing medical care, sanitisation, safe drinking water, environmental sustainability and conservation

of natural resources, promoting gender equality and nurturing sporting talent. Besides conducting voluntary tree plantation drives within and in the vicinity of all our campuses, we also regularly support the local administration in their green drives. As a part of this, we have developed parks and green belts in Begumpet area in Hyderabad and Bommasandra in Bengaluru. Ongoing campus initiatives include awareness programs on the reduction of single-use plastic, food wastage in the cafeteria, and water conservation. Our sustainability initiatives have also earned us recognition from the industry. The manufacturing unit and research laboratory at Nacharam campus in Hyderabad have been awarded Green Company – Silver rating by CII. We have also received the bronze medal in Ecovadis global sustainability assessment. To summarise, sustainability at Aragen is not merely responding to the need of the hour but is a sustained, long term commitment to hold ourselves socially, environmentally, and economically responsible. Our sustainability initiatives are based on three pillars - business growth, social development and environment protection. We will continue to strengthen our sustainability initiatives such that we meet the expectations of all our stakeholders – be they customers, investors, employees, community or the environment.

AUTHOR BIO

Shivaji Dashrath Jadhav VP & Head, EHS & Sustainability Aragen Life Sciences Shivaji Jadhav is responsible for driving EHS and sustainability across Aragen. He has 25+ years of experience across pharmaceutical and chemical manufacturing industries, with expertise in EHS management, process safety management, regulatory compliance, emergency management and risk mitigation.

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BOOKS

The Vaccine: Inside the Race to Conquer the COVID-19 Pandemic

The War on Drugs: A History

Real-World Evidence in the Pharmaceutical Landscape

Author: David Farber

Author: Joe Miller, Uğur Şahin, Özlem Türeci

Year of Publishing: 2021

Author: Sunil Dravida , Abhishek Dabral , Jugal Sharma

Year of Publishing: 2021

No. of Pages: 372

Year of Publishing: 2021

No. of Pages: 332 Shedding a light on the science behind the breakthrough, The Vaccine tells the story of the trailblazers who led the fightback against Covid-19, whose discoveries could now help the world tackle cancer, along with many other pervasive diseases. It draws back the curtain on one of the most important medical achievements of our age, containing contributions from the fascinating couple themselves, as well as more than 60 scientists, politicians, public health officials, and BioNTech staff. More suspenseful than a novel, this is a real-life story of an extraordinary race against time to save the world.

No. of Pages: 304 By analyzing the key issues, debates, events, and actors surrounding the War on Drugs, this timely and impressive volume provides a deeper understanding of the role these policies have played in making our current political landscape and how we can find the way forward to a more just and humane drug policy regime.

In Real-World Evidence in the Pharmaceutical Landscape, life science industry experts Sunil Dravida and his co-authors have developed the first comprehensive overview of its kind on Real-World Data (RWD) in the pharmaceutical industry. The authors examine the challenges and opportunities in applying real-world data along the pharmaceutical continuum, from clinical development to medical affairs, health economics and outcomes, and marketing. They address the difficulties identifying the suitable data sources, ensuring compliance with privacy, security and regulatory requirements, and the big job of translating data into Real-World Evidence (RWE) to generate meaningful insights that can improve decision making by stakeholders and measurable outcomes that can enhance people’s health and well-being. www.pharmafocusasia.com

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WHERE ARE WE HEADING IN 2022? COVID-19 has caused medical, social, and economic havoc globally and triggered an unprecedented development of therapeutics and prophylactics for its eradication. Difficulties in vaccine distribution and acceptance and new potentially more transmissible SARS-CoV-2 variants have slowed down the progress. The prospects of COVID-19 for 2022 and beyond are discussed here. Kenneth Lundstrom, PanTherapeutics

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OVID-19 has posed an unprecedented threat to the health and economy globally since its first detection in December 2019 with more than 435 million cases and 5.9 million deaths (as of February 27, 2022). The impressive co-operation between academic institutions, pharmaceutical and biotech companies, and governmental organisations has resulted in never-before-seen progress on many fronts. Especially, vaccine development has been swift with the Emergency Use Authorization (EUA) of both adenovirus- and mRNA-based vaccines and the FDA approval of the BNT162b2 mRNA vaccine in August 2021. The development of efficient antiviral drugs has turned out to be more difficult. For this reason, one approach has been to develop repurposed drugs, previously approved for viral and tropical diseases.

STRATEGY

Vaccine development so far

The mRNA-based BNT162b2 (Pfizer/ BioNTech) and mRNA-1273 (Moderna) SARS-CoV-2 vaccines both express the SARS-CoV-2 Spike (S) protein as the antigen. Good safety and protection have been achieved in animal models and 95 per cent and 94.1 per cent vaccine efficacy, respectively, obtained in clinical trials (Polack et al., 2020; Baden et al., 2021). Today, a third vaccination dose has been recommended and also executed in several countries due to waning of immune responses with time and the appearance of novel potentially more transmissible and virulent SARS-CoV-2 variants. In the context of adenovirusbased SARS-CoV-2 vaccines, four vaccine candidates all based on the delivery of the full-length S protein have received EUAs in at least some countries (Lundstrom, 2021). The ChAdOx1 nCoV-19 (AstraZeneca/University of Oxford) is based on a chimpanzee adenovirus and requires two immunisations to reach vaccine efficacy (Voysey et al., 2021). In contrast, a single dose of the Ad26. COV2.S (Johnson & Johnson/Jansen Pharmaceuticals) vaccine based on the human adenovirus serotype 26 provided strong immune response and protection in clinical trials (Sadoff et al., 2021). The Russian made Sputnik V vaccine rAd26-S/rAd5-S utilises a strategy of prime vaccination with an adenovirus serotype 26 vector followed by a booster vaccination with the adenovirus serotype 5 to avoid immune responses against the adenovirus vector, which can reduce expression levels and immunogenicity (Logunov et al., 2021). Finally, the Ad5-S-nb2 (CanSinoBIO) vaccine candidate based on the adenovirus serotype 5 showed efficacy in clinical trials and has received EUA in China (Zhu et al., 2020). Complications related to vaccines

Although the current vaccines have proven efficacious against SARS-CoV-2 in general, concern has been raised about the longevity of the protection and the

Safe vaccines against SARS-CoV-2 have shown substantial reduction in severe cases and deaths of COVID-19. Anti-SARSCoV-2 drug development has been slower although monoclonal antibodies have been promising.

discovery of some breakthrough infections, where fully vaccinated individuals developed COVID-19. Another concern relates to SARS-CoV-2 variants/mutants, which have appeared frequently. Variants of concern (VoC) such as alpha, beta, gamma and especially delta have been proposed to be more transmissible and virulent than the original SARSCoV-2 Wuhan strain. Recently, the novel omicron strain was declared to be at least 10 times more infectious than any previously discovered variant albeit based on an artificial intelligence (AI) model (Chen et al., 2021) and not evaluated in in vitro or in vivo settings. Bioinformatics approaches have indicated that the omicron shows lower pathogenicity but higher antigenicity than the Wuhan wildtype or the delta and gamma variants (Barh et al., 2022). The SARSCoV-2 VoC therefore pose a threat to the protection offered by current COVD19 vaccines. Recent preliminary evaluations have suggested that for example the mRNA-based vaccines provide approximately 40 per cent protection against the omicron variant after two doses, whereas three doses are expected to provide excellent protection. Especially mRNA-based vaccines are prone to degradation meaning that

the BNT162b2 and the mRNA-1273 vaccines need to be stored and transported at -80°C and -20°C, respectively. Adenovirus-based vaccines demand less stringent conditions and can be stored for up to two weeks at +4°C. The logistics of transportation, distribution, and administration of COVID-19 vaccines have presented a serious problem for achieving the maximum global vaccine coverage. As of February 27, 2022, 10.7 billion doses of COVID-19 vaccines have been administered globally and 62.7 per cent of the world population has received at least one dose. The low rate of only 12.3 per cent of people vaccinated in developing countries is of great concern. Another complication related to vaccines has been the discovery of rare cases of vaccine-induced thrombotic thrombocytopenia (VITT) after vaccinations with both adenovirus- and mRNAbased vaccines. However, the rate is by far lower than seen in COVID-19 patients and should not discourage vaccination efforts. Unfortunately, the anti-vaccine campaign based on misinformation, disinformation, and even conspiracy theories have further hampered the progress of vaccination worldwide. COVID-19 drug development

In parallel to vaccine development, extensive unprecedented research and development of antiviral drugs against COVID19 have been conducted. Engineering of efficacious antiviral drugs has been demanding, and due to the urgency, existing antiviral and parasitic drugs have been repurposed for COVID-19 in parallel to the discovery of novel antivirals. In this context, drugs such as remdesivir, chloroquine, hydroxychloroquine, lopinavir/ritonavir, favipiravir, and ivermectin have been repurposed for COVID-19. Despite early promising findings from preclinical studies and preliminary clinical trials, in most cases no significant reduction in mortality, time to fever resolution, or clinical benefits have been observed compared to standard of care. For these reasons, neither

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hydroxychloroquine nor ivermectin have been approved for COVID-19 treatment by the FDA. However, the FDA approved in October 2020 the use of remdesivir for the treatment of hospitalised COVID-19 patients. Very recently, two oral antivirals, molnupiravir (Merck) and paxlovid (Pfizer) were developed for COVID-19. Molnupiravir inhibits SARS-CoV-2 by widespread mutations in the replication of viral RNA by RNA-directed RNA polymerase (RdRp).Two phase I clinical trials demonstrated a significant reduction in both hospitalisation and death rates in patients with mild COVID-19 disease (Singh et al., 2021). Although molnuvirapir was approved in the UK, its lower-than-expected efficacy of 30 per cent reduced risk of hospitalisation the approval by the FDA was first put on hold (Kozlov 2021), but then received an EUA on December 23, 2021(Kozlov 2021). Paxlovid is a 3C-like protease (3CLpro) inhibitor, which in combination with ritonavir disrupts the SARSCoV-2 replication. Preliminary data from clinical trials indicated that the risk of COVID-19 associated hospitalisation or death was reduced by 89 per cent (www.pharmaceutical-technology.com/ features/paxlovid-pfizer-covid-19-pill/ 1 ).Unfortunately, paxlovid was inaccurately described as a merely “repackaged” version of ivermectin although it is not structurally related or similar to ivermectin (Bloom 2021). Paxlovid is significantly more potent with a 10,000-times lower IC50 value. The FDA granted Paxlovid an EUA on December 22, 2021. Several monoclonal antibodies such as LY-CoV555named bamlanivimab (Ely-Lilly) and the monoclonal antibody cocktail REGN-COV2 (Regeneron) consisting of REGN10987 (imdevimab) and REGN10933 (casirivimab) have demonstrated good efficacy, but the requirement of high-dose intravenous injections make their therapeutic utilisation less convenient. LY-CoV555 received EUA by the FDA in November 1 http://www.pharmaceutical-technology.com/features/ paxlovid-pfizer-covid-19-pill/

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2020 for treatment of mild to moderate COVID-19 in adult and paediatric patients. Moreover, REGN-COV2 was given EUA as prevention in adults and paediatric individuals, who are at high risk of developing severe COVID-19. Complications related to COVID-19 Drugs

Most of the currently available drugs developed for treatment of COVID19 patients only provide modest efficacy in case studies and clinical trials. Although some drugs such as remdesivir and favipiravir have been approved by the FDA for limited applications in mainly hospitalised COVID-19 patients more efficient drugs are needed. Recently the orally administered RdRp inhibitor molnuvirapir and the 3CLpro inhibitor paxlovid have been presented as “gamechangers” in the fight against COVID19, but especially the former showed lower-than-expected efficacy in clinical trials. Monoclonal antibodies have demonstrated efficacy, but the need of high doses of intravenous administration has made their application complicated and expensive. Interestingly, repurposed and novel antiviral COVID-19 drugs have not been subjected to the same unsubstantiated and unprofessional scepticism, which has been seen for vaccines. Repurposed

drugs such as chloroquine, hydroxychloroquine and ivermectin have been too quickly announced as the “magic bullets” or “miracle cures” without being properly evaluated in large, well-planned and executed clinical trials. Illogically it has been stated that these drugs have been used in humans for decades without any safety issues. However, treatment of malaria and worm-diseases should not be compared to therapeutic interventions against COVID-19, which was dramatically experienced for hydroxychloroquine, resulting in a higher risk of ECG abnormalities/arrhythmia. What can we expect in 2022?

In the context of vaccines, the race to vaccinate the global population will continue in 2022 for sure. The appearance of highly transmissible VoCs quickly becoming dominant worldwide and their potentially increased resistance to vaccines have required new strategies. In one strategy, booster doses of existing vaccines aim at enhancing immunogenicity leading to better protection. Another strategy comprises the adjustment of existing vaccines to adapt them more efficiently the VoC and

Despite higher transmissibility the lower pathogenicity of emerging SARS- CoV-2 variants might downgrade the COVID-19 pandemic to an endemic status. However, preparedness for emerging SARS-CoV-2 variants and other future viral threats is necessary.

AUTHOR BIO

in parallel to develop totally new vaccine candidates. The majority of COVID-19 vaccine development has focused on the SARS-CoV-2 S protein as an antigen. In some unique cases other SARS-CoV-2 proteins such as the nucleoprotein (N) or the membrane protein (M) have been targeted. It would be useful to develop pan-vaccines targeting a broader range of the SARS-CoV-2 structure to avoid the continues “catch-up game” with the new variants harbouring a modified S protein structure. So far, all approved COVID-19 vaccines are based on intramuscular administration. However, adenovirus- and influenza virus-based vaccine candidates have been subjected to intranasal administration in animal models. The influenza virus-based intranasal COVID-19 vaccine candidate is currently in phase III in China. In the context of mRNA-based vaccines the stability has been improved for the new liposome nanoparticle encapsulated SARS-CoV-2 S RBD mRNA (ARCoV) vaccine, which provided protection in mice and due to temperature stability could be stored at room temperature for one week. COVID-19 drug research and development of repurposed and novel drug candidates has continued. Inhaled corticosteroids have proven beneficial for dealing with viral infections and their use by patients with stable asthma or chronic obstructive pulmonary disease (COPD), should also reduce the risk of SARS-CoV-2 infections. Moreover, it was demonstrated in patients with moderate to severe COVID-19 that low dose treatment with prednisolone was superior in shortening the length of hospital stay compared to lopinavir/ritonavir treatment (Ghanei et al., 2021). The development of monoclonal antibodies is also an area of high potential. However, the need of intravenous administration of expensive high doses of monoclonal antibodies has put limitations on their applicability for large-scale use for COVID-19 treatment. However, a novel approach of DNA plasmid-based in

Photo by Alexander Lundstrom

STRATEGY

Kenneth Lundstrom received his Ph.D. in Molecular Genetics at the University of Helsinki, Finland. He has spent most of his career in big pharma and biotech start-ups in cancer therapy and vaccine development. Lundstrom has published more than 300 scientific articles. He is currently involved in vaccine development against SARS-CoV-2 and cancer immunotherapy.

vivo monoclonal antibody expression has generated peak plasma levels of 270 ng/ ml showing superiority to protein-based administration (Vermeire et al., 2021). Obviously, this approach can also be applied for the expression of monoclonal antibodies targeting SARS-CoV-2. Finally, application of mesenchymal stem cells (MSCs) for therapeutic intervention have produced some promising results making it an attractive technology also for COVID-19 treatment. Preliminary findings indicated that MSCs can be effective in treatment of acute respiratory distress syndrome (ARDS) caused by SARS-CoV-2. How should we prepared beyond 2022?

The question everybody is asking is when will the pandemic end? Will SARS-CoV-2

disappear like SARS-CoV did within two years after the outbreak of SARS? The world has recently experienced the fifth wave of COVID-19. Certainly, we are better off now than at the beginning of the pandemic. We have safe and efficacious vaccines, which will eventually need second and third generation versions. Antiviral drug development is moving forward at full speed. We have to some extent learned to live with the pandemic although it has been hard both physically and psychologically. Can we see the light at the end of the tunnel? For certain to cite Winston Churchill: “Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning”. References are available at www.pharmafocusasia.com

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Motonori Araki, Partner, Tokyo Todd Liao, Partner, Shanghai Joo Khin Ng, Partner, Singapore Billy Wong, Partner, Hong Kong Nancy Yamaguchi, Partner, San Francisco Morgan, Lewis & Bockius’s Global Life Sciences Industry Group

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BRIGHT FUTURE FOR ASIA M&A The past two years have seen a bright light shone on the global pharmaceuticals industry, perhaps more so than ever before, the world’s eyes have been watching closely what may come, and of course for the next blockbuster product. From a business perspective, this has in part given rise to a range of opportunities in the sector, and among other trends, it has seen an uptick in the level of M&A activity, which has of course been true for many Asian life science companies. Housing one of the world’s largest pharmaceutical companies, Asia is on the world stage for investment and a combination of global and local developments throughout 2021 seem set to further enhance the opportunities in the sector in 2022 and beyond. With international appetite growing for SPAC transactions, we saw Singapore and Hong Kong open up their regulatory regimes to listings on their local exchanges, providing a new investment route for pharma companies. From Japan to Singapore, we saw governments throughout the region make announcements to assert their focus and attention on development in the sector. We also saw increasing regulatory oversight, particularly in the areas of data privacy and national security, which are likely to be a key factor and consideration for deal activity in the coming months and years too. We take a closer look at some of these themes in a little more detail in China, Hong Kong, Singapore and Japan. www.pharmafocusasia.com

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CHINA M&A transactions in China’s life sciences market experienced a resurgence in the past year, despite distressing economic, health and social impacts caused by the global pandemic. As such, for 2022 and beyond, we are likely to see a continuation of this with the emergence of a number of trends within China’s life science M&A market. Investment in China’s life sciences industry will continue to benefit from the nationwide medical reform, the Chinese government’s encouragement and policy support for R&D investment, technology acquisitions, and a trend of enterprising Chinese talent returning in China in recent years. We expect to see vibrant M&A activity in both deal volume and deal value in the market. China’s biopharmaceutical market is expected to continue to attract interest and investment from global biotech giants, especially from the US. Technological innovations, in particular, novel market segments such as cell and gene therapy (CGT), new drugs and vaccine will remain to be popular acquisition targets. The pandemic accelerated demand for virtual healthcare in China and has attracted cash-rich tech giants to invest in digital health development such as online health consultation services in recent years. We expect to see more transactions driven by tech giants in the digital transformation of health care. The trend of increased scrutiny of transactions from competition, foreign investment and data security regulators continued across the globe in 2021.

We expect this to continue, and likely accelerate, in 2022. The escalating trade tension between China and the U.S. may impact the outbound transactions, which has been low in the past year as compared to inbound investment. The more flexible listing requirements in HKEx and SSE’s STAR have contributed to the new highs of biotech IPOs. Driven by this trend, ongoing acceleration of finance investment transactions in China’s life science market is expected to continue.

HONG KONG Despite the pandemic, M&A activity in Hong Kong experienced a healthy jump last year. M&A transactions in Hong Kong tend to involve listed companies, which include mergers with SPACs in the US. The Stock Exchange of Hong Kong Limited (HKSE) introduced its own listing regime for SPACs on 1 January 2022 and many Hong Kong SPACs are now in the making. This will open up

Motonori Araki primarily advises on mergers and acquisitions (M&A), commercial transactions, intellectual property licensing, and international dispute resolution. Moto has worked with clients across all industries with a focus on life sciences and technology, representing major US and Japanese companies in cross-border transactions and regulatory matters. His M&A work includes representing buyers and sellers on cross-border transactions and covers structuring, documenting, and negotiating transactions.

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opportunities for private companies in the life sciences sector, particularly those based in Asia with a focus on China, to become a de-SPAC target and be given access to public equity. With the stringent Hong Kong SPACs regime, competition for quality de-SPAC targets is expected to increase, and outbound activities, particularly with targets in the PRC, are expected to be strong. Medical devices and digital health are areas that will likely see continued interest in 2022. HKSE became Asia's largest fundraising venue for the sector, following some major reforms allowing

Todd Liao works with clients on a wide range of privacy, financial transactions and legal issues involving China, particularly in the life sciences industry. He frequently works with multinational corporations on cross-border mergers and acquisitions, foreign direct investment and investment financing, disposal of Sino-foreign joint ventures and assets, and the structuring of complex commercial transactions.

STRATEGY

pre-revenue biotech companies to list under Chapter 18A. These companies are eligible for the Stock Connect scheme, giving access to capital flow from the PRC. Private equity appetite in the acquisition of life sciences companies will also likely continue. No major changes to the legal framework governing M&A transactions are foreseen and Hong Kong continues to have no merger control regime for the sector. The tax regime is expected to remain unchanged after a 30 per cent increase in stamp duty rates for transfer of shares in Hong Kong companies last year, which was the only increase in almost three decades. The Hong Kong Government remains committed to developing biotechnology in the city and to increase collaboration in the Greater Bay Area. Predictability and a favourable policy environment mean Hong Kong is well-positioned to take advantage of the surge in global M&A activities in the sector.

Billy Wong concentrates his practice on capital markets, mergers and acquisitions, private equity investments, and venture capital financing. Billy has represented Chinese issuers, including H Share and Red Chip companies, and sponsors in numerous initial public offerings on the Stock Exchange of Hong Kong Limited, and a diverse range of post-listing transactions, such as debt offerings, follow-on equity offerings and spin-off listings. He works with companies of all sizes withing the life sciences industry.

SINGAPORE In 2021, the Singapore Government announced its 10-year “Manufacturing 2030” plan, to grow the country’s manufacturing sector and to attract companies at the frontier of manufacturing. Singapore’s vision is to become a global business, innovation and talent hub for advanced manufacturing and the biomedi-

Nancy Yamaguchi advises global technology companies, including those in biopharmaceutical and medical technology (MedTech) industries, on cross-border mergers and acquisitions (M&A), strategic and venture capital investments, joint ventures, strategic alliances, technology transactions, and licensing. With more than 20 years of experience, Nancy is a trusted advisor to private and public multinational companies, especially those based in the United States and Japan, on all aspects of their corporate legal needs, including inbound and outbound M&A transactions.

cal and other life sciences clusters are key contributors to this vision. As a competitive life sciences hub in the Asia-Pacific region, Singapore has attracted a high proportion of the world’s largest pharmaceutical firms to set up manufacturing bases and R&D centres. In addition, Singapore has an ecosystem of strong local enterprises

Joo Khin Ng counsels capital markets and corporate finance clients. Clients seek his commercial skills and ability to bring transactions to the market. Over the past two decades, he has worked on all forms of equity and debt capital-raising transactions as well as pre-listing private equity and strategic investments. He also provides counsel for real estate investment trusts (REIT) and business trust initial public offerings (IPOs).

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that are pioneering developments in the biomedical space. According to the Singapore Manufacturing Federation, the pharmaceuticals industry accounted for 20 per cent of the manufacturing sector which in turn represents about a fifth of Singapore’s gross domestic product in 2019. The Singapore Government aims to make pharma the fourth largest pillar amongst all industries. In recent years and notwithstanding the pandemic, Singapore has been attracting experienced accelerators and venture capital firms to invest in Singapore (including in local life sciences industry aspirants). According to Enterprise Singapore, the biomedical innovation ecosystem has grown nearly six times over the last decade, with funds raised for the biomedical sector having increased more than five times from about US $86 million in 2016 to US $464 million in 2020. Similar to a move by Hong Kong and other major global financial centres, 2021 saw the rollout of a regulatory framework to facilitate SPAC listings on the Mainboard of the Singapore Exchange. Given the strong demand across Asia for

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the Asian-sponsored SPACs that have listed in other exchanges so far, as well as the growing familiarity that the local and regional investor base has with some recent SPACs, this development opens up an exciting new funding avenue for companies in the region, including the pharma sector With M&A activities within Singapore and the region expected to remain robust coupled with a maturing and rapidly expanding life sciences industry in Singapore, accelerators, venture capital firms, listed companies (including those looking to deSPAC) as well as big pharma companies that are looking for growth targets, we can expect to see an increasing number of opportunities and targets for mergers and acquisitions in the life sciences industry in Singapore, particularly in the biotechnology sector.

JAPAN In recent years, Japan has taken its place as home to one of the largest pharmaceutical companies in the world. This development resulted from a blockbuster M&A deal and one of the largest deals that the industry has ever seen. It seems

likely that Japan’s outbound M&A deal activity to continue to flourish with reports of further outbound acquisitions on the horizon. Until recently, Japanese life sciences companies had been less active in M&A deals compared to their counterparts in the US and Europe, and most of the M&A activity in the Japanese life sciences industry during the 1990s and 2000s revolved around domestic consolidation and restructuring. The pharmaceutical industry in Japan had been historically dominated by four main players, which controlled multifarious wholesalers and distributors through equity holdings. Following a series of consolidations and restructurings, all around the same time in the early 2000s, the leading pharmaceutical companies in Japan integrated these wholesalers and distributors as part of their own operations. This internal consolidation was largely driven by the impetus towards globalisation and the need for Japanese companies to scale and build the critical mass necessary to expand business and operations outside of Japan. As a result, major Japanese pharmaceutical

STRATEGY

companies have been able to steadily gain traction in the global pharmaceutical industry through key acquisitions outside of Japan. Another trend in the life sciences space in Japan is the entry of non-pharmaceutical companies. For example, the beer maker, Kirin Brewery, established its new pharmaceutical arm, Kirin Pharma, which then merged with Kyowa Hakko Kogyo in 2008 to become Kyowa Hakko Kirin following the merger. In 2011, Kyowa Hakko Kirin acquired ProStrakan Group Plc in Scotland, which subsequently became Kyowa Kirin International PLC to enhance Kyowa Hakko Kirin’s brand in Europe and the U.S. Other food and beverage companies have also entered the pharmaceutical industry, and it is expected that there will be increased competition in Japan in the life sciences industry with new market entrants. Today, life sciences companies in Japan are poised to take on the world and further extend their reach beyond Japan

through M&A and related transactions. These companies not only include pharmaceutical companies but also medical technology (MedTech) and diagnostic companies. Japan is known as a “super ageing” society with a high number of retirees and elderly who need medical attention. Accordingly, we expect both outbound and inbound M&A, licensing and strategic collaborations involving Japanese companies in the life sciences industry. In September 2021, Japan’s Ministry of Health, Labor and Welfare (MHLW) announced its “vision” for Japan’s pharmaceutical industry and highlighted, inter alia, digital transformation of the healthcare industry (including use of artificial intelligence), generic drugs, domestic sales of biopharmaceuticals and biosimilars, and new drug development, including anti-cancer drugs,

through acquisition of and partnerships with foreign companies as vital growth areas. We expect to see an uptick in M&A and other strategic transactions in these areas. Conclusion

Following the events of the past two years the M&A outlook across China, Hong Kong, Singapore and Japan has been buoyant and currently shows no signs of slowing down. As governments seek to remain regionally and globally competitive in this flourishing sector, we are likely to see a continued focus on ensuring they remain attractive to investors. Referance: Japan Ministry of Welfare and Labor, Pharmaceutical Industry Vision 2021; available at https://www.mhlw. go.jp/content/10800000/000831973.pdf

This article is provided as a general informational service and it should not be construed as imparting legal advice on any specific matter.

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THE AGGREGATE SAFETY ASSESSMENT PLAN A valuable tool for clinical trial safety planning The Drug Information Association / American Statistical Association Interdisciplinary Safety Evaluation working group has proposed an Aggregate Safety Assessment Plan (ASAP). The ASAP promotes a consistent approach to safety data collection and analyses across studies. The ASAP is a valuable tool for sponsors to enhance characterisation of the emerging product safety profile. Barbara A Hendrickson, Immunology Therapeutic Area Head, Pharmacovigilance and Patient Safety, AbbVie

ecently, a Drug Information Association / American Statistical Association-sponsored Interdisciplinary Safety Evaluation working group published a recommended approach to the aggregate assessment of clinical trial safety data. The proposed Aggregate Safety Assessment Plan (ASAP) has several components including identification of the safety topics of interest, how the safety data will

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be pooled across clinical studies and the data analysis standards that will be employed. In addition, the ASAP delineates how the safety data will be reviewed in aggregate to enable earlier signal detection as well as to promote consistent messaging regarding the emerging safety profile of the product. Lastly, the ASAP prompts a clinical trial sponsor to consider what key gaps in safety knowledge will remain at the time of product filing and potentially require further data collection or safety studies. The ASAP is an internal document compiled by a clinical trial sponsor early in the investigation of a product. The ASAP is meant to be a ‘living’ document that evolves over the different phases of clinical development. At a minimum, clinical scientists familiar with the product and disease under study in conjunction with safety scientists and statisticians with expertise in the analysis of safety data should collaborate on the creation of the ASAP. Ideally, the ASAP effort should also be supported by an epidemiologist. This team starts by reviewing what is known about the mechanism of action of the product, pre-clinical study results, drug-related adverse events reported in early human studies and, if applicable, available safety information from related products. This information, coupled with knowledge about the epidemiology of the study population (such as associated co-morbidities), forms the basis for the selection of the safety topics of interest. The safety topics of interest require collection and analysis of data beyond that which is routine for a clinical study. Creation of an ASAP should prompt team members to consider questions about the safety topics of interest that will be posed by regulatory authorities, healthcare providers and patients. These questions drive decisions about the data, which will be needed at regulatory submission. In addition, team members should research how the safety topics of interest have been assessed in the past by other clinical trial

sponsors. Pre-emptive and thoughtful aggregate safety evaluation is critical in order to thoroughly characterise a product’s safety profile and important product risks. Why should company management invest more resources earlier into safety assessment?

A comprehensive understanding of the safety data from completed and ongoing clinical trials is critical to understanding the benefit: risk profile of a product. A common objection to devoting resources to more in-depth safety planning earlier is doubt about whether a product will progress into later stages of development. However, formation of an ASAP may improve efficiency by serving as the reference point for the safety standards used in individual study statistical analysis plans. In addition, a proactive dialogue regarding the statistical outputs needed by the clinical team for documents such as the Investigator Brochure or Development Safety Update Report can minimise the need for ad hoc requests and missed timelines. Lastly, even if a programme does not advance

into late-stage development, the learning gained from populating an ASAP is carried over to work on the next project which may be successful. In addition, over the past 10 years, health authority expectations have risen regarding the quality of clinical trial safety data. As more therapies become available for specific diseases, the focus progressively shifts to how the safety of various products is differentiated. Product approvals may be denied or delayed due to safety concerns or an uncertain benefit: risk profile for the drug doses studied in the pivotal trials. Moreover, a lack of safety planning may lead to less favourable labelling than anticipated. Consequently, devoting resources to the characterisation of a product’s ‘safety story’ is just as important as to its ‘efficacy story’. Nonetheless, clinical trial sponsors may not concentrate closely on the safety package until after the registrational studies have started. The dangers of this approach are important missing data, challenges in data integration due to lack of standardisation across studies, and concerns arising about the adequacy

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of the safety data. For example, regulatory authorities may expect expert adjudication of designated adverse events or request specific statistical analyses, both of which may not have been considered or planned before the start of the clinical trials. Once the pivotal studies have begun, the case report forms would have been finalised and the initial patients enrolled. At that point, a course correction of the study can be problematic and costly. In addition, often there is a lack of foresight as to how the safety information will be put into the appropriate context at the time of product submission. For instance, the observation of certain adverse events during the clinical studies may raise concerns, particularly if there is a higher number of events in the active drug treatment group versus the control arm. While such an imbalance may be a chance occurrence, without information about the event background rate in the study population, this possibility cannot be assessed. An example is the surprisingly increased incidence of melanoma in patients with Parkinson’s Disease (PD). Although the underlying basis for this finding is not clear, a mutation or other alteration in a gene or protein conferring an increased risk for both PD and melanoma is possible. Knowing this association between PD and melanoma is critical to understanding an observation of a higher than anticipated rate of melanoma in PD clinical trials. How does the ASAP facilitate ongoing safety monitoring and signal detection?

While the evaluation of individual case reports remains valuable, regulatory authorities increasingly are focused on the monitoring of clinical trial safety data in aggregate. A single case report can be informative for an adverse event that is typically drug related, temporally associated with experimental product administration and for which there is no clear alternative etiology (e.g., anaphylactic reaction occurring less

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early detection and a sponsor could be surprised with an unanticipated safety concern at study completion.

The proposed Aggregate Safety Assessment Plan (ASAP) has several components including identification of the safety topics of interest, how the safety data will be pooled across clinical studies and the data analysis standards that will be employed.

than 30 minutes after ingestion of a product with no other cause identified). However, aggregate data assessment is needed for adverse events which are anticipated to occur in the patient population regardless of study participation (e.g. stroke in patients with osteoarthritis). For these events, noting that individual subjects have risk factors for the occurrence of an event is insufficient justification for a lack of association with product administration. Instead, the frequency, nature and severity of similar event reports in patients receiving the drug requires scrutiny. The ASAP has a section which is devoted to the description of the methodology for monitoring of aggregate safety data from the ongoing clinical trials, including potentially still blinded studies. Such assessments can support investigational new drug safety reporting decisions. Without a systematic approach to continual safety evaluation, signals may escape

How does the ASAP help a sponsor recognise key safety knowledge gaps?

One of the other sections of the ASAP prompts the clinical trial sponsor to consider what key questions about the safety profile of the product will remain unanswered at the time of regulatory submission. The cross-functional team also should be cognisant of the queries from healthcare professionals and patients regarding the safety of the product. More information may be needed regarding the frequency of the event, including in selected patient subpopulations, as well as the adverse event’s range of severity, reversibility and risk factors for occurrence. Another critical question may be how effective proposed measures are in mitigating the risk of an adverse effect of the product. By considering what will be important missing information at product filing, the clinical trial sponsor can proactively plan for how these knowledge gaps will be addressed either in an additional study or sub-study or through postmarketing safety surveillance. How does the ASAP support the safety messaging for a product?

Another valuable aspect of the ASAP is the foundation set for consistent safety messaging. Throughout a product’s lifecycle, communications regarding safety data occur to both internal and external stakeholders. Safety information is transmitted externally to regulatory authorities, clinical trial investigators and participants and more generally via public disclosures such as press releases, meeting presentations and publications. To help direct these communications, the ASAP refers to the concept of a “safety storyboard” which could be a slide deck or a written document. The safety storyboard changes in content over the course of clinical development. Initially the emphasis is on the

CLINICAL TRIALS

Summary

The ASAP puts a clinical trial sponsor in a better position to detect safety risks earlier and to optimally support the benefit:risk

profile of the product at submission and in communications to various internal and external stakeholders. References

Hendrickson, B.A., Wang, W., Ball, G., et al. (2021) Aggregate Safety Assessment Planning for the Drug Development LifeCycle. Therapeutic Innovation & Regulatory Science. 55(4): 717-732. Bose, A., Petsko, G.A., and Eliezer D.(2018) Parkinson’s Disease and Melanoma: Co-occurrence and Mechanisms. Journal of Parkinson’s Disease 8:385-398.

Barbara Hendrickson is the Immunology Therapeutic Area Head in Pharmacovigilance and Patient Safety at AbbVie. She is a subspecialist in Pediatric Infectious Diseases and has 18 years of pharmaceutical and clinical trial experience. Dr. Hendrickson also coleads the DIA-ASA Aggregate Safety Assessment Planning Task Force.

AUTHOR BIO

preclinical safety results and first in human study conclusions. Later as more clinical trial data accumulates, identified risks may emerge for which there is sufficient data to conclude a causal association with product administration. In addition, available data should be described relevant to potential risks for which there is a basis to suspect a link with product use. Other safety topics of interest may also warrant documentation of agreed upon conclusions based on current data. Examples include events of higher regulatory or prescriber interest based on the epidemiology of the patient population (e.g., major cardiovascular events in diabetes) or traditional safety concerns (e.g., drug induced liver injury). In addition, if risk minimisation measures are recommended for certain identified and potential risks, these actions should be part of the key safety messages. The safety storyboard can serve as the source of aligned safety messages which guide communications to various safety stakeholders.

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EXECUTIVES SPECIAL ISSUE 4 8 AUGUST 2022

Special issue is designed to focus on a theme or a sector trend. This issue is aimed at facilitating the industry leaders share perspectives and insights with our readers on key issues impacting and influencing the industry. The issue would also cover a few articles on trending topics in the pharma industry.

If interested in contributing, please reach out to prasanthi@ochre-media.com or gracejones@ochre-media.com

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IMCD A global leader in

speciality chemicals and ingredients Over recent years, IMCD has strengthened its position as a global leader in the distribution of specialty chemicals and ingredients. IMCD is committed to creating solutions that meet the demands of healthcare and product development. Paul Mimnagh, APAC Regional Director at IMCD, talks about the company’s post-covid strategy, missions for 2022, and the future of IMCD in the APAC region. Paul Mimnagh, Business Group Director Pharmaceuticals, Asia Pacific

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1) Can you begin by introducing IMCD and the business principles guiding the company? The IMCD Group is a global leader in the formulation, sales and distribution of speciality chemicals and ingredients. As the Pharmaceuticals Business Group, our goal is to advance ideas for a healthy future. We seek to achieve this by co-creating with our customers and partners in the development and manufacture of today’s and tomorrow’s medicines. IMCD focuses on meeting the needs of all stages of healthcare development, from fine chemical synthesis or upstream development of APIs, to the formulation and manufacture of the final dosage form.

2) Can you outline IMCD’s footprint in the region and the areas of its global portfolio you are currently prioritising? Globally, IMCD has around 300 technical sales experts who are experienced and professionally trained to understand the needs of our industry. Our network of Pharma Technical Centres (PTCs)

underpins their ability to support our customers in delivering their medicines meaningfully. Our teams are focused on innovation, sustainability, and providing the best customer solutions. Asia is the youngest of our global regions. But in a short period, it has grown to be our largest, with over 100 sales professionals and four Capitalise

PTCs. We are channelling investment into ensuring the highest calibre of professionals in each country, supported by a matrix of sub-sector specialists and technical product managers. We are adapted to the nuanced needs of each country, but critically, as a company, we have a team of regional experts covering the key subsectors of

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our industry to support each local team in the APAC region, with a sharpened focus and understanding of the regulated synthesis, API, topical/ dermal, nutraceutical, and biopharma markets. 3) Speaking about products and therapeutic areas, how has IMCD’s portfolio evolved and where are you investing? IMCD has long been a world leader in excipient distribution and this remains a core element of our business today and in the future. The APAC region closely follows IMCD’s global trend, and in line with global developments, has been focusing on strengthening our presence in APIs, nutraceuticals, and biopharma in recent years. The acquisitions of DCS, Signet, Whawon and Megasetia, provide our APAC business with a world-class portfolio, regional strength in these key territories, and of vast importance — an infrastructure of exceptional compliance and regulatory support in the field of APIs. APIs are core to a successful portfolio, and as we strengthen our position here, we further increase our portfolio’s relevance to our customers. Additionally, the continuing expansion of our pharma

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technical network allows us a more robust geographic coverage and capabilities across the network, particularly in tablet coating, nutraceutical concept development, and API testing and formulation. Our next focus is further expansion in biopharma, novel drug delivery, and analytical capabilities to better support our customers in generic and novel drug formulation. 4) Can you briefly explain the impact of COVID-19 on the company’s business and production? As a speciality distributor, our first responsibility is to deliver quality ingredients to our customers. Our investment and focus on technical capabilities never overlook that absolute priority. This has never been more tested than during the COVID pandemic of the last two years. Early in the pandemic, we saw a massive surge in demand across our portfolio, from basic ingredients for over-the-counter medicines, to crucial APIs such as muscle relaxants for the process of intubation. We were able to draw upon global inventories and our leveraged positions with suppliers and

providers to help many of our clients with critical supply issues. In terms of market focus, the COVID-19 pandemic has been the biggest challenge and focus for the biopharmaceutical industry in 2020. Innovative solutions have been developed in diagnosis, treatment, and vaccination. Among these solutions, monoclonal antibodies are considered promising to treat people in intensive care. When it comes to vaccines, billions of dollars are being invested into development and improvement. Vaccines are being produced with well-known technology like mRNA, but we’re also seeing interest in protein-based vaccines or viral vectors. IMCD’s partners invest in capacity and portfolio extension to ensure the security of supply of those critical raw materials to the market. IMCD in turn provides essential services in logistics to make the supply chain robust, efficient, and available at the point of need. 5) What is IMCD’s approach in creating opportunities through technical expertise and experience to the APAC pharma manufacturing community?

Globally, IMCD has a network of seven PTCs. Under the coordination of the Cologne headquarters, these Technical Centres deliver on the following areas: training and development of our team, studying and understanding our suppliers' ingredients in challenging formulations, assisting our customers in developing their formulations, and in the development of novel concepts and formulations. By successfully harnessing IMCD’s and our partners' knowledge with these capabilities, we equip ourselves to meet our customers' requirements, whether that is a simple need to source an ingredient, or our being intrinsically involved in developing new product ideas with our customers. Specifically in APAC, we have four PTCs in Mumbai, Shanghai and two in South East Asia. Each PTC carries a fundamental responsibility to meet the service needs of customers in all aspects of Oral Solid Dosage Forms (OSDF) and dermal technologies. Additionally, each of our PTCs is an integral cog in a co-ordinated network. Each centre focuses on a particular area of expertise, topical dermal, controlled release, tablet coating, reverse engineering for our clients in the generic field. 6) How is IMCD’s APAC network expanding through organic growth, global relationships, and strategic acquisitions? Since our first pharma greenfield sales operations in India and China in 2010, we have grown organically in doubledigit figures every year. The key to our success is organic growth, so organic growth remains our team’s first point of focus irrespective of what developments and successes we have. We have expanded across the region with our key global partners. This expansion is based on our delivery of differentiated channels to the market, reflecting the wide diaspora of market dynamics and customer needs within Asia.

To truly offer value and expertise in this sector, IMCD has to add new areas of expertise to our team.

Strategic acquisition is also a major part of our development in APAC. In the last three years, we have closed several acquisitions, building our pharma positions in Vietnam, China, India, Korea and Indonesia. Of particular importance to our business were the acquisitions of Signet India, Megasetia Indonesia and Whawon in Korea. In each of these three cases, we have partnered with leading pharma distributors in their respective markets. In addition to strengthening our position in these markets, these acquisitions also bring new degrees of expertise in our target growth markets and high degrees of experience and learning in fine-tuning our customer intimacy in APAC. As we look to the immediate future, IMCD will focus heavily on the continued expansion of our position through all three of these channels, with particular focus on the vast scope and potential for us to grow in China, Japan, Thailand, and Vietnam while also looking to strengthen our specialist positions in APIs, nutraceuticals and biopharmaceuticals. 7) Can you elaborate on IMCD’s capturing approach to emerging trends such as biopharma and wellness through nutraceuticals? The biopharmaceuticals market is the fastest growing sector in the pharma industry today, with a CAGR of 7.32 per cent over the forecast period, 2021-2026. The market is driven mainly by the growing geriatric population, rising chronic

diseases, and increasing acceptance of and huge market demand for biopharmaceuticals. The ability of biopharmaceutical products to address previously untreatable conditions has introduced innovative drugs in the market. An accelerating focus on research and related investments facilitates the massive demand for biopharmaceuticals. In the biopharma field, IMCD's strategy is based on the fact that while our partners invest in capacity and portfolio extension, IMCD has to provide essential services in logistics to make the supply chain robust and efficient. In addition to growing into this vibrant sector with our principal partners, we seek to expand our portfolio to new and innovative partners, and technologies, focusing on offering products for upstream, downstream, and final formulations. These include low endotoxin carbohydrates, amino acids and polyols. Additionally, IMCD has dedicated our resources to mapping this market and targeting key players, CMOs, CDMOs, CROs, and universities. To truly offer value and expertise in this sector, IMCD has to add new areas of expertise to our team. In 2021, we added several biopharma experts to our team, driving our coordinated global effort in this area. We will further expand our team with investment in biopharma experts in the APAC market. With respect to nutraceuticals, APAC is a region where cultural diversity results in a wide range of consumer demands for nutraceutical end products. This is a complex challenge, but we see that the markets in Asia Pacific are very connected. Our most recent APAC-wide campaign covered multiple segments within the broad and growing cognitive health category. Nutrition Business Journal states that consumers concerned about brain health far outweighs category sales. A significant health concern in the market surrounds the much-publicised mental health crisis resulting from the lockdowns and restrictions. IMCD has delivered innovative product concepts

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8) IMCD made headlines last year by joining forces with Megasetia. How does this fit into your longterm strategy? Over the years in EMEA, we have refined the formula of how we offer true value to our customers, based on combining in-depth knowledge of the pharma industry needs with an intimate understanding of the local needs of our customers. Our partnership with Megasetia, just like Whawon and Signet, accelerates our objectives to deliver the same knowledge and local understanding in APAC. Each of these companies surpasses all the others in their markets in technical support, market intelligence, and, most importantly, customer intimacy. 9) How does IMCD support its customers to overcome the challenges? We have built a broad portfolio of pharmaceutical ingredients with the industry’s leading suppliers in terms of quality and innovation, as well as a strong infrastructure of technical and formulation capabilities. We have built a global team of best-in-class pharma experts who have access to industry-leading training academies. When we successfully integrate and deploy these resources, we are equipped to support any challenges that they encounter. Later this year, IMCD is launching our next phase of the digital platform providing secured access to our pharma solutions. This is an exciting step into our digital journey, which we look forward to sharing with you in the months ahead.

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10) Looking towards the future, how do you expect the market to evolve in the coming years? In the coming years, we should see a greater emphasis on segmented patient drug delivery tethered to the regulatory constraints around ingredient use. After the FDA announced its pilot program to review novel excipients, we will see novel excipients back on the agenda. As an engine for supply to the USA market, the APAC region needs to stay clear on its objectives. As such, IMCD needs to ensure the availability of regulatory, technical, and innovative input to our customers. ‘Traditional’ dosage forms still dominate in manufacturing, but orodispersible line extension, topical, and nasal/ oral spray delivery dosage forms will show much more growth potential than in previous years. The old topics of improving bioavailability are only going to increase in importance, improving the potency of drug product performance can result in lower doses being required. There will be more emphasis on delivering drugs based on personalised medicine. Last but not least, sustainability. This is a growing area of concern in corporate responsibility, but also in many consumer's minds. This is especially true when you consider the ultimate goal of personalised medicine is disease prevention, rather than traditional diagnosis and treat/cure. We will see more ‘collaboration’ between medicine segment types such

Paul Mimnagh joined IMCD as International Product Manager in 2006, managing the pharmaceutical excipients portfolio through the IMCD sales network and developing the IMCD pharmaceutical business in emerging markets. He took up the role of Regional Director for Pharmaceuticals APAC in 2016 to drive IMCD’s expansion into the APAC market as the leading distributor of speciality pharmaceutical raw materials, to develop and implement regional business development and strategy to uncover new opportunities.

as prescription medicine for acute or medium-term chronic conditions, followed by symptom or side effect management and reduction and ending up with longer-term prevention of occurrence or recurrence. There are many exciting pathways to look at, and the APAC markets are a compelling ground for product development. 11) Is there a final message you would like to share with our international audience on IMCD APAC? Our pharma business is just over 10 years old in APAC, but our growth has surpassed even our expectations. We have an increasing toolbox of digital and technical tools, a rapidly-expanding portfolio, and a business network spanning the globe. But the key element to IMCD’s success is our people. We are rightfully proud of our team's diversity, which draws from a range of backgrounds and nationalities, and enables us to benefit from fresh perspectives and ways of problem-solving. They engender a free and entrepreneurial spirit that breeds success for IMCD, our customers and partners.

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that cover nootropics (focus), cognitive decline, and stress and mood. An example of one of our recent innovations is Ginkgosome™. This is a fully-formed liposomal complex developed by IMCD’s internal herbal extract business, Network Nutrition. Two clinical trials demonstrate increased absorption with sustained release, maximising the health benefits of Ginkgo biloba in an easy and convenient one-a-day dose.

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St.Gallen OPEX Benchmarking for Pharmaceutical Manufacturing Sites Measure yourself against the best but do it right

An understanding of own performance compared to a meaningful peer group is key to launch and sustain the Operational Excellence (OPEX) journey. The St.Gallen OPEX Benchmarking approach supports companies in that undertaking. This article illustrates how it differs from other benchmarkings and takes a look at the historical development of OPEX in pharma. Grothkopp, M., Pirrone, L., Friedli, T. University of St.Gallen

ompared to other industries, the history of OPEX in the Pharmaceutical Industry is a relatively short one (Friedli & Werani, 2013). Starting in the early 2000s, pharmaceutical companies began to introduce OPEX methods and tools because of rising cost pressure, the productivity crises in R&D, and the end of the traditional blockbuster business model. These developments, in combination with a push of regulatory authorities to apply as much science to production as to discovery, led to further investments into OPEX activities (Friedli et al., 2013). As more and more pharmaceutical companies reported their OPEX success stories, learning from industry practices and company specific approaches turned into a valuable source for own improvements. Accordingly, the investigation of OPEX success factors became a focal point of the St.Gallen research since 2003. The St.Gallen Model for Operational Excellence, which was presented in the article The Link between Plant Performance & Maturity – Seeing the whole picture, has been continuously further developed. Based on that model,

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Figure 1: St. Gallen OPEX Benchmarking Process

the Institute of Technology Management conducts international benchmarking projects to support pharmaceutical companies on their OPEX journey. This article will continue to present insights into the St.Gallen OPEX Benchmarking approach and will then look back on the last 15 years development of Pharmaceutical Operational Excellence from a St.Gallen perspective. St.Gallen OPEX Benchmarking

Benchmarking can be considered as a practice to compare business concepts, processes and performance to successful practices. A benchmarking then provides necessary insights to identify areas of potential improvement. The St.Gallen OPEX Benchmarking, initiated in 2003, pursues that aim by helping pharmaceutical companies to locate themselves within their competitive landscape, creating meaningful comparisons and striving for sustainable improvements. In doing so, the Institute of Technology Management advances the industry in its endeavour towards OPEX and can, to this day, draw on the world’s largest independent pharmaceutical OPEX-database. Therefore, the database includes data from more than 400 pharmaceutical manufacturing sites from over 143 companies ranging from

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small- and medium sized companies to big pharma companies. Five years ago, the St.Gallen OPEX Benchmarking was revised to allow an even more targeted comparison among plants that manufacture different drug substances and products. Additionally, the latest update provides for the inclusion of a full operationalisation of the ICH Q10 pharmaceutical quality model. In accordance to a holistic understanding of performance, the St.Gallen OPEX Benchmarking takes into consideration a balanced management of cost, quality, and time. It also comprises structural and behavioural aspects, which are necessary to support continuous improvement activities and it further addresses those elements that are directly linked to the field of management and the engagement of employees. To systematically collect benchmarking data the St.Gallen OPEX model is operationalised in the St.Gallen OPEX questionnaire. Scientifically influenced by a system perspective, the questionnaire considers key performance indicators (KPIs), enablers (maturity) and structural factors together. That way KPIs are not going to be analysed without the consideration of implementation levels of specific approaches and tools, nor without

understanding of the specific context of a plant. In total, the questionnaire asks for 36 KPIs in the technical system consisting of the three categories Total Productive Maintenance (TPM), Total Quality Management (TQM) and Justin-Time (JIT). Thereby, each category is operationlised to measure effectiveness and efficiency, e.g. TPM is not only measured with overall equipment effectiveness (TPM effectiveness) but also with the share of maintenance costs to conversion costs (TPM efficiency).Furthermore 12 KPIs are queried in the social sub system, to which can be referred to as Effective Management System (EMS). Besides taking performance metrics into account, the questionnaire also asks for enablers that are operationalised in five-point likert scales with distinct descriptions of each stage. Enablers, in this sense, measure the degree of implementation or proportion of usage of practices, eventually determining a sites OPEX maturity. Lastly, structural factors like product type, size or complexity are considered to ensure a holistic picture of the site’s current situation. Due to the broad St.Gallen experience in the field of benchmarking, a standardised and efficient procedure is applied to each individual benchmarking project. In this procedure (cf. Figure 1),

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Figure 2: OPEX Score Calculation

the benchmarking partner gathers the data while getting continuous support in dedicated Q&A sessions from the St.Gallen team. Once the completed questionnaire is sent back, the data will then be validated from the St.Gallen team to ensure data quality. The standardised benchmarking process then terminates with the generation of a personalised report. On the one hand, this report comprehensively illustrates the performance of the benchmarking partner compared to the technology peer group. On the other hand, the report reveals the implementation of enablers and shows the comparison to the industry. Figure 1. As a balanced approach for performance calculation the report also provides an overall OPEX score. This single, aggregated metric considers a variety of KPIs and makes the meaningful comparison of different sites possible in the first place. In order to calculate the overall OPEX score, several aggregation steps need to be made (Figure 2). First, KPIs are normalised to account for different logics and scales of metrics. That is, the best value within a sample of a certain metric equals 100 per cent, the worst value equals 0 per cent, and values in between receive a percentile rank accordingly. Secondly, the relative values for a specific set of KPIs are going to be aggregated for each

category (TPM, TQM, JIT). The average of these category scores then defines the technology performance score (e.g., solids technology score). Lastly, if the site produces multiple technologies, the average of all technology scores defines the overall site OPEX performance score. Figure 2. What differentiates the St.Gallen OPEX Benchmarking logic from other often consultancy benchmarking is the identification of and the comparison to high-performers. A typical consultancy benchmark demonstrates performance for each KPI against the highest values in the sample for this respective KPI. This however leads to an unrealistic benchmark perspective, in which the high-performer values of one KPI might stem from a totally different site than the high-performer values for another KPI. In other words, the consultancy benchmark compares a site always to the highest values even though this combination of high-performer values has never been achieved by a single site. This unrealistic combination of high-performer values is, therefore, called a “virtual best practice” site, which is actually composed of various sites. An analogy to the sports world is the decathlete who competes in every single discipline. The St.Gallen OPEX Benchmarking, however, provides

a more realistic, trade-off aware comparison. Before comparing on a KPI level, the St.Gallen OPEX Benchmarking defines a high-performer peer group, which includes sites that achieve true excellence managing existing trade-offs between KPIs. The definition of high-performers is based on the above mentioned OPEX score, whereas the top 25 per cent performing sites make up the high-performer peer group. This peer group is kept unchanged while a benchmarking partner’s site is compared within each KPI to the highperformers value which is the average of the high-performer peer group. Hence, the decathlete is competing in a decathlon. In order to deepen the understanding of the benchmarking results, the St.Gallen OPEX team provides the possibility to conduct a company specific tailored workshop. Main goal of that workshop is an open discussion around sharing of successful practices, identifying of improvement areas and deriving an improvement action plan. In addition to the described St.Gallen OPEX Benchmarking, the Institute of Technology Management developed a second benchmarking, which is especially tailored to QC Labs. Providing more details on the St.Gallen approach for QC labs will be of main interest in our forthcoming article. Nevertheless,

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from our experience, combining both benchmarkings at one site allows to draw a more holistic picture of OPEX performance throughout the entire value chain of drug production. Development of OPEX in Pharma in the last 15 years

Following the scientific discussion of OPEX, scholars like Clode (1993), Billesbach & Hayen (1994), De Menezes et al. (2010) or Yang et al. (2012) have already shown early that specific improvement concepts like JIT or TQM eventually lead to significant increases in performance. However they focused on achieving OPEX in other industries than the pharmaceutical industry. The development of OPEX in the pharmaceutical industry took place in three major phases (cf. Figure 3). Starting with a Pre-OPEX phase, which lasted until the late 1990s, no structured and carefully designed approaches to improve manufacturing processes were carried out. Furthermore, the underlying culture of ”no change” was predominant within the industry. With the second phase, the Best Practice Transfer phase, starting around the early 2000s, pharmaceutical production managers began to visit automotive

Especially practices related to quality show the highest levels of implementation, while improvements in maintenance and equipment show the strongest increase over time.

plants like Toyota, BMW, Daimler etc. Their goal was to copy proven OPEX practices to the pharmaceutical production floor. Nevertheless, it became clear, that just copying practices was not sufficient to get the buy-in from employees. Therefore, the third phase, the Transformation-phase, in which we can find most of the advanced companies in today, focuses on people and change management. The last phase that is gradually emerging is the “Integrated Operations System” phase. That phase

Figure 3: The pathway to operational excellence (Gronauer et al. 2010)

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will, from our understanding, combine preventive and reactive OPEX and align all improvement initiatives on the top management level (Friedli & Werani, 2013). Figure 3 From our benchmarking data, we also see that the implementation of OPEX practices for TPM, TQM and JIT has progressed over the last 15 years. On average the data show that the implementation of practices related to TQM is the highest, which might lead back to the point that some of the practices in TQM are related to the regulatory authorities and Good Manufacturing Practices (GMPs). As GMPs need to be followed to be compliant, the high overall implementation in this category does not come as a surprise. With respect to practices centred around equipment stability, respectively technology management (TPM), and flow (JIT) it can be seen that these two categories started at the same implementation level. However, the implementation level of TPM then evolved stronger, which can be aligned with literature proposing that TPM practices need to be implemented in the beginning of each OPEX program (cf. Ferdows & Thurnheer, 2011; Bortolotti et al., 2015). In addition to analys-

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Outlook

Due to an increasingly difficult environment combined with the support of regulatory agencies, Pharma companies have embarked on their OPEX journey. Since then the Institute of Technology Management has been supporting them in their OPEX activities by helping to position themselves in their competitive landscape and to identify improvement potentials with the St.Gallen OPEX Benchmarking approach. Overall, the benchmarking data shows that pharmaceutical manufacturing sites are adopting more and more OPEX practices and techniques. Especially practices related to quality show the highest levels of implementation, while improvements in maintenance and equipment show the strongest increase over time. Additionally, it can be seen that companies increasingly pay attention to social and cultural aspects in their OPEX activities. Our forthcoming article will present the St.Gallen QC Lab Benchmarking in more depth and will look at QC as part of the entire value chain. That way the holistic St.Gallen perspective towards benchmarking pharmaceutical companies will be extended.

Literature

Billesbach, T. J. and Hayen, R. (1994). "Long-term impact of just-in-time on inventory performance measures". Production and Inventory Management Journal, 35(1), pp. 62–67. Bortolotti, T., Boscari, S., Danese, P. (2015). "Successful lean implementation: Organizational culture and soft lean practices". Int. J. Production Economics, 160 (2015), pp. 182-201. Clode, D. M. (1993). "Survey of U.K. manufacturing control over the past ten years". Production and Inventory Management Journal, 34(2), pp. 53–56. De Menezes, L. M., Wood, S. and Gelade, G. (2010). "The integration of human resource and operation management practices and its link with performance: A longitudinal latent class study". Journal of Operations Management, 28(6), pp. 455–471. doi: 10.1016/j. jom.2010.01.002. Eich, S., Grothkopp, M., Macuvele, J., Friedli, T. (2020). "Progress of Operational Excellence implementation and performance in pharmaceutical manufacturing sites – descriptive study from 2003 to 2018”. 27th EurOMA conference 29th - 30th June 2020, University of Warwick (UK). Ferdows, K., & Thurnheer, F. (2011). " Building factory fitness". International

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ing isolated implementation levels of enablers, we especially looked at simultaneous implementation of enablers as literature suggests building capabilities integratively. Indeed, the data showed that there is a trend towards slight improvement of implementing enablers in a more integrative manner. A possible explanation is that manufacturing sites make an effort to implement practices simultaneously instead of piecemeal improvement. Another explanation could be that manufacturing sites are increasingly capable of closing gaps between enabler implementation levels after the implementation of certain practices has already taken place. Overall, we observe an increasing implementation degree of OPEX in the Pharma industry over the last 15 years (Eich et al., 2020).

Journal of Operations & Production Management, 31(9) pp. 916-934. https:// doi.org/10.1108/01443571111165820. Friedli, T. & Werani, J. (2013). "The History of OPEX in the Pharmaceutical Industry". In: Friedli, T., Basu, P., Bellm, D., & Werani, J. Leading Pharmaceutical Operational Excellence: Outstanding Practices and Cases. Berlin: Springer; 2013. pp. 27-34. Friedli, T., Lembke, N., Schneider, U., Gütter, S. (2013). "The Current State of Operational Excellence Implementation: 10 Years of Benchmarking". In: Friedli, T., Basu, P., Bellm, D., & Werani, J. Leading Pharmaceutical Operational Excellence: Outstanding Practices and Cases. Berlin: Springer; 2013. pp. 35-58. Gronauer, T., Friedli, T.,Götzfried, M. (2010). "The roadmap to operational excellence – pattern and elements of OPEX programs". In: Friedli et al. (2010) The pathway to operational excellence – overcoming the internal inertia. Editio Cantor Verlag, Aulendorf. Yang, C.-C., Yeh, T.-M. and Yang, K.-J. (2012). "The implementation of technical practices and human factors of the toyota production system in different industries", Human Factors and Ergonomics in Manufacturing & Service Industries, 22(6), pp. 541–555. doi: 10.1002/hfm.20296.

Mark Grothkopp is a research associate at the University of St.Gallen. At the Institute of Technology Management, he coordinates the Operational Excellence team with a special focus on the pharmaceutical industry. Currently, his academic research focuses on production systems evolutions.

Lorenzo Pirrone is a research associate at the University of St.Gallen. At the Institute of Technology Management, he works in the Operational Excellence team with a special focus on the pharmaceutical industry. His research focus lies in the field of maturity development and performance measurement.

Thomas Friedli is a director at the Institute of Technology Management. He leads a division of 14 PhD students and two post-docs. His research areas include strategic management of production companies, management of industrial services, and operational excellence. He is editor, author and coauthor of numerous books and articles.

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VACCINES AGAINST SARS-COV-2 Current situation and future perspectives

Safe and effective vaccines to prevent COVID-19 caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARSCoV-2) have been developed within a year after the onset of the pandemic. As of December 2021, 54.5 per cent of the world population had received at least one dose, but Africa is lagging behind. Full, lasting protection against severe disease will require two doses plus a booster, and preferably incorporating emerging virus variants such as omicron. Ger Rijkers, Science Department, University College Roosevelt Microvida Laboratory for Medical Microbiology and Immunology, St Elizabeth Hospital

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s a rule of thumb in epidemiology, the world faces a pandemic once every 100 years. The previous one was the Spanish flu in 1918. At the end of World War I, a new strain of the influenza virus, H1N1, broke out in the United States. The disease mainly affected young adults, initially recruits in army camps, who were in training to be sent to Europe. Ultimately, more American soldiers died from the flu than in the battlefields of Europe. During wartime, most news-

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papers were censored, and coverage of the outbreak of this very serious form of influenza was prohibited. However, Spain was neutral during the First World War, and Spanish newspapers did report on this disease, which subsequently became known as Spanish flu. The Spanish flu lasted for two years and by the time it was over, more than 50 million people worldwide had died. Every place on earth was affected. Douglas Island, a small off the coast of Alaska, in the second week of November 1918 had 100 patients with influenza admitted to the local hospital. There was one death, Maude Kelly, who was a nurse of the influenza patients at the local hospital. That after the Spanish flu another pandemic would come was to be expected. The question, therefore, was not “if” but “when”. The risk of outbreaks of diseases that can spread from animals to humans inevitably increases when animals and humans come into close contact with each other, caused for example by habitat degradation, intensive livestock breeding (e.g., Q fever) and the trade of wild animals. Combined with other factors such as increased air traffic, urbanisation (more than 50 per cent of the world's population lives in urban areas) and climate change, the chances of another pandemic were high. In 2018, the World Health Organization (WHO) listed a number of infectious diseases that can pose a serious threat to public health, for most of them no vaccines or effective drugs are available. One of these could be "Disease X" — a future disease that humans had never seen before that would cause a pandemic. We now know that Coronavirus Disease 2019 (COVID-19) is disease X. Douglas Island in Alaska already had a local newspaper in 1918: Douglas Island News. In the same issue that reported Maude Kelly's death, it also published a list of 11 Do's and Don'ts to get safely through the influenza pandemic. It is striking that almost all these advices are fully applicable at the time of COVID-19. Just a few examples: wear your face mask, do not ignore the advice of specialists

because you do not understand them, do not think that an exception can be made for you, do not think that you cannot contract or spread influenza (for influenza read corona), and finally, don't worry! COVID-19, a word that did not exist in January 2020, has infected more than 260 million people worldwide and killed 5.2 million on December 2, 2021. Also by December 2 2021, a total of 203,479 scientific publications on COVID-19 had been published, with over 2,000 publications in November 2021, a number that reflects how all efforts are being made to better understand the disease, ways to treat it and prevent it by vaccination. Naturally, also in 1918 clinicians and scientists worked hard to develop an influenza vaccine. Unfortunately, they were not successful and the Spanish flu pandemic only ended when everyone (on the world!) who was sensitive had contracted the disease, and was either cured and subsequently immune, or had died. The development of mRNA-based and other vaccines to prevent COVID-19 caused by SARS-CoV-2 has taken place within a year. This speed of development has been unrivalled in the pharmaceutical world, and an example of global collaboration between governments, science and industry. All this took place within a time frame of 12 months, calculated from the elucidation of the sequence of this new coronavirus up to and including the completion of phase 3 studies and the

start of the first actual vaccinations. In the publications on the results of the phase 3 studies of both the BNT162b2 mRNA vaccine from Pfizer (Comirnaty) and the mRNA-1273 SARS-CoV-2 vaccine from Moderna, the words "efficacy" and "safety" appear prominently in the title. Pfizer's mRNA vaccine, BNT162b2, has been tested and found to be 95 per cent successful in preventing COVID19. The Moderna mRNA vaccine, scores comparably high at 94.5 per cent. Crucial for the success of the mRNA vaccines was the incorporation of modified uracil and it is more than deserved that Katalin Karikó received the 2021 Lasker Award for her work in this field. We would wish the Nobel Committee follows next year. Seven vaccines have obtained the WHO Emergency Use Listing (EUL), which means that the vaccine meets all safety and efficacy requirements and is (also) suitable in low- and middleincome countries. These vaccines include the mRNA vaccines of Pfizer/ BioNTech Comirnaty, and the Moderna COVID-19 vaccine (mRNA 1273), the viral vector vaccines SII/COVISHIELD and AstraZeneca/AZD1222 as well as the Janssen/Ad26.COV 2.S vaccine. Furthermore, the Sinopharm COVID-19 vaccine, Sinovac-CoronaVac, and Bharat Biotech BBV152 COVAXIN vaccine (all inactivated virus vaccines) also have EUL status. Another 109 vaccines are being studied in clinical trials under development. www.pharmafocusasia.com

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Figure 1: Corona vaccination in the world (December 2021). Average numbers, per continent or sub-continent, of people (above 12 years) who have received 1, 2, or a 3rd booster dose of any corona vaccine.

In December 2021, 54.5 per cent of the population of the world has received at least one dose of a COVID-19 vaccine. A total of 8.03 billion vaccine doses have been administered globally. Merriam Webster has declared vaccine as the 2021 word of the year, while for the Oxford English Dictionary this is vax. In Northern- and Latin America, in Europa, and in Asia-Pacific, over 50 per cent of the adult population has received two doses of a COVID-19 vaccine (Figure 1). It must be kept in mind that vaccine uptake can vary per country. Lowest scoring countries in above continents are Guatamala (24 per cent two doses of vaccine), Bosnia and Herzegovina (22 per cent), Kyrgystan (14 per cent) and Papua New Guinea (2.3 per cent). Overall, only 6 per cent of people in low-income countries have received at least one dose.Especially Africa as a continent lags greatly behind the rest of the world. COVAX, the joint initiative of the WHO, Unicef and GAVI, therefore is of crucial importance to facilitate production and equitable access to COVID-19 vaccines, but also tests and treatment.

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Shortage of vaccines is a major hurdle, but also the required infrastructure and logistics for vaccine delivery (the last mile that a vaccine has to travel from the production facility to the recipient is the most difficult one) and strong vaccine hesitancy and resistance sentiments should be overcome. Figure:1 None of the continents, not even a single country, has reached an overall 2-dose vaccination rate to ensure group immunity (with the delta variant estimated to be above 95 per cent). In most publications thus far, two doses of vaccine are indicated as “fully vaccinated”. This term may have to be reconsidered, because booster vaccinations are now implemented in order to protect the most vulnerable groups in the population and in order to reduce spread of the virus variants. A new SARS-CoV-2 variant of concern has emerged which has been termed termed omicron. Its genome is mutated at 32 positions (of the 671) of the Spike protein, of which 15 are located in the receptor binding domain (122 aa). These mutations have been called

a “Frankenstein mix of greatest hits”. At the moment of writing (December 2, 2021) there are still many unknowns: when will the omicron variant displace the delta variant?, will it cause mild or severe disease?, and will the current vaccines offer protection against disease? All major vaccine producers have already started preparing for a next generation of vaccines, which will incorporate (the genetic information of ) these new variants. These vaccines will be needed in 2022 to control SARS-CoV-2 and hopefully put an end to the pandemic. Selected publications:

Leerboek immunologie. G.T. Rijkers F.G.M. Kroese, Uitgever: Bohn Stafleu van Loghum, Co-auteur: R.H.W.M. Derksen C.G.M. Kallenberg, 2de druk 2016, ISBN 9789036802574 Differences in Antibody Kinetics and Functionality Between Severe and Mild Severe Acute Respiratory Syndrome Coronavirus 2 Infections. Rijkers G, Murk JL, Wintermans B, van Looy B, van den Berge M, Veenemans J, Stohr J, Reusken C, van der Pol P, Reimerink J.

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Ger Rijkers (1952) is emeritus Professor of Biomedical and Life Sciences, University College Roosevelt, and Utrecht University, the Netherlands and a medical immunologist and senior scientist at the Microvida Laboratory of Medical Microbiology and Immunology at St Elisabeth Hospital in Tilburg, the Netherlands. Rijkers has studied biology at Wageningen University and became (medical) immunologist in the Wilhelmina Children’s Hospital in Utrecht, specializing in paediatric immunodeficiencies, autoimmune diseases, and respiratory infections. He next went on to work on gastrointestinal mucosal immune systems and the interaction with gut microbiota at the University Medical Centre Utrecht and the St. Antonius Hospital in Nieuwegein. In 2010 he accepted the position as head of the Science Department of UCR in Middelburg. In 2019 he joined the Laboratory of Medical Microbiology and Immunology of the St Elisabeth Hospital in Tilburg as medical immunologist, a position which includes consulting for immunology in the Admiral De Ruyter Hospital in Goes and Zorgsaam Hospital in Terneuzen.

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J Infect Dis. 2020 Sep 14;222(8):1265-1269. More bricks in the wall against SARSCoV-2 infection: involvement of T cells. Rijkers G, Vervenne T, van der Pol P.. Cell Mol Immunol. 2020 Jul;17(7):771772. doi: 10.1038/s41423-020-0473-0. Genetics in community-acquired pneumonia. Rijkers GT, Holzer L, Dusselier T. Curr Opin Pulm Med. 2019 May;25(3):323-329. Rocking pneumonia. Rijkers GT, Rodriguez Gomez M. Pneumonia (Nathan). 2017 Dec 15;9:18. doi: 10.1186/s41479-017-0043-0. Dexamethasone and length of hospital stay in patients with communityacquired pneumonia: a randomised, double-blind, placebo-controlled trial. Meijvis SC, Hardeman H, Remmelts HH, Heijligenberg R, Rijkers GT, van Velzen-Blad H, Voorn GP, van de Garde EM, Endeman H, Grutters JC, Bos WJ, Biesma DH. Lancet. 2011 Jun 11;377(9782):2023-30. doi: 10.1016/ S0140-6736(11)60607-7.

He has published over 375 papers in peer-reviewed scientific journals and has supervised over 25 PhD students in their thesis work. Ger Rijkers is co-editor in chief of Pneumonia. He also is Editor for the journals Biology, and Vaccines. Ger Rijkers is married to Riky Lievendag for 45 years, they have 3 adult sons and 3 grandchildren.

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Proposome, an Efficient and Safe Topical Formulation The study developed a nanosized vehicle named'proposome' to enhance the skin absorption of drugs. Proposomes are propylene glycol-based liposomes. The study investigated the skin permeation of proposomes loaded with ibuprofen, tofacitinib citrate, rhodamine B, and lidocaine. These drugs have different physicochemical properties, which was needed to observe the differences in skin absorption of drugs loaded in proposomes. The proposomes had an average diameter of 128 to 148 nm, measured using dynamic light scattering. The drug entrapment in proposomes varied between 42.9 and 52.7 per cent at the same total concentration, enhancing drug delivery by 1.4 to 4.0 times than free drugs. The skin absorption enhancement through proposomes was linearly correlated with the physicochemical properties of the loadeddrugs. Confocal imaging also confirmed higher skin permeation using proposome than free molecules. The safety of the proposomes was assessed using bioengineered reconstructed human skin tissue equivalents thatshowed proposome was safe for skin application. The enhancement of skin delivery of loaded drugs depended on the drug's lipophilicity, which affected drug entrapment efficiency into proposomes, and in turn drug absorption through skin. Himanshu Kathuria, Department of Pharmacy, National University of Singapore Lifeng Kang, School of Pharmacy, Faculty of Medicine and Health, University of Sydney

opical delivery is the most acceptable route for treating skin conditions as it provides localized and fast effects. However, the drug delivery through the skin is challenged by the skin outermost layer, which is made up of dead cellsand the lipid matrix. This outermost layer is a primary barrier for therapeutics absorption into the skin, allowingonly small and lipophilic molecules to be absorbed. Various approaches have been developed to overcome this barrier to enhance the skin absorption of therapeutics. Enhanced absorption translates into desired therapeutic effect or fast effect.

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Figure 3: The schematic representation of fabricating RHS from human cells and hydrogels.

Figure 1: Chemical structure, molecular weight (MW) and logP of model drugs loaded into proposomes to study the skin delivery.

Lipid-based vehicles have been extensively explored to enhance the skin absorption of therapeutics, where especially nanosized lipid vehicles have shown great promise. The lipid vehicles can also be used with other safe topical vehicles such as glycerol, and propylene glycol (PG), to further improve skin absorption of therapeutics while also improving drugand formulation stability. Recently, a PG-based liposome, namely, proposome, showed that it can enhance the skin absorption of to facitinib citrate, used for arthritis and psoriasis. Tofacitinib citrate has low skin absorption, which delays the onset of therapeutic effect when given topically. However, proposomes improved the skin absorption of tofacitinib citrate by many folds. This finding became the base for the current study to explore proposomes as topical vehicles for other therapeutics and study skin enhancement. The study hypothesized that proposomes could improve the skin absorption of molecules with different physicochemical properties. Moreover, the study established the www.pharmafocusasia.com

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correlations between skin absorption enhancement and physicochemical properties of molecules loaded in proposomes. The study also assessed the safety of proposomes which is critical for developing new formulations. The safety was assessed using in-house produced bioengineered reconstructed human skin (RHS) tissue equivalents that mimic the native skin tissue. Methodology

Figure 2: (A) Schematic of preparation process. The dropwise addition of water into PG (also SPC and drug) with constant magnetic stirring causes proposome

Proposomes were prepared by hydration of lipids dissolved in PG. The hydration was doneunder constant magnetic stirring(~1500 rpm) at room temperature and Milli-Q water addition(1 mL/min) using a syringe pump. Proposomes were prepared with 1 per cent soya phosphatidylcholine (SPC), 30 per cent PG, and the following drug molecules were incorporated: Ibuprofen, Tofacitinib Citrate, Rhodamine B, Calcein, and Lidocaine at fixed 5.64 mM concentration. Rhodamine B and Calcein

Figure 4: Skin permeation of proposomes and control for 24 h_ drug retention in skin and the sum of permeated and retained. indicates statistically signifi

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were used as fluorescent probes to observe the skin absorption using confocal laser scanning microscopy (CLSM). The skin absorption was assessed using Franz diffusion apparatus and quantified using a validated analytical method using high-performance liquid chromatography. Results and discussion

Figure 5: (A) Effect of logP of drugs delivered through proposomes on amount retained and amount permeated. (B) Effect of logP on entrapment efficiency and

Figure 6: The confocal microscopic images showing fluorescent calcein control (A) proposome (B) and rhodamine B (C) proposome (D) penetration into human ski

Proposomes sizes were measured using dynamic light scattering. The average size (diameter) of formulations varied between 128 nm to 150 nm, with the narrow distribution shown by a low polydispersity index (less than 0.2). This size is small and can increase skin absorption of molecules. The encapsulation efficiency of molecules varied from 44 per cent to 55 per cent at fixed total concentration. The encapsulation efficiencycan be optimised to increase drug loading by varying the composition of the proposomes and loading techniques. The studies showed that proposomes could enhance the skin absorption of various molecules. The proposome increased both drug permeation through the skin and drug retention in the skin. However, the extent of skin absorption varies depending on drug physicochemical properties. Ibuprofen loadedinto proposome showed at least four times higher skin absorption thanunloaded ibuprofen. While other drugs loaded in proposomes had lower skin absorption than ibuprofen, which depends on their physicochemical properties. Rhodamine B (log P = 2.43, MW = 479.0) and lidocaine (log P = 2.44, MW =234.3) have similar log P while the significant difference in molecular weight; however, both drugs, when delivered with proposomes, showed skin permeation enhancement (two times) close to each other. This could be attributed to the fact that drugs were loaded into the proposomes, changing their skin absorption nature. It showed that drugs with high molecular weight but good lipophilicity could have good skin absorption using proposomes. The enhancement and log P showed a positive linear correlation, where this association between log P and enhancement can be explained by entrapment efficiency. The log P of drugs and their entrapment efficiency in proposomes was www.pharmafocusasia.com

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loaded with fluorescent molecules was analysed using fluorescent microscopy, which confirmed that proposomes helped in better absorption of both hydrophilic and hydrophobic molecules. Moreover, proposomes helped in deeper absorption of molecules into the skin, which was more than 100 µm deep from the skin surface. Lastly, the safety study shows that the proposomes did not affect the cell viability and did not trigger inflammatory markers in the re-consituted human skin model. These findings that proposomes were non-toxic and safe to human skin. Conclusion

Figure 7: Histological section after hematoxylin and eosin (H&E) staining of human cadaver skin and RHS before and after treatment. (A1) Untreated human cad

Proposome is an efficient vehicle for skin delivery of therapeutics, and safe for skin applications.The nanocarriers can increase drug permeation through skin by X folds. X is a number close to the LogP of the drug molecule. References Kathuria H, Handral HK, Cha S, Nguyen DTP, Cai J, Cao T, Wu C, Kang L. Aug 2021. Enhancement of skin delivery of drugs through proposome depends on drug lipophilicity. Pharmaceutics. 13, 1457. DOI:10.3390/ pharmaceutics13091457.

interrelated, resulting in higher skin absorption.The study shows that even a small increase in entrapment efficiency into proposomes significantly increased skin absorption, which shows the potential of proposomes in enhancing skin delivery. The relationship between drug's physicochemical properties and their skin absorption has been established earlier in literature. However, those relationships are applied to free drugs or drugs delivered without delivery vehicle. In contrast, this study has emphasised the correlation between drug's skin absorption enhancement and drugs loaded in proposomes. Further, skin treated with proposomes

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Figure 8: RHS results after treatment for 24 h with PBS, 30% PG, 5% wv SDS, and blank proposome. (A) Tissue viability (%) measured using MTS assay. (B) IL and (C) IL-8

Kathuria H, Nguyen DTP, Handral HK, Cai J, Cao T, Kang L. Jul 2020. Proposome for transdermal delivery of tofacitinib. International Journal of Pharmaceutics. 585:119558. DOI: 10.1016/j.ijpharm.2020.119558

Himanshu Kathuria is a postdoctoral research fellow in Department of Pharmacy, National University of Singapore (NUS). He obtained his Ph. D in 2018 in NUS, M. Pharm. in 2013 and B. Pharm in 2011. His research interests include drug delivery via nano/microscale approaches, alternative medicine, naturopathy, homeopathy, and Ayurveda.

Lifeng Kang is a Senior Lecturer at the School of Pharmacy, Faculty of Medicine and Health, University of Sydney. His laboratory is focused on microscale technologies and 3D printing for drug delivery and tissue engineering. He has published 3 books, 5 book chapters, 70 peer-reviewed journal articles (56 as the main author), 81 abstracts and filed 7 patent applications (2 granted, 3 licensed to 3 companies). His work has been published in leading journals such as Advanced Drug Delivery Review, Journal of Controlled release, International Journal of Pharmaceutics, Advanced Functional Materials, Biofabrication, Biomaterials Science.

BOOKS

The Pharma World Author: Prasanna Sagar

Building Breakthroughs: On the Frontier of Medical Innovation

A Handbook on Fundamental Concepts in Pharmaceutical Industry

Year of Publishing: 2021

Author: Raju Prasad

No. of Pages: 146

Year of Publishing: 2022

Author: Prem Swaroop Adhikarla

No. of Pages: Not enabled

Year of Publishing: 2021 No. of Pages: 120

This Handbook sized resource offers details of pharmacy and its profession. An effort is made to cover every aspect of pharmacy to the greatest possible extent. - It is a book for all the pharmacy profession lovers. The book has tiny 3 chapters. Each chapter has information pertaining to pharma profession. - It’s systematic point-based flow helps to understand the basics of pharmacy, the Indian Pharmaceutical Industry and the Global Pharma world.

For those seeking to understand the vitally important processes that lead to new medicines and the surrounding ecosystem that is enabling the next generation of innovative medicines that have the potential to transform patient outcomes, Building Breakthroughs is essential reading.

This Handbook sized resource offers rapid, portable access to Pharma concepts you need to know. It is a wonderful source for quick answers, and an efficient review tool for any pharma aspirant. It is a must-read book for every student aspiring for good placement in any pharmaceutical industry. Its point-based approach will help aspirants to revise the concepts and perform well in interviews. Presents information in a concise, at-a-glance format for a convenient reference anytime. The Information is densely packed and can be read in shortest possible time with high degree of retention.

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Mathematical Modelling of Gene Expression A toolbox for treatment design targeting modulation of gene networks dynamics Designing efficient therapies to modulate epigenetics is a major challenge of precision medicine. Cells are composed by a plethora of molecular species subjected to randomness and multiple time scales, while dynamically interacting with environment. Application of mathematical methods for control of processes helps on the development of personalised treatment strategies. Alexandre Ferreira Ramos, School of Arts, Sciences and Humanities University of São Paulo, São Paulo Guilherme Giovanini, School of Arts, Sciences and Humanities University of São Paulo, São Paulo

espite all recent advances of molecular biology and imaging techniques, treatment designs based on pharmaceuticals still need enhancement to improve prognostics of patients while reducing the severity of side effects. The development of DNA sequencing techniques enabled an unprecedented increase of our understanding of genetic diseases such as cancer [1]. Cancer sub-types classification based on specific mutations, such as the mutation of Epidermal Growth Factor Receptor (EGFR) gene related to lung cancer, increased prognostic accuracy while providing the opportunity for early interventions. In some cases, that may even result in pre-disease surgical intervention as it may happen when mutations are detected in BRCA1 and BRCA2 genes as those may be key factors underpinning emergence of breast cancer. Because of

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its stationary character, however, knowledge of the genome of a patient is not sufficient to understand when or how a genetic disease manifests. The effects resulting from interaction with environmental factors and the dynamic character of expression of genetic information require the use of an additional conceptual framework. For that, experimentally validated mathematical models may play an important role. The post-genomic age is characterised by the necessity of knowing not only which genes are inside a cell but also when, where and how many products are synthesised from those genes. That propelled the field of epigenetics and opened a new avenue for designers of treatment strategies. As our understanding of epigenetics advances, treatment may be designed to exploit the coordinated dynamics of a plethora of

chemical components interacting inside the cell. A major goal of such an epigenetic engineering is to reprogram the cellular behaviour to increase chances of treatment success. That reprogramming is achieved by the proper manipulation of either gene networks or signalling pathways by means of genetic techniques that enable one to change the DNA or inputting chemicals that intervene on the amounts of products synthesized from a set of genes. In its simplest representation, a gene network is a set of genes and their products, namely proteins, also termed transcription factors (TF) because of their biological function. TFs bind to the regulatory regions of a gene and either stimulate or repress its expression. If the transcription factor from a gene A binds to the regulatory region of gene B to stimulate or repress its expression, we say that genes A and B interact. The reverse interaction may also happen. One may affect the dynamics of a gene network, EPIGENETICS is the discipline dedicated to the investigation of how the expression of a genome is governed by the multiple environmental inputs that affect the cell behaviour. GENE can be considered as a DNA sequence composed by the region encoding its protein and the regions to which regulatory components bind to modulate the amounts of products expressed from a gene.

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and hence, the amounts of products that it generates, by modulating the numbers of specific TFs. This modulation can be done by means of specific chemical agents driving the activity of signalling pathways that activate some TFs of a gene network governing a specific cellular process. This sort of reprogramming is achieved by target treatments, such as it happens in cancer [2]. Gene editing provides an additional opportunity for reprogramming cellular dynamics. One may inject Plasmids which will interact with the intracellular machinery participating in gene expression. Alternatively, one may use CRISPR to insert a specific sequence in the cellular DNA. Either the plasmid or the inserted sequence will drive the expression of transcription factors responsible for modulating the expression of specific gene networks so that the internal state of a cell may be redirected towards a condition favouring a patient. Note, however, that one designing treatment strategies based on re-modulation of gene networks may need to take into consideration a few intrinsic features of the intracellular environment. Here we consider the unavoidable stochasticity and multiple time scales of the internal processes of the cell. Randomness of intracellular biochemical processes was predicted a long time ago by Max Delbruck. That happens because of the small number of copies of reactants interacting inside the cell. Hence, the time interval between subsequent reactions vary and, that causes a more proeminent variability on the number of reaction products. Such a randomness introduces an additional challenge for engineering the epigenetics of a cell, since predictability of stochastic processes can only be done in terms of probabilities. Hence, treatment designers will need to incorporate the probabilistic thinking to their conceptual framework. Besides, the processes taking place inside the cell have a multiplicity of characteristic time-scales. That sets an additional challenge, because one may aim to design a treatment in which the

EXAMPLES OF GENE NETWORKS Externally regulated gene is a gene which expression is regulated by TF encoded on other genes. Self-regulating gene is a gene which expression is regulated, positively or negatively, by the TF that it encodes. Repressilator is composed of two genes, A and B, and the TF from one gene represses the expression of the other. drug and the chemical process affected by it have an optimal coupling. However, either the drugs and the cellular processes have their own characteristic time scales. Therefore, the time of response of each combination of drug and chemical process will vary accordingly. This biological picture illustrates some complex challenges to be faced by those aiming to design new treatment strategies based on genetics or epigenetics tools. Experimental methods have been employed with success on treatment design, but precision medicine will also benefit from the use of mathematical and computational tools. These enable the construction of testable quantitative models aimed to help experimentalists to reduce their set of hypothesis to be tested at the bench. Computational tools, mainly devoted to data analysis, may enable the discovery of unexpected patterns on the dynamics of biological systems. One example is the analysis of gene expression in the cells of a tissue under healthy or disease condition. Application of bioinformatics methods on online data revealed that variability in gene expression levels, measured by variance, increases during disease. Indeed, a major feature of tumours is their heterogeneity, caused by re-modulation of gene networks towards differential expression levels that are still capable of holding the viability of cells [3]. Besides insights about the biology of cells, the results of data analysis may also be summarised in effective mathematical models which may play a descriptive role at first and, eventually, provide testable

predictions. The latter is a more ambitious goal of theoreticians as it means a deeper understanding of the workings of biological systems. To be considered as predictive, however, a model is subjected to multiple tests designed to provide validation. As those models "pass the tests" they motivate insights about the functioning of biological systems that can be increasingly useful. One possible approach for building such effective models is to consider the building blocks (or elementary processes) composing a given system. One example is the functioning of an externally regulated gene. In a human, regulation of gene expression is a complex process which is hard to assess experimentally. Thus, one might use a mathematical model to aid on the understanding of the dynamics of an eukaryotic gene . For simplicity, we take the externally regulated gene. As a first approximation, we describe it as a source that switches between ON and OFF states. When the source is ON, the gene products are synthesised at a rate that depends on specific characteristics of the gene such as its affinities to the transcriptional machinery. The rate of the switching of the source may be represented by constants that PLASMID is a small DNA commonly found in bacteria, in circular form. It is transcribed independently of the DNA of the chromosomes. Currently, techniques allow the synthesis of artificial plasmids to serve as vectors that carry genes of interest to be expressed in a particular cells, which may be prokaryotic or eukaryotic. CRISPR (clustered regularly interspaced short palindromic repeats) is the term used for a set of stretches of DNA repeated in a region of the strand, which were first identified as an antiviral defense mechanism in bacteria. The association of CRISPR with DNA-cleaving enzymes, such as Cas9, allowed the creation of a gene editing technique in specific regions of the DNA strand. www.pharmafocusasia.com

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MATHEMATICAL MODELS: we consider as a mathematical model a system which state is described by some set of equations built to govern the dynamic behaviour of the dependent variables of the system. Typically, the independent variables of those systems are time and position of a given entity which is aimed to be described by the mathematical model. STOCHASTIC MODELS: mathematical models may be divided in deterministic and stochastic. A model is called deterministic if one may predict its state at a future time once the initial conditions of the system are provided. Alternatively, if the future state of a system, provided its initial conditions, is predicted accordingly with probabilities, then we have a stochastic model. reflect the state of the regulatory region of the gene during some small time interval. Additionally, the gene products also decay. Hence, the state of this system is determined by the source being ON or OFF and by the number of gene products being 0, 1, 2, and so on. The cartoon in Figure 1 is an effective description of the functioning of an externally regulated gene. It indicates the existence of a combination of four parameters, each related to one process participating on the regulated expression of a gene. Additionally, one needs to consider the randomness of the intracellular processes. That leads to the necessity of building a stochastic model to govern the evolution of the probabilities of finding the gene in a given state. One possible model has been around for a few decades and is fully solvable [4,5], which means that one may get explicit mathematical formulas to express the probabilities of finding the gene in a given state either at the timedependent and stationary regimes. After obtaining the time-dependent solutions one notes the existence of two time-scales governing the dynamics of expression of the externally regulated gene: the first is associated with the i. synthesis and 52

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degradation of gene products which is the degradation rate; the second is related to the ii. promoter switching between ON and OFF states and is given in terms of the average frequence for the gene to complete a switching cycle between states ON/OFF/ON (or vice-versa). A next step on the modelling procedure is to perform an inference of the values of the parameters of the model for a specific gene. The estimation is based on experimental data and can be considered as a challenge per se. First one must build a system which gene expression dynamics can be monitored. Molecular biological techniques recently developed enabled one to introduce fluorescent proteins which can be imaged by means of confocal microscopy. Those techniques are sufficiently advanced to enable one to molecularly engineer a large set of potentially useful genes. Hence, the selection of the gene may be mostly guided by biological or biomedical criteria such as its potential role as a master regulator in a cancer cell. Once a model system is devised, it may be used for benchmarking treatment designs by monitoring how it affects the expression of a master regulatory gene. One may combine both the experimental data and the mathematical model for parameter values inference. Since the

TIME-DEPENDENT AND STATIONARY REGIMES. In the time-dependent regime, the dependent variables governed by the system of equations representing a given system do change with time. In the stationary regime, the variables stop changing. A warning is necessary: in the stochastic description a system is in the stationary regime if the probabilities of finding the system in each state do not change. However, it does not mean that the state of the system is constant. One example is an unbiased coin being flipped: the probabilities of finding the head or tail are constant but at each toss the face up may change with probability 0.5. mathematical model is fully solvable, one may establish the dynamics of the average number of transcripts and their fluctuations. Moreover, in disease state, such as cancer, the patterns of expression of master regulatory genes may be changed. Hence, a fair treatment goal is to reestablish gene expression levels towards those found in a healthy state. In the case of cancer, that may imply on the need of administration of multiple doses to ensure that the expression does not return to disease related levels.

Figure 1: Drugs aiming at kinetic rates of the gene target transcription. Here we only consider two drugs. Drug aims to increase the proportion of time during which the gene is in the ON state. Drug increases the affinity of the gene to the transcriptional machinery. Treatments consist of administering one (or a combination of) drug(s) following a dose agenda.

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Figure 2: The effectiveness of a treatment that targets the four processes of the externally regulated gene of Figure 1. Graph A shows the effect of decay rates of drugs on the increase of mean expression levels (fold-change) for a dose of both drugs administered concomitantly. In this graph, the region colored in red shows the most effective combination of drug decay rates. Graph B shows the dynamics of the average levels (green line) and fluctuations of the number of gene products (region delimited by the red lines). Treatment aims at keeping lower red line above a threshold (dashed black line). In our simultions, that is reached using four drugs, where effectiveness is measured by the speed with which the response reaches a threshold (dashed line). That goal enables a reduction of the heterogeneity of response to treatment. <n> and std are, respectively, the average and the standard deviation of gene products number n. Time is given in hours.

Bibliography

[1] Mukherjee, S. The emperor of all maladies: a biography of cancer. 2011. Harper Collins Ed. [2] Yesilkanal, A.E.; Yang, D.; Valdespino, A.; Tiwari, P.; Sabino, A.U.; Nguyen, L.C.;

Lee, J.; Xie, X.H.; Sun, S.; Dann, C.; et al. Limited inhibition of multiple nodes in a driver network blocks metastasis. eLife 2021, 10, e59696. doi:10.7554/elife.59696. [3] Zaravinos, A.; Bonavida, B.; Chatzaki, E.; Baritaki, S. RKIP: A Key Regulator in Tumor Metastasis Initiation and Resistance to Apoptosis: Therapeutic Targeting and Impact. Cancers 2018, 10, 287. doi:10.3390/cancers10090287.

AUTHOR BIO

The above goal of maintaining expression levels, and fluctuations, of specific genes within specific ranges of values can be approached by means of control theory. This mathematical formulation enables one to dynamically adapt drug dosage to ensure that expression levels and fluctuations remain within the necessary range [5]. That formulation must be fully tested in laboratory before it can become available for treatment. However, it is a promising direction for further developing gene therapies or treatment designs aiming at modulating gene networks dynamics. Once a control model for regulation of gene expression becomes fully validated, one may even consider the possibility of designing drug delivery machines that would control drug dosage automatically based on some set of data about a specific process taking place in a tissue.

[4] Peccoud, J.; Ycart, B. Markovian modelling of gene product synthesis. Theor. Popul. Biol. 1995, 48, 222–234. doi:10.1006/ tpbi.1995.1027. [5] Giovanini, G.; Barros, L. R. C.; Gama, L. R.; Tortelli Jr, T. C; Ramos, A. F. A Stochastic Binary Model for the Regulation of Gene Expression to Investigate Responses to Gene Therapy. Cancers, 2022, 14, 633. doi:10.3390/cancers14030633.

Alexandre Ferreira Ramos (Assistant Professor, University of São Paulo, Brazil) coordinates the Applied Mathematics and Biological Physics laboratory (AMPhyBio). Investigates biological and biomedical phenomena using group and graph theory, stochastic processes, statistics, simulations, digital image analysis, machine learning, and high performance computing. Control theory-based treatment design is a next frontier of investigation. Guilherme Giovanini holds a degree in biological physics and a master degree in modeling complex systems (University of São Paulo, Brazil). Under the supervision of Prof. Alexandre Ramos, he studies quantitative models for designing treatments aiming the expression of target genes in cancer.

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INFORMATION TECHNOLOGY

DRIVEN BY DATA A ROADMAP TO BIOPHARMA’S DIGITAL FUTURE Biopharma’s efforts to digitally transform operations are proving more important than ever to drive improvements in process efficiency and deliver essential treatments to patients. However, the industry’s attempts are returning mixed results and the digital transformations of many enterprises remain in early-phase development. As with any business initiative, a lack of clear goals and strategies keeps some biopharma programs from being successful. As a result, these shortfalls may be further preventing many companies from moving toward the more data-driven future the industry needs to deliver reliable access to better performing, more affordable medicines. It is clear biopharma needs a shared vision and a strategic roadmap to achieve digital transformation. Samsung Biologics’ technology strategist James Choi proposes an instrumental strategy that could drive the digital transformation of biopharma organisations and prepare themselves and the industry for the road ahead. James Choi, Executive Vice President and Chief Information & Marketing Officer and head of Global Public Relations and Process Improvement, Samsung Biologics

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espite great effort and expense implementing data-driven business models and processes, the biopharma industry’s attempts to digitally transform operations are returning mixed results. Those in the industry understand the competitive and pertinent imperatives, especially post COVID-19, but recent polling indicates that for many enterprises, their digital transformations remain in early-phase development. As with any business initiative, lack of standards, vision, and strategy are hindering digitalisation programs from success. This is preventing biopharma from moving toward the more data-driven future which the industry needs to offer reliable accessibility to better performing and more affordable medicines. It is clear that biopharma needs a shared vision and a clear strategic roadmap to achieve digital transformation. Samsung Biologics’ Executive Vice President and Chief Information & Marketing Officer

INFORMATION TECHNOLOGY

and head of Global Public Relations and Process Improvement, James Choi offers fresh thinking and a vision biopharma’s leaders need to drive digital transformation in their organisations and prepare themselves and the industry for the road ahead. Accelerating biopharma’s digital transformation

The rise of globalisation and business expansion has led to more and more companies undergoing mergers and acquisitions and as a result, siloed approaches, digital infrastructure compromised of dated legacy systems, and poor data integrity have become increasingly common. Despite the biopharma industry being heavily focused on accelerating change, polling has revealed that there is still some hesitancy to accelerate the pace of adopting data-driven digital business models1. The lack of consistency in the uptake of innovative methods to implement digitalised solutions is proving to be unsustainable. Addressing this problem and accelerating progress will require the adoption of industry-developed standards to ensure improvement of efficiency and maintenance of data integrity. The need to alleviate manufacturing complexity

Innovative technical advancements and discoveries have allowed us to enter into an era in development where drugs have become increasingly personalised. This has been highlighted by the rising popularity of cell and gene therapies. However, as biologics become progressively more complicated, the complexity of their manufacturing process rises in parallel. Their production can also necessitate more convoluted supply chains or special logistics and handling requirements than traditional small molecule drug products. It is essential that the quality of the biologic is maintained despite rising intricacies, but as the complexity of a process increases, so does the probability of error. This is further compounded by manual processes that add to the

likelihood of mistakes being made. As a result, biologic production could face an increase in cost, a reduction in product quality, and ultimately, the potential to impact patient safety. Manufacturers will need to carefully consider methods to prevent increasing production complexities from affecting the quality of the biologic while improving efficiency. This can be achieved by correctly implementing digital tools, data-driven business models, and operational models while having a thorough understanding of their potentials and limitations. Set goals strategically from the start

True digital transformation should be focused on reducing complexity as well as transforming and easing the experience employees have managing it. Before embarking on a digital transformation journey, the organisation must clearly outline the goals it hopes to achieve. These goals should be centered around

The major regulations currently governing electronic records and DI controls are 21 CFR (Code of Federal Regulations) Part 11 published by the FDA and its European equivalent EudraLex (the collection of rules and regulations governing medicinal products in the EU) Vol.4, Annex 11.

implementing digital transformations in a way that is client-focused while optimising business or operational processes by applying process improvement principles. Go digital, not paperless

Digital transformation initiatives can often result in false starts and inefficiencies if goals and objectives are not well thought through. A common mistake that is made in digitalisation efforts is the focus on ‘going paperless,’ with the primary performance metric being the elimination of paper alone. When digital technologies are implemented correctly, they have the potential to minimise human error throughout the creation, recording, management, storage, and archival of data. As a result, the use of digitised solutions in previously paper-based processes is often mistakenly equated with improvement and enhanced data integrity. Example: Digital logbooks for tracking assets

Converting paper entries into electronic logs via a digital logbook can make assets and any changes made to them easier to track. However, from an end-user perspective, switching from manual entry to a keyboard and screen may only be marginally more convenient. Although a paperless environment can be achieved with digitalisation efforts, it should not be the sole indicator of success nor the initial objective. Identifying and converting paper-based forms and procedures to electronic means requires broader, strategic reasoning as opposed to merely forgoing manual processes and can jeopardize potential productivity gains. A more optimal approach in this example would be to analyse the actual information that is needed from the source (asset) and eliminate the need to manually collect it in the first place. By connecting the asset (a lab instrument or equipment) to a centralised system instead, information that would have been entered into the logbook can be collected automatically, obviating the need for a logbook – paper or electronic – to begin with.

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INFORMATION TECHNOLOGY

SOAO approach: Simplify, Optimise, Automate, Outsource

The ideal digitalisation strategy is counterintuitive. Rather than focusing immediately on the technology solution, the existing manual processes first need to be examined using the SOAO method: Simplify, (then) Optimise, (then) Automate, (then) Outsource (if appropriate). Implementing a SOAO approach can ultimately drive business growth and innovation by offering several advantages: • Business optimisation enabling real scalability • Enhanced employee experience and productivity • Faster access to the right information when needed • Greater returns on digital investments • Improved customer value Simplification

Implementing digitalisation without process simplification is not advised. The goal of the simplification step is to streamline all parts of the procedures and processes to maximise efficiencies while delivering client value. Achieving this necessitates the thorough evaluation and assessment of each step, ensuring that all are critical and/or add real value, and removing those that do not.

• Eliminating the need for certain forms or existing procedures entirely (as in the previous logbook example) • Facilitating comprehensive data reporting in real-time • Allowing data to be followed throughout its lifetime with time stamps • Centralising all sources to a single hub or data repository for more efficient and in-depth analysis Outsource

Optimisation

Once non-critical aspects of the chosen process have been eliminated, those remaining should be optimised to the highest degree possible. There are various methodologies that could be applied and adopted, including Lean Six Sigma, DMAIC (define, measure, analyse, improve, and control), and SIPOC (suppliers, inputs, process, outputs, and customer) analysis. By optimising before automating, businesses can avoid proliferating poor processes that can create even more waste and inefficiencies. Automate

Following optimisation, organisations can begin to introduce automation and computerised systems. These can improve processes in many ways: 56

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Finally, companies implementing the SOAO method will need to carefully consider whether outsourcing digital business processes could be a suitable longer-term strategic decision. This decision should ultimately be made with the interest of its clients and shareholders held above all else. Outsourcing certain digital processes to reliable companies can improve both agility and focus. It also provides the ability to leverage cost structure and expand scalability. The advantages of implementing the SOAO method

Adopting the SOAO approach to a digitalisation strategy can impact and improve many different important areas in manufacturing by alleviating challenges surrounding their complexities.

Data integrity and compliance efficiency

One of the most important factors in regulatory compliance currently is data integrity. The major regulations currently governing electronic records and DI controls are 21 CFR (Code of Federal Regulations) Part 11 published by the FDA and its European equivalent EudraLex (the collection of rules and regulations governing medicinal products in the EU) Vol.4, Annex 11. These regulations have been consistently updated since their introduction and have helped to shape local regulations around the world. The adoption of digitalised solutions by manufacturers in a “technology-first” approach has led to a considerable increase in breaches of these regulations. In 2018, up to 75 per cent of the FDA’s manufacturing warning letters cited DI as an issue, as compared with 28 per cent in 20142. By adopting a digitalisation strategy like SOAO, as well as assuring data integrity with ALCOA principles (attributable, legible, contemporaneous, original, accurate, enduring, available, accessible, and complete), companies can avoid non-compliance with regulations. If not, they may risk recalls, delays, and denied drug approvals.

INFORMATION TECHNOLOGY

There are many elements and processes involved in a secure supply chain that are data-driven, and these can present significant challenges: • Raw material supplies require monitoring to avoid potential disruptions • Track and trace and serialisation are needed to meet security compliance • Cold chain capabilities and personalised medicines have additional demands during transport Digitalised solutions, including blockchain (a shared ledger that can be used to record transactions and track assets) and other technologies, offer potential solutions. Using an approach like SOAO to implement these solutions and alleviate supply chain challenges is necessary to avoid building processes on poorly designed strategies, which could cause more problems in the long run.

their implementation. It is understandable that companies are wary of adopting the wrong strategy in their digitalisation. A “technology-first” approach with an aim to go paperless without a thorough understanding of the process that is being improved can cause more challenges in the future, particularly when considering regulatory compliance. The digital future of biopharma is still in its formative stages, but the path to digitally-enabled data-driven operations and business practices is becoming well defined. It is therefore important to choose a manufacturing partner that

has adopted strategies like the SOAO approach to systematically simplify, optimise, automate, and potentially outsource processes to improve efficiency and quality.

1.https://www.pharmamanufacturing.com/ articles/2021/smart-pharma-survey-resultspharmas-digital-prowess-put-to-the/ 2. https://redica.com/pharma-medicaldevices-data-integrity-breaking-downkeywords-and-citation-trends-from-the-fda/

AUTHOR BIO

Supply chain integrity and reliability

Customer and regulator communication and transparency

It is important that clients can access their data throughout the project, as well as their quality information and the status of their products. This can be achieved by leveraging secure cloud technologies, providing an infrastructure that is scalable and accessible to clients, contract partners, and regulators regardless of where they're located. Cloud technologies also act to reduce human errors, thereby ensuring that quality is maintained. Transparent communication with customers and regulators is essential to build trust and prevent project delays. As well as cloud technologies, there are many solutions and resources available that can further facilitate open communications and foster strong relationships: • Secure portals for document access • Virtual PIP (person in plant) • Live Virtual Tour (Remote audits and inspections) Time for biopharma to secure its digital future

Biopharma manufacturers may be aware that viable technologies are currently available, but there is a significant delay in

Prior to joining Samsung Biologics in 2014, James Choi held various technology and operations leadership positions at major global healthcare and informatics corporations. Choi began his career with Philips Healthcare in 1989 as Site Planning Manager and advanced through leadership positions in Customer Service eBusiness and Technology, Operations, and Information Systems for North America. Mr. Choi then transitioned to the Informatics and Security industry and was CIO for a major background investigation, insurance intelligence, and commercial pre-employment screening company.

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Research Insights VACCINE EQUITY

A fundamental imperative in the fight against COVID-19 • The PLOS Medicine Editors • Affiliation Public Library of Science, San Francisco, California, United States of America and Cambridge, United Kingdom Published: February 22, 2022 Citation: The PLOS Medicine Editors (2022) Vaccine equity: A fundamental imperative in the fight against COVID-19. PLoS Med 19(2): e1003948. https://doi.org/10.1371/journal.pmed.1003948 Published: February 22, 2022 Copyright: © 2022 The PLOS Medicine Editors. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors are each paid a salary by the Public Library of Science, and they wrote this editorial during their salaried time. Competing interests: The authors’ individual competing interests are at http://journals.plos.org/plosmedicine/s/competing-interestsof-the-plos-medicine-editors. PLOS is funded partly through manuscript publication charges, but the PLOS Medicine Editors are paid a fixed salary (their salaries are not linked to the number of papers published in the journal). Provenance: Written by editorial staff; not externally peer reviewed. The PLOS Medicine Editors are Raffaella Bosurgi, Callam Davidson, Louise Gaynor-Brook, Caitlin Moyer, Beryne Odeny, and Richard Turner.

On March 11, 2020, WHO declared the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) a global pandemic. Now, almost 2 years on, COVID-19 continues to cause widespread morbidity, mortality, and disruption, both directly and indirectly, on a global scale. The speed at which multiple effective vaccines were developed is a remarkable achievement and testament to scientific advances and collaboration. However, numerous barriers to global vaccination efforts have left 47% of the world’s population unvaccinated or only partially vaccinated to date, with huge disparities between countries in the proportion of fully vaccinated individuals ranging from 0% to 95%. Barriers such as vaccine hesitancy and anti-vaccine

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movements have hindered the progress of vaccination efforts, and have been perpetuated by fears over vaccine safety and the spread of misinformation and disinformation, despite the wealth of evidence supporting the benefits of vaccination. Adding to the evidence on vaccine safety, in this issue of PLOS Medicine, William Whiteley and Steven Kerr and respective colleagues have shown in large-scale observational studies that the Oxford-AstraZeneca vaccine is associated with no more than a small elevated risk of intracranial venous thrombosis and cerebral venous sinus thrombosis, respectively. The risks of cerebral venous thromboses are far greater following COVID-19 infection, further underlining the demonstrated benefits of vaccination.

Inequity of access to vaccines has posed a significant barrier to vaccination in low- and middle-income countries (LMICs), despite calls for action to achieve equitable distribution and production of COVID vaccines from WHO and the UN Development Programme [6]. In addition to the health risks to unvaccinated individuals of contracting COVID-19, greater opportunities for infections and viral mutations leave the world vulnerable to the emergence of new variants which threaten to evade our defences and undo progress made. Most recently, this has been seen in the emergence of the Omicron variant of concern. It is without doubt that vaccination rollout must be equitable and fair on a global scale. Despite tireless efforts by public health experts to extol the benefits of vaccine equity throughout the pandemic, global vaccination rates remain woefully unequal. As of February 1, 2022, approximately 183 COVID-19 vaccine doses had been administered per 100 people in high-income countries, compared to just 14 doses per 100 people in LMICs. The COVID-19 Vaccines Global Access (COVAX) initiative was launched in April 2020 with the intention of addressing this imbalance through accelerated development, production and equitable distribution of vaccines. Yet, by December 30, 2021, only 7 African countries had achieved their target 40% vaccination rates, which leaves us with the question of how vaccine inequity can be tackled and what can be done to overcome barriers to vaccination. To begin untangling this complex issue, we must first consider what a country needs to successfully vaccinate its population. A reliable supply of vaccines is the first step. The COVID Global Accountability Platform (COVID GAP) reported that in November 2021, just 20% of the doses pledged by G7 countries had been shipped to LMICs and there are additional reports of vaccines arriving close to their expiration dates, rendering them unusable. Equally essential to vaccine rollout are health infrastructure, trained medical personnel, appropriate vaccine storage facilities, accessible vaccination sites, health literacy, and public willingness to take vaccines. Furthermore, limited supplies of vital equipment such as syringes risk derailing vaccination efforts, with shortfalls of between one and two billion syringes projected by the end of 2022. Scientists, academics and public health experts have collaborated to publish open letters to governments in high-income countries, recommending increased financial and operational support, and a temporary waiver of intellectual property rules to expand capacity for vaccine manufacture in LMICs themselves. Of particular relevance is the World Trade Organisation (WTO) Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS), which sets the minimum standards for regulation of different forms of intellectual property applicable to WTO member nations. In May 2021, delegations from WTO members representing multiple LMICs issued a communication proposing a waiver from certain provisions of the TRIPS agreement to facilitate

‘the prevention, containment and treatment of COVID-19’. At the time of writing, a decision regarding the proposal is yet to be reached. Expanding vaccine manufacturing capacity in LMICs offers an opportunity to bring the current pandemic under control and to enable a more coordinated, rapid global response to the current and future pandemics. Currently, Africa imports 99% of its vaccines, but the Africa Centre for Disease Control and Prevention (Africa CDC) launched the Partnership for African Vaccine Manufacturing in April 2021, with ‘the proposed ambition to manufacture 60% of Africa’s routine immunisation needs on the continent by 2040’. With this independence comes the potential to tailor vaccines to the needs of local populations, such as in outbreak situations, and to maintain the efficacy of vaccines through improved management of the vaccine cold chain. Such an ambition will only be possible with international cooperation, including from the pharmaceutical companies that own the intellectual rights to the vaccines. Progress is being made towards increasing production of COVID-19 vaccines in Africa; however, the projected annual manufacturing rates fall short of meeting the needs of the continent’s 1.3 billion inhabitants, particularly when factoring in the multi-dose regimen for COVID vaccines. Given that 120 pharmaceutical companies have been identified as meeting the technical and quality standards required for manufacturing sterile injectables across Asia, Africa and South America, there is significant potential for introducing geographic diversity in vaccine manufacture. The right support from pharmaceutical companies, medicines regulatory authorities and national governments is essential. Achieving vaccine equity presents an essential, but substantial and highly complex, policy challenge. Beyond fundamental issues such as health infrastructure and the availability of trained personnel and medical equipment, unreliable supply and distribution of vaccines in LMICs must be addressed as a matter of urgency, and must happen alongside public health campaigns to challenge misconceptions and address vaccine concerns. Empowering LMICs to develop and/or expand their own vaccine manufacturing capabilities provides a longerterm and more sustainable solution to achieving global vaccination coverage, for COVID-19 and many other infectious diseases. Achieving this necessitates a coordinated effort across multiple agencies, requiring strong national and international leadership and formation of public–private partnerships, as well as scientific and technical expertise and public pressure to instigate change. To surmount this global pandemic, we have a collective responsibility to find a global solution. References are available online at https://journals.plos. org/plosmedicine/article?id=10.1371/journal.pmed.1003948.

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Pharma Focus Asia - Issue 46

Articles inside

Vaccine Equity A fundamental imperative in the fight against COVID-19

Driven by Data A roadmap to biopharma’s digital future

Bright Future for Asia M&A

Mathematical Modelling of Gene Expression A toolbox for treatment design targeting modulation of gene networks dynamics

Vaccines Against SARS-CoV-2 Current situation and future perspectives

The Aggregate Safety Assessment Plan A valuable tool for clinical trial safety planning

Proposome, an Efficient and Safe Topical Formulation

St.Gallen OPEX Benchmarking for Pharmaceutical Manufacturing Sites Measure yourself against the best but do it right

2022 Trends in Pharma Marketing

COVID-19 Where are we heading in 2022?