IPI Spring 2022

Volume 14 Issue 1

Peer Reviewed

Reasons Why Flexibility is the Secret to Pharma Success in 2022 The Enigma of Topical Biologics Development Improved Antibody Purification Process Through Use of Additives New Manufacturing Technology Platforms for Biosimilars

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Contents 06 Editor’s Letter REGULATORY & MARKETPLACE

DIRECTOR: Mark A. Barker BUSINESS DEVELOPMENT: Michael Hossain michael@senglobalcoms.com Imran Sheikh imran@senglobalcoms.com EDITORIAL: Virginia Toteva virginia@senglobalcoms.com DESIGN DIRECTOR: Jana Sukenikova www.fanahshapeless.com FINANCE DEPARTMENT: Akash Shama accounts@senglobal.com RESEARCH & CIRCULATION: Jessica Chapman jessica@senglobalcoms.com COVER IMAGE: iStockphoto © PUBLISHED BY: Senglobal Ltd. Unit 5.02, E1 Studios, 7 Whitechapel Road, E1 1DU, United Kingdom Tel: +44 (0) 2045417569 Email: info@senglobalcoms.com www.international-pharma.com All rights reserved. No part of this publication may be reproduced, duplicated, stored in any retrieval system or transmitted in any form by any means without prior written permission of the Publishers.

The next issue of IPI will be published in Summer 2022.

ISSN No.International Pharmaceutical Industry ISSN 1755-4578.

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

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08 How Managing the Simple Medical Device Label Could Make or Break Nordic Expansion Ambitions for Manufacturers The Nordic region is a potentially lucrative area for medical device companies to expand into, with analyst research estimating Sweden alone to have a 2.7% market share of the €140bn European medical device market. But practical challenges, in particular operational obstacles on the regulatory side, have deterred many manufacturers from making the leap into this geography. Bob Tiling at Kallik, explains how effectively managing the simple device label could be key to overcoming the challenges of entering the Nordic market.

10 Will Universal Pharmacare be Introduced in Canada?

Prescription drug insurance in Canada is provided by a mixture of government and private plans. Government plans offer coverage to about a quarter of the population comprising seniors, social assistance recipients, children and some other groups, while private plans cover over two-thirds of Canadians paid for by themselves or cost-shared with employers, unions or associations. Nevertheless, a significant proportion of Canadians have no insurance. This situation has led to inequalities in patient access to medicines. Nigel Rawson discusses the current federal government plans to introduce a universal pharma care program to overcome these issues, but he reckons that one of the challenges will be its cost.

14 The Big Debate: Will Quality Management Still Exist in 2025?

Late last year, visionaries from Merck, Syneos Health and Accenture took part in a live video debate on what now influences the way life sciences companies manage Quality – and what the future holds for the discipline, including the potential to pre-empt and minimise Quality issues using AI technology. James Kelleher at Generis chaired the proceedings, which included a live audience poll.

16 Reasons Why Flexibility is the Secret to Pharma Success in 2022 Ben Wylie at ChargePoint Technology looks back on key learnings from 2021 for cleanroom pharmaceutical manufacturing. He explores why flexibility is key to overcoming sterile processing and efficiency challenges to achieve market success in 2022.

Accelerating Asia’s Digital cGXP Transformation with Industry 4.0 Technologies Across Asia, pharma leaders are working hard to accelerate their Industry 4.0 digital transformation and, in the process, ensure current Good Practice (cGXP) compliance. IDC analysts found Asia’s digital transformation is accelerating in response to post-pandemic market dynamics. How can Asia’s drug manufacturers throttle up digitisation efforts effectively? Kenneth Teo at Cognizant offers insight into IDC findings as well as fresh strategies on how the region’s leaders can improve operations by adopting digital technologies.

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DRUG DISCOVERY, DEVELOPMENT & DELIVERY 24 Roundtable: The Continuing Evolution of Bioinformatics in the Pharma Industry In life sciences, research, advances in instrumentation, new types of measurements that are now possible and improved computational tools are generating not only significantly more data than ever before but also more diverse modalities and higher resolution data. Marilyn Matz and Zachary Pitluk at Paradigm4 discusses how pharma and biopharma organisations, can leverage the new ‘mountain’ of available INTERNATIONAL PHARMACEUTICAL INDUSTRY 1

Contents data to open the potential for them to expedite the discovery and delivery of new, more effective, safer therapies for patients.

28 Improving Outcomes for Gastric Cancer Patients via a Novel Oral Daily Dose Chemotherapy Formulation, Oncoral Gastric cancer is the fifth most common cancer, with around one million annual incidences worldwide, and it represents the fourth most common cause of cancer deaths. High incidences of the disease in Asia mean that screening in countries like Japan have made survival rates better than in Western countries, where the disease is often already advanced by the time of diagnosis. The gastric cancer drug market is growing rapidly and is expected to approach USD 4 billion by 2029 according to GlobalData. Carl Bjartmar at Ascelia Pharma analyses why this growth, is fuelled by several factors, including an increase in the overall incidence, as well as higher treatment rates and extended treatment duration.

32 The Enigma of Topical Biologics Development Traditionally, most marketed drugs, irrespective of their route of delivery, have had relatively low molecular weights. Nowhere has this been more markedly true than in topical drug delivery.

Historically, it was thought that to successfully permeate healthy skin, molecules must be of less than 500 Daltons, and must be moderately lipophilic with a low melting point and high potency.

These rules, of course, were driven by the need to overcome the natural barrier function of the skin, which is designed to protect the body from physical, mechanical and chemical insult whilst further providing a barrier to endogenous water loss. The barrier function of the skin largely derives from the non-viable, thin (10–30 µm) cornified outermost layer, the stratum corneum. Dr. Jon Lenn and Marc Brown at MedPharm tries to answer the question as to whether large biologics can be delivered to/through the skin effectively enough for clinical relevance.

CLINICAL & MEDICAL RESEARCH 36 Study Coordinators Speak Out on Trial Site Diversity: 4 Ways to Move the Needle In recent years, a consensus has grown around the concern that clinical trials in the United States are neither adequately inclusive nor diverse.

For example, the latest data shows that nearly 75% of patients who are enrolled in industry-sponsored clinical trials in academic medical centres and community hospitals are white – as compared to 58% of the general U.S. population. These realities are reflected in trial performance and outcomes of approved medicines in the general population – a population only partially represented in the research. That means that medicines are not being created for everybody. While this isn’t new, Mary Costello at Medablethe discusses the COVID-19 pandemic and the corresponding race for vaccines and treatments have shone a spotlight on the problem so bright that it can no longer be ignored.

38 Tackling the Challenges with Decentralised Trials Decentralised clinical trials (DCTs) have existed for years in different shapes and forms. Urged by the COVID-19 pandemic, restrictions to in-person patient visits and other challenges with access accelerated the implementation of new tools and technologies to keep trials moving forward. Rik Van Mol at Veeva Systems reveals that the pandemic also unveiled many of the challenges of traditional clinical trial models, including the fragmented use of digital, stand-alone applications.

42 Evolving Clinical Trial Landscape Requires Quality Focus The strive to deliver the very best outcomes sits at the heart of clinical research. Arguably the mechanism for delivering that “perfect” outcome 2 INTERNATIONAL PHARMACEUTICAL INDUSTRY

rests squarely on the shoulder of a single key principle – quality. Quality permeates all areas from study design to data collection, to successful publication, and many more. The idea of quality includes a vast array of perspectives gained from the evolution of trends in the development of quality management practices. For example, Good Clinical Practice (GCP) is regarded as the ethical and scientific quality standard for conducting a trial and applies to all steps in the process that combine for a successful trial conclusion. John Buchan at Pharmasol states, that the GCP role is to ensure that the clinical trial data and reported results are credible and accurate and that the rights, integrity, and confidentiality of the trial subjects are protected.

44 Real-world Data Can Bridge the Gap Between Traditional Trials and a Patient-centric Future Patient safety has been the primary focus of clinical trial design since 1947 when the Nuremberg Code outlined the ethical guidelines for clinical research. Consisting of ten points, those most directly relating to patients dictated that trials must be designed to avoid all unnecessary injury or suffering, that patients must give consent and are free to leave the trial at any point. Karen Ooms at Quanticate, discusses that the Code pervades all existing guidance and the current world of drug development governed by ICH-GCP makes it mandatory to have all necessary steps taken by sponsors, CROs and investigators to keep patient safety as utmost priority.

TECHNOLOGY 48 Improved Antibody Purification Process Through Use of Additives Downstream biopharmaceutical processing utilises a series of interlocking and sequential operations, including filtration and process chromatography steps, that incrementally increases the purity of the target therapeutic molecule by exploiting the physical and chemical properties of that molecule. Jungmin Oh at Avantor, says that it is critical for therapeutic monoclonal antibodies (mAbs) to have very high purity with low product-related and process-related impurities (host-cell proteins, DNA, leached protein A and aggregates) in order to be administered to patients safely.

MANUFACTURING 52 The Role of the Clean Room in LAL Production The standard endotoxin test utilises a reagent called Limulus Amoebocyte Lysate (LAL). This test is the most widespread test of bacterial endotoxin in parenteral injections and medical accessories. In the production of LAL, many invisible factors contribute greatly to the quality of the product.

Since it is the de-facto standard for the vital detection of endotoxins in pharmaceuticals and medical instruments, the production of the reagents must be at the highest order of cleanliness. The development of cleanroom technology has created an environment that allows for large scale production of an extremely effective endotoxin test. As clean rooms allowed the LAL test to become a widely produced pyrogen test, Timothy Francis at FUJIFILM Wako Chemicals U.S.A. Corporation, reckons that clean rooms also allow for the continued development of the next generation of endotoxin tests.

56 Putting your ATMP Process on the Map: Strategies for Scaling out Facilities to Meet Commercial Development Realities Cell, gene, and tissue therapies are transforming medicine, showing meaningful efficacy in treating – or even curing – diseases once thought intractable, says Grant Merrill at AES Clean Technology. Known as Advanced Therapy Medicinal Products (ATMPs) these, modalities exhibit the potential to cure disease by addressing its root cause rather than treating it symptomatically.

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Contents 60 Emerging Challenges for Data Integrity in the Pharmaceutical Sector Processing power has completely reshaped manufacturing over the last 20 years, especially in pharmaceutical production. Businesses can now monitor, analyse and model far more data than ever before, which has led to significant advances in drug discovery and development, says Peter Cusworth at Yokogawa. Automated machinery has also allowed production to expand at an unprecedented scale giving more people greater access to the medicines they need.

PACKAGING 64 Automation in Pharma Packaging – When and When not to Invest The pharmaceutical and biotech industry has expressed clear imperatives when it comes to automation. According to Pharmaceutical Manufacturing’s Smart Pharma survey, in 2021 88% of pharma manufacturers believe their company will choose to immediately automate processes if given the option and approximately 90% said they had already begun broader transformation efforts. Here, Boy Tjoa at Tjoapack, explores the ifs and whys of when to automate packaging lines and how to balance the design and flexibility of lines to serve all the needs of different customers.

66 One Thing After Another – The Pathway Towards Successful Serialisation Pharmaceuticals will always be attractive to counterfeiters. They are relatively inexpensive to produce and easy to make look convincing.

The regulation and enforcement infrastructure to protect against counterfeiting varies considerably worldwide; even in developed nations, the penalties are an inadequate deterrent to organised criminals. The serialisation of pharmaceutical products is vital to eliminate counterfeiting and increase patient safety, yet such a complex addition to the packing line can cause significant challenges.

Mark King at Essentra Packaging explores the benefits of outsourcing serialisation.

LOGISTICS & SUPPLY CHAIN MANAGEMENT 68 A Robust Product Delivers a Reliable Solution to the Pharmaceutical Cold Chain At its simplest, logistics is the art of getting a product from A to B. When it comes to the pharmaceutical cold chain, however, nothing is ever this simple. Factor in the high value of pharmaceutical goods, their perishable nature and susceptibility to temperature changes, the urgency of demands from healthcare practitioners to meet patient care and the numerous (often uncontrollable) complexities of the supply chain, the reality is more like getting from A to Z. Secure transit packaging is crucial to protect temperature critical pharmaceutical deliveries. Martin Hawes at Tower Cold Chain, explains how solutions that are built to last mean that some are still in active use after 15 years.

72 Purchase or Rental Temperature-controlled Packaging for Pharma Logistics – One Size Doesn’t Fit All Cold chain packaging and logistics perform an integral part in the safe shipment of pharmaceutical payloads worldwide. To ensure the efficacy of high value, life-giving pharmaceutical products requires high-performance cold chain thermal shipper solutions.

Whether purchased or rented, temperature-controlled packaging is a crucial component within the cold chain, explains Paul Terry at Peli BioThermal. The industry of cold chain logistics requires specific, specialist handling end to end as well as adherence to regional regulatory compliance criteria when shipping products from the manufacturer to end destination.

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76 Transport Risk Assessment and Verification – from Theory to Practice Legal and regulatory requirements, including GMP and GDP guidelines, require consistently that medicinal products shall be stored and transported in a way that the product delivered maintain their quality and integrity and remain within the legal supply chain during storage and/or transportation. Annegret Blum at PharmaLex explains that, while the respective requirements seem well implemented for storage facilities in the pharmaceutical industry and the supply chain, observations in audits and inspections, as well as frequent questions concerning implementation of transport requirements, demonstrate that consultancy on this topic is highly valued.

80 Getting More Value from Logistics Quality With its raison d’etre of saving lives and improving the health of people around the world, the assurance of quality lies at the very heart of the pharmaceutical production and distribution process. Cost Of Quality (COQ) is a measure of all the costs relating to the quality of a product and its adherence to regulatory and in-house standards, guidelines and expectations. Alan Kennedy at Poseidon and Courtney Soulsby at BSI British Standards Institution, explain that “Any cost that would not be incurred if the quality were perfect” is a simple way of describing COQ. LOGISTICS – CORPORATE ANALYSIS 84 Relevance of Vaccine Cold Chains Around the World for the Effective Storage and Transport of Vaccines Ever since Dr. Edward Jenner pioneered the concept of vaccines in the West by inoculating a 13-year-old boy with the cowpox virus and subsequently demonstrating the child’s immunity to smallpox because of that treatment, vaccines to many different infectious diseases were created over the centuries, saving millions of people. Some diseases such as smallpox, have been globally eradicated and others, such as measles, whooping cough and polio are among the many diseases that are now considered rare in many parts of the world. Luc Provost at B Medical Systems explains how this achievement has been possible by the large-scale vaccination programs which ensured the establishment of the herd immunity needed to stop the spread of the pathogens causing these diseases.

86 How to Save 1,000 kilos of CO2 The First-ever Circular Economy Pharmaceutical Packaging 2019 was a turning-point. It was the year when fears of palpable global climate change gripped society, including the worlds of business and industry. In 2020 the COVID-19 pandemic led to a second dramatic realisation. To increase the resilience of global supply chains there is a radical need for greater sustainability. Sven Rölle of Eutecma GmbH describes the enormous potential which climate-friendly, no-waste packaging can offer the temperature-controlled transportation of pharmaceuticals.

90 Why Pharmaceutical Manufacturers and Airport Logistics Should Grow Hand in Hand While the past two years have been very turbulent in many ways, the air cargo industry has seen unprecedented growth levels, providing vital resources globally, whilst under constant pressure. In early 2020 global air cargo volumes collapsed due to the sudden loss of wide body passenger jets. In addition, there was a very high demand for PPE. Air cargo capacity was vitally needed to ship COVID-19 vaccines and now the industry is charged with the supply of the COVID-19 antiviral medicines on top of the regular pharmaceutical traffic. Samuel Speltdoorn at Brussels Airport explains how the industry should collaborate better on good communication and handling practices.

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Editor's Letter The Dermatology Life Quality Index (DLQI) is commonly used to assess the quality of life of patients with skin diseases.

Clinical trials confirm the positive effect of the use of biologics and new molecules on the quality of life of patients. Biologic therapy represents a relatively new class of drugs which have revolutionized the treatment of skin ailments and are used with increasing frequency to control this chronic, systemic inflammatory disease. However, it is unclear what role there is for combination therapy of biologics with traditional topical agents. In general, the addition of adjuvant topical therapy to systemic biologic therapy allowed for a reduction in dosage and side effects of both agents, maintenance of initial response to biologics, treatment of recalcitrant lesions in partial responders, and potential acceleration of response to biologic therapies. The current data, though limited, suggest that using topical therapies as adjunct treatment to biologics is a well-tolerated and effective means of controlling conditions like psoriasis and improving quality of life for patients.

Topical Biologics is our cover story in this issue of IPI. The Enigma of Topical Biologics Development Traditionally, most marketed drugs, irrespective of their route of delivery, have had relatively low molecular weights. Nowhere has this been more markedly true than in topical drug delivery. Dr. Jon Lenn and Matt Traynor at MedPharm discusses whether large (and often very potent) biologics can be delivered to/through the skin effectively enough for clinical relevance. Nevertheless, by understanding this history, and deploying a pragmatic approach using healthy and diseased human skin in-vitro permeation and penetration testing systems, in combination with skin disease pharmacodynamic models, it is possible to explore development more effectively in this space.

In the article, Improving Outcomes for Gastric Cancer Patients via a Novel Oral Daily Dose Chemotherapy Formulation, Oncoral, Carl Bjartmar at Ascelia Pharma addresses the development in the treatment of Gastric cancer. Gastric Cancer is the fifth most common cancer, with around one million annual incidences worldwide, and it represents the fourth most common cause of cancer deaths.

There has been a huge progress in Advanced Therapy Medicinal Products (ATMP). Cell- and genebased therapies form one of the pillars of regenerative medicine. They have the potential to transform quality of life and improve the health status of patients with genetic and cellular defects, including genetic diseases, neurodegenerative diseases, and tissue malignancies, amongst others. Despite numerous challenges, in the last decade, tremendous, unified efforts by research and clinical scientists in academic, translational and industry settings have resulted in tangible outcomes in the form of many marketing authorizations and approved commercial firsts, such as Glybera®, Kymriah®, YESCARTA®, Holoclar®, and Luxturna™.

Grant Merrill at AES Clean Technology discusses how ATMP exhibits the potential to cure disease by addressing its root cause rather than treating it symptomatically.

Welcome to the Spring 2022 Issue of the IPI journal.

Against the backdrop of the Covid-19 pandemic, pharma and biotech companies continue to innovate not just in the field of therapeutics and vaccines, but also in terms of the science to develop them.

Overall trends indicate a move toward adopting emerging technologies to discover drugs, adapting existing scientific techniques to find new therapeutic approaches within the RNA field, and decentralising clinical trials.

Here we look at some of our recent coverage mapping the road ahead for the pharmaceutical industry and the broader healthcare space in 2022.

Gastric cancer is the fifth most common cancer, with around one million annual incidences worldwide, and it represents the fourth most common cause of cancer deaths. The gastric cancer drug market is growing rapidly and is expected to approach USD 4 billion by 2029 according to GlobalData. This growth, is fuelled by several factors, including an increase in the overall incidence, as well as higher treatment rates and extended treatment duration.

This edition of IPI has an extensive section on Logistics & Supply chain Management.

Within the article, Transport Risk Assessment and Verification – from Theory to Practice, Annegret Blum at PharmaLex discusses the Legal and regulatory requirements, including GMP and GDP guidelines. While the respective requirements seem well implemented for storage facilities in the pharmaceutical industry and the supply chain, observations in audits and inspections, as well as frequent questions concerning implementation of transport requirements, demonstrate that consultancy on this topic is highly valued.

I hope you enjoy the first issue of IPI in 2022. I wish you a good year ahead.

Lucy Robertshaw, CEO LucyJRobertshaw While the pandemic continues to disrupt and transform industry’s business strategies and practices, it also offers new solutions to perennial challenges such as pricing, reimbursement and customer engagement caused by the tensions between innovation, market access and financially pressed health systems. In addition, the industry’s efforts to combat the pandemic have created fresh platforms for innovation and growth. These include the messenger RNA (mRNA) technology used in Covid-19 vaccines and the monoclonal antibodies (mAbs) used in several treatments for the virus.

In this issue of IPI we have a wide array of article and features to keep you entertained and exited.

Much awaited, Exhibitions & Conferences have started in person again. We are partnered with the likes of Pharmapack, Logipharma, Festival of Biologics, CPHI/ICSE, Vaccines Europe and many more. I hope to meet you at most or any one of these events.

I wish you all a great year ahead and look forward to supporting you with exciting contents and your marketing strategies.

Virginia Toteva, Editorial Manager – IPI

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

Georg Mathis Founder and Managing Director, Appletree AG

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

Catherine Lund, Vice Chairman, OnQ Consulting

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

Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

Deborah A. Komlos, Principal Content Writer, Clarivate

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

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

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

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

Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group

Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

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

Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

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

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

Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting Stefan Astrom, Founder and CEO of Astrom Research International HB T S Jaishankar, Managing Director, QUEST Life Sciences Spring 2022 Volume 14 Issue 1

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 7

Regulatory & Marketplace

How Managing the Simple Medical Device Label Could Make or Break Nordic Expansion Ambitions for Manufacturers The Nordic region is a potentially lucrative area for medical device companies to expand into, with analyst research estimating Sweden alone to have a 2.7% market share of the €140bn European medical device market. But practical challenges, in particular operational obstacles on the regulatory side, have deterred many manufacturers from making the leap into this geography. Bob Tilling, VP Global Sales at Kallik, explains how effectively managing the simple device label could be key to overcoming the challenges of entering the Nordic market.

Expansion into one or even several Nordic countries may seem like a minor leap to today’s large, multinational medical device manufacturers – but business leaders with an eye on new market growth should beware the pitfalls. These range from special logistics labels on products for each healthcare association through to large-scale downstream compliance challenges.

Dedicated label and artwork management software solutions have made significant strides in bringing advanced digital capabilities to bear on many of these challenges – and could yet again bring peace of mind to those exploring a push into the Nordic medical device market.

Here are my three major considerations that medical device manufacturers should focus on when weighing up expansion into the Nordics – and how technology can help solve them: High Risk, High Reward? Weigh the Costs vs. Benefits to Your Business At first glance, expansion into the Nordic market may seem like a case of ‘high effort, low reward’ for many medical device companies. The entire Nordic medical device market, for example, is smaller than the German market alone, and the Nordic market is far from the largest by value, given the relatively small populations of each nation within the region.

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Yet medical device margins are significantly higher in the region when compared to most European nations and indeed to countries beyond. Nordic countries have a very high standard of living and per capita wealth is equally strong, with effective healthcare systems and high-quality products used in treatment.

Healthcare spending is also typically very high as a percentage of GDP. Expanding into or setting up in the Nordic market ultimately represents a calculated risk for many medical device companies – do they replicate compliance tasks and increase the volume of labels and assets managed internally to sell into this market, or do they cut their losses and focus on large, more lucrative targets such as Germany and the UK? If manufacturers conduct suitable research and can identify a strong appetite or market niche in the Nordics to position proven, fully compliant medical device ranges, there is a potentially rewarding opportunity. The short-term risk, therefore, may be comfortably worth the long-term reward – but only if manufacturers have suitable systems in place to comfortably handle country-specific labelling and artwork requirements that can be customised to effectively handle national nuances.

National Nuances Mean Labelling is a Nightmare – A Wake-up Call for Digital Management One of the main challenges facing medical device companies looking to ‘crack’ the Nordic market is the scale of it. Spanning Denmark, Norway and Sweden, Finland and Iceland, the market is fraught with differing product preferences, healthcare system priorities and customer expectations.

Each national healthcare authority is also far smaller than other European counterparts such as the NHS, and each has differing back-end processes such as those covering general management, documentation and reimbursement.

Beyond this, Nordic regulation and labelling requirements also closely follow the same path as the majority of Europe – following EU directives as a core regulatory framework.

This today includes the recently introduced MDR and IVDR, and formerly MDD. As a result, medical devices sold to and used in these Nordic countries require extra labels and markings on product packaging.

Some manufacturers, still conscious of their often-disruptive compliance efforts to satisfy MDR and IVDR deadlines, have opted to avoid the market for fear of replicating similar compliance burdens several times over.

Again, by looking to digital alternatives to the more ‘traditional’ legacy methods of manual spreadsheets and disparate systems, this is far easier to get to grips with on a single easily managed platform.

M&A Ambitions Just Add to the Problems with Onboarding Challenges Can you buy your way in? Can medical device companies looking to expand in the Nordic market instead aim to achieve this relatively pain-free through merger or acquisition?

The answer is not so simple.

Manufacturers that take over existing Nordic medical device companies could face a burden similar to the scale of MDR or IVDR compliance projects – something we at Kallik have seen pose a major challenge to day-to-day operations of medical device companies of all sizes.

Significant increases in the number of assets that must be amended for rebranding product lines, newly discovered siloes of information and a scattered workforce could all threaten to make a typical acquisition into an unexpected time- and resourceconsuming challenge. Add the usual M&A challenges of translating assets into multiple languages for the region, and without the right digital backbone this quickly becomes a non-starter.

Focus on Digital Maturity Now to Avoid New Market ‘Growing Pains’ It is clear that expanding existing medical device operations into the Nordic market is far easier said than done, with downstream compliance challenges, asset management and multiple languages all obstacles to be overcome. Embracing end-to-end label Spring 2022 Volume 14 Issue 1

Regulatory & Marketplace

– a lesson the industry as a whole learned during the MDR and IVDR compliance rush.

Digital alternatives offer far more than a ‘luxury’ alternative to this – they are increasingly the norm for manufacturers to weather the storm of emerging regulations, customer expectations around product traceability, and other unexpected industry disruption. Those that can deploy and maintain a truly mature digital environment for label and artwork management will be laying the groundwork to flourish in potentially lucrative markets such as the Nordics.

Bob Tilling

and artwork management within a single digital system offers a lifeline to medical device manufacturers. It helps ease the onboarding burden by allowing companies to establish pre-set templates and layouts suitable for products being sold into each wwww.international-pharma.com

Nordic country, and bulk update existing assets for acquired product lines.

Most problems stem simply from an enforced need to manually create, update and manage labels and other product assets

Bob Tilling is the VP of Global Sales at Kallik, an enterprise labelling and artwork management company. He has a wealth of knowledge when it comes to the life sciences industry, particularly regarding medical devices. Bob helps businesses in highly regulated industries begin their journey of transforming their labelling and artwork management.

Email: bob.tilling@kallik.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 9

Regulatory & Marketplace

Will Universal Pharmacare be Introduced in Canada?

Abstract Prescription drug insurance in Canada is provided by a mixture of government and private plans. Government plans offer coverage to about a quarter of the population comprising seniors, social assistance recipients, children and some other groups, while private plans cover over two-thirds of Canadians paid for by themselves or cost-shared with employers, unions or associations.

Nevertheless, a significant proportion of Canadians have no insurance. This situation has led to inequalities in patient access to medicines. The current federal government has plans to introduce a universal pharmacare program to overcome these issues, but one of the challenges will be its cost.

With the intention of making drugs (and consequently pharmacare) more affordable, the government intends to add regulations to reduce medicine prices in Canada. Developers already face several obstacles, such as rigid and sometimes hostile health technology assessments and rigorous price negotiations, that must be overcome before government and, to some extent, private drug plans will consider insuring their medicines. These hurdles already delay or deny Canadians’ access to new medicines. Requiring significantly reduced prices would be yet another barrier. In response, manufacturers are highly likely to place Canada further down their priority list of countries in which to launch new medicines and, thus, further delay or deny access to Canadians who need them. The primary aim of universal pharmacare should be to ensure that the best medicines are made accessible so that patients receive the most appropriate therapy depending on their individual situation. This will not be achieved if patients are denied access to new specialised treatments that can improve or extend their lives, any more than if patients who cannot afford basic primary care medicines are not helped.

An affordable program is important, but so is ensuring Canadians’ access to innovative life-changing medicines.

10 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Introduction Canada is a large, geographically diverse country consisting of a federation of 10 provinces and three sparsely populated northern territories governed by a federal government and individual provincial and territorial legislatures. The federal government is responsible for matters that affect the whole country, such as national defence and foreign affairs, while the provinces and territories are responsible for areas of direct concern to their populations, such as education and health care; some responsibilities are shared. Despite its size, Canada has a relatively small population of 38 million and constitutes only about 2% of the global pharmaceutical market.

Government Insurance for Prescription Medicines in Canada Universal government health care insurance covering physician, hospital (including medicines administered there) and laboratory services exists in Canada, but medicines dispensed in the community are not universally covered. Federal, provincial and territorial governments have their own prescription drug plans offering a varying degree of coverage to about a quarter of the population comprising seniors, social assistance recipients, children and some other special groups, such as cancer patients, or when costs are deemed catastrophic.

Adults of working age receive little to no coverage from most government drug plans.

Several obstacles must be overcome by pharmaceutical manufacturers to have a drug listed in government benefit lists. The first is health technology assessment. To be considered for coverage in all government plans, except those in the province of Quebec, manufacturers submit an application to the Canadian Agency for Drugs and Technologies in Health (CADTH)1 to demonstrate the medicine’s value based on its clinical benefit relative to its cost (Quebec has its own health technology assessment agency). CADTH is owned and funded by federal, provincial and territorial health ministries (except Quebec’s) and, consequently, its claim of independence is invalid because it does not operate at armslength from these governments. CADTH’s processes fail to adhere to good governance

principles, particularly accountability, transparency, and stakeholder participation,2 which has led to criticism from patients and others, especially regarding how CADTH assesses costly rare disorder drugs.

Following health technology assessment, manufacturers usually look to be invited into the federal, provincial and territorial governments’ collective price negotiating process, known as the pan-Canadian Pharmaceutical Alliance (pCPA), whose main objective is to capitalise on the combined governments’ buying power.3 Each government drug plan decides at the beginning of a negotiation whether to be included. When a negotiation is successfully completed, the cost and criteria under which governments will pay for the drug are agreed. CADTH and the pCPA are closely aligned so that, in general, a negative health technology assessment recommendation results in no negotiation and a positive one sets up negotiating factors, frequently the need for a substantial price reduction.4 A successful pCPA negotiation does not, however, guarantee that all government plans will cover the medicine because a separate agreement must also be reached with each plan, since coverage is an individual drug plan decision. Like the pCPA negotiation, negotiations with drug plans are confidential so that, when a medicine is not listed by a drug plan, it is not known whether this is because its government opted out of the negotiation or because it opted in but failed to complete its own agreement with the manufacturer.

It is important to be aware that “coverage” does not necessarily mean all patients have easy and inexpensive access. Government plans have complex systems of deductibles, copayments and premiums and, for many medications, restrictive access criteria that result in variation between plans in patient eligibility, out-of-pocket expenses and degree of coverage.5 This has led to inequalities in what drugs are insured, who gets access, and how much patients pay.

Significant improvements in equality could be realised within government drug plans by eliminating deductibles and copayments for lower income Canadians and making the clinical criteria required to obtain coverage Spring 2022 Volume 14 Issue 1

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Regulatory & Marketplace for many medicines consistent across all plans.

Private Insurance for Prescription Medicines in Canada Coverage of medicines is also available through private insurance paid for by individuals themselves or cost-shared with their employers, unions or associations.

Over two-thirds of Canadians rely on private insurance to obtain medicines they would otherwise be unable to access due to cost or delays in government plans.

Private insurance plans range from those offering relatively limited drug coverage to ones covering virtually all medicines with regulatory approval, the extent of each plan’s coverage being determined by how much clients are willing to pay in premiums.

Some private plans have lifetime capitation values, meaning that an expensive drug may only be covered for a few years after which the patient is faced with paying themselves or not having the medicine. Private insurance companies take note of health technology assessment recommendations but do not necessarily base coverage on them.

Private insurance is commonly part of the employment package offered in higher paid jobs or unionised workplaces. Canadians in lower income, non-unionised employment are less likely to have access to private insurance and may find even the cost of inexpensive prescription medicines for common disorders difficult to pay.

Universal Pharmacare When opinion polls ask Canadians about universal pharmacare, they are almost always highly supportive. However, the sort of program they envisage varies widely, but most anticipate improved access to medicines at a lower cost. Many academics, politicians, government officials, clinicians and patients advocate for universal pharmacare being incorporated within the existing Canadian health care system. They believe that universal pharmacare would bring equality in access to medicines, although it could just as well deny access to medicines to all patients as provide access for all.

When elected to form the federal government in 2015 after nearly a 10-year hiatus, one of the Liberal party’s priorities was the introduction of universal pharmacare. To provide advice on how to move forward, the government created the Advisory Council on the Implementation of National Pharmacare, which produced a final report in 2019 that included 60 recommendations.6 The 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Council recommended a publicly-funded, universal, comprehensive and accessible program portable across Canada, with a broad national formulary to provide patients and prescribers with effective treatment choices. The Council recommended that initially the formulary should only include essential medicines, which were undefined but appeared to be basic primary care therapies for common disorders. Other medicines would be added over a period of years. The question who would decide which medicines were considered “essential” was left unanswered.7 Universal pharmacare should, as the Council advised, be focused on fair and just delivery of medicines for everyone to benefit based on their health care needs. Although it may be difficult and complex to achieve, the objective should be a program that allows a patient to receive the medicine deemed most appropriate by the patient and their health care provider for the patient’s specific condition. This would provide coverage to patients who presently have none because they have no private insurance and are ineligible for government benefits. It should also extend coverage to patients whose insurance, whether government or private, denies access due to a drug’s cost or limits access by requiring a patient’s circumstances to match criteria that are overly restrictive or make little clinical sense. Furthermore, it should satisfy present unmet needs and lead to appropriate prescribing and improved health outcomes, which must be a primary goal of any pharmacare scheme.

To achieve this type of program would require a high level of funding. The Council put the cost of implementing its recommendations at about $40 billion, but others have estimated the cost to be much higher.8 Price Regulations For the last five years, the federal government has promoted affordability, accessibility and appropriate use of prescription drugs,9 although affordability seems to be the main objective, especially if the cost of universal pharmacare is to become more reasonable.

The government sees the road to achieving accessibility as one in which affordability is attained by introducing new powers for a unique-to-Canada tribunal, known as the Patented Medicine Prices Review Board (PMPRB) which, for the last 35 years, has set price controls on new medicines. With new PMPRB regulations, the government intends to reduce the prices of new high priority

medicines by 40% on average, which actually could mean medicine developers may be required to drop prices by up to 70%, perhaps more.10,11 A reasonable reduction might be manageable, but 40–70% or more would be unsustainable, leading to manufacturers launching new medicines in Canada much later than in other countries or not at all.12 Appropriate drug use is unattainable if Canadians cannot access new medicines because manufacturers avoid Canada due to punitive price controls.

Since pharmaceutical manufacturers seek regulatory approval in Europe before Canada13 and may launch their products at lower prices than in Canada, many politicians, government officials and academics believe that dramatically reduced drug prices would have little impact on how developers view Canada’s attractiveness as a market for their medicines. They ignore the facts that many western European countries present much larger markets than Canada, have pharmaceutical company headquarters or major research and manufacturing facilities within their borders, and have governments that offer a collaborative approach to the biopharmaceutical industry. In contrast, almost all brand name companies in Canada are affiliates of companies whose headquarters and facilities are based in other countries and the attitude of Canadian federal governments towards the industry has been antagonistic for decades.14 Canada is not in a strong position to demand major reductions in drug prices without pushback from manufacturers. Its relatively small market and the barriers that must be overcome by drug developers to get their products to Canadians make the country less appealing than larger markets with fewer obstacles. Regulations that drastically reduce prices will make Canada an even less attractive market. A survey of global and Canadian pharmaceutical executives about the new pricing regulations found that 97% of the respondents foresaw “no launch” or delayed launch decisions being made for Canada.15 Other evidence already indicates a slowdown in regulatory approvals for late-stage clinical trials and of new medicines.16 The federal government is aware that its planned regulation changes are a heavy burden on drug developers and an obstacle to meeting patients’ needs, because it exempted COVID-19 vaccines and medicines from PMPRB scrutiny to get them to Canadians quickly.17 Much opposition to Spring 2022 Volume 14 Issue 1

Regulatory & Marketplace the new regulations has been expressed by biopharmaceutical manufacturers, health care providers and patients and their caregivers and calls have been made for the government to reconsider them,18 but the government has chosen to ignore their concerns.

The government has already postponed the implementation of the new regulations three times over the last two years – ostensibly to allow manufacturers time to adjust to them during the COVID-19 pandemic. However, the reason seems more likely to be court decisions striking down a requirement in the new regulations for manufacturers to report to the PMPRB details of confidential discounts and rebates offered to insurers, and a Constitutional challenge which includes Quebec’s government arguing that the new regulations are a trespass by the federal government into provincial jurisdiction.19 The regulation changes were to be implemented in January 2022 but have been postponed yet again.

The federal government is likely waiting for the outcomes of the court cases before deciding on a course of action. If the government cannot move forward with the regulation changes as intended or decides not to proceed at all, it is unclear what this will mean for a universal pharmacare initiative. The Liberals were re-elected to form a minority federal government in 2021.

While universal pharmacare continued to be part of their agenda, it did not feature highly.

As a minority government relying on support from other parties to pass legislation (particularly the socialist party which is enthusiastic about universal pharmacare), the Liberals may be pressured to move ahead with at least some action. This could simply be providing funds to provinces and territories that want to improve the scope of their present drug benefit lists.20 Conclusion Medicines for common illnesses are essential and lower income Canadians should not have to choose between paying for them or other life necessities. Innovative drugs for formerly untreatable disorders that save lives or significantly improve life quality are also vital.21 These new drugs can cost many thousands of dollars per year and frequently require life-long use, but without private or government insurance, they are unaffordable irrespective of a Canadian’s level of income.

It is these drugs for which provincial and territorial government premiers, who are unenthusiastic about universal pharmacare, wwww.international-pharma.com

want financial assistance from the federal government. Pursuing a course expected to severely reduce prices is not the way to go to improve patient access to these or any other medicines.22 The primary aim of a quality universal pharmacare program should be to ensure the best medicines are made accessible without excessively restrictive or nonsensical clinical criteria so that patients receive the most appropriate medicine depending on their individual situation. This will not be achieved if patients are denied access to new specialised medicines that can improve or extend their lives, any more than if patients who cannot afford basic primary care medicines are not helped. An affordable program is important, but so is ensuring Canadians’ access to innovative life-changing medicines. The introduction of a quality universal pharmacare in the foreseeable future in Canada seems unlikely.

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https://www.cadth.ca/about-cadth, visited on 4 Jan 2022.

Rawson, N.S.B. & Adams, J. Do reimbursement recommendation processes used by government drug plans in Canada adhere to good governance principles? Clinicoecon.

Outcomes Res. 9, 721-30 (2017). https://www.pcpacanada.ca/node/30, visited on 4 Jan 2022.

Rawson, N.S.B. Alignment of health technology assessments and price negotiations for new drugs for rare disorders in Canada: does it lead to improved patient access? J. Popul. Ther. Clin.

Pharmacol. 27, e48-64 (2020).

Rawson, N.S.B. Drug Safety: Problems, Pitfalls and Solutions in Identifying and Evaluating Risk. Victoria: Friesen Press (2016). https://www.canada.ca/en/health-canada/ corporate/about-health-canada/publicengagement/external-advisory-bodies/ implementation-national-pharmacare/finalreport.html, visited on 4 Jan 2022. https://financialpost.com/opinion/nationalpharmacare-which-drugs-are-essential, visited on 4 Jan 2022. https://nationalpost.com/opinion/opinioncivil-servants-get-the-rolls-royce-ofpharmacare-while-party-leaders-cant-evenmuster-a-decent-plan, visited on 4 Jan 2022. https://www.canada.ca/en/health-canada/ news/2017/05/economic_club_ofcanadamay162017.html, visited on 4 Jan 2022. https://www.canada.ca/en/patentedmedicine-prices-review/services/legislation/ about-guidelines/guidelines.html, visited on 4 Jan 2022. https://www.canadianhealthpolicy.com/ products/new-patented-medicine-regulationsin-canada--updated-case-study---en-fr-.html, visited on 4 Jan 2022. https://www.macdonaldlaurier.ca/canadians-

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will-pay-heavy-price-ottawa-cuts-drug-costs/, visited on 4 Jan 2022.

Rawson, N.S.B. Canadian, European and United States new drug approval times now relatively similar. Regul. Toxicol. Pharmacol. 96, 121-6 (2018). https://www.macdonaldlaurier.ca/newfederal-hinder-innovation/, visited on 4 Jan 2022. https://lifesciencesontario.ca/wp-content/ uploads/2020/05/Research-Etc.-PMPRBSurvey-02-03-20.pdf, visited on 4 Jan 2022. https://www.canadianhealthpolicy.com/ products/clinical-trials-in-canada--worryingsigns-remain-despite-pmprb---s-superficialresponse.html, visited on 4 Jan 2022. https://www.nationalnewswatch.com/2020/ 10/14/exempting-covid-medicines-fromnew-price-controls-ottawa-hypocrisy/#.

YdYHLWjMKM-, visited on 4 Jan 2022. https://financialpost.com/opinion/opinionuse-covid-pause-to-reconsider-drug-priceregulation, visited on 4 Jan 2022. https://financialpost.com/opinion/opinionappeal-court-exposes-pmprb-abuse-of-powerand-bias-on-drug-pricing, visited on 4 Jan 2022. https://healthydebate.ca/2021/11/topic/ pharmacare-affordability-access/, visited on 4 Jan 2022. https://www.canadianhealthpolicy.com/ blog/politically-instituted-barriers-againstinnovative-medicines-have-a-human-toll.html, visited on 4 Jan 2022. https://www.healthing.ca/policy/pmprb-whylower-drug-prices-may-mean-less-access/, visited on 4 Jan 2022.

Nigel Rawson Nigel Rawson, PhD is a pharmacoepidemiologist and pharmaceutical policy researcher, an Affiliate Scholar at the Canadian Health Policy Institute, and a Senior Fellow with the Fraser Institute. He has performed prescription drug safety and pharmaceutical policy issue analyses for over 40 years and authored more than 150 publications.

He has held academic positions in the United Kingdom, Canada and the United States and worked in the pharmaceutical industry.

Email: eastlakerg@gmail.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 13

Regulatory & Marketplace

The Big Debate: Will Quality Management Still Exist in 2025?

Late last year, visionaries from Merck, Syneos Health and Accenture took part in a live video debate on what now influences the way life sciences companies manage Quality – and what the future holds for the discipline, including the potential to pre-empt and minimise Quality issues using AI technology. Generis CEO James Kelleher chaired the proceedings, which included a live audience poll.

On the panel were: • Dr. Heiner Niessen, Head of Application Technology Quality & Compliance at Merck • Peter Brandstetter, Quality and Regulatory expert at Accenture • James Man, Quality subject expert and R&D Advisory Managing Director at Syneos Health.

Challenging the Status quo The panel began by giving their frank views of where the role of Quality is heading in life sciences.

James Man (JM), Syneos Health: I think about Quality in quite a radical way – e.g. could it be more embedded so that improvements happen incrementally; could we rethink the whole vision about what the function does, especially now we're moving towards decentralised clinical trials?

Peter Brandstetter (PB), Accenture: I think companies will reach a point where they don't need Quality Management or people working in Quality. When everything is digital and automated, Quality Management loses its relevance.

Heiner Niessen (HN), Merck: I disagree.

The demands on Quality keep growing: more parameters are being measured and Quality spans the whole supply chain. In the future a product’s carbon dioxide footprint might become a Quality parameter.

PB: Certainly the whole system is becoming increasingly complex, which is why it’s important to address the manual Quality effort. There’s an opportunity here: the more we learn about the manufacturing process from all of this data, and about the context, the better we can predict quality – rather than retrospectively checking whether 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

everything was created as it should have been. For me, that’s the goal. The priority must be to use all the data we have in the right way. Technology-wise we have the means – it's just a matter of connecting all the different pieces.

HN: Quality efforts don’t stop at the company boundaries, certainly. Just capturing and collating all of this data, keeping it up to date and following up change requests across the supply chain is a significant undertaking.

James Kelleher (JK), Generis: Could smart automation help here?

HN: Technology could certainly help manage information from different sources.

With improving digitalisation, it’s much easier to capture and track this information, right out into the real world.

Poll Question 1 – The Current Status of Quality Initiatives In a spot poll during the live debate attendees were asked about the current status of quality initiatives in their organisation. The vast majority – 87% – indicated that they had initiatives underway.

People Considerations: Should Quality be Blended Into Everyday Operations?

JK: What about the human aspects of Quality improvement?

JM: Ultimately people make decisions and promote change. They're informed by data though – as long as it’s possible to turn the data into decision-supporting insights.

Think of project teams back in the day.

First there would only be a scientific lead.

As things grew, a clinical trial would have an operational lead; then Regulatory got involved, and Safety and Disclosure – more people needed to sit, debate and make decisions together. It wouldn’t be beyond the realms of possibility to have a Quality person there now too – to help think through the risks with a study.

Right now, there isn't typically a role of Chief Quality Officer – but perhaps there should be. If companies want to be more pre-emptive, and for Compliance to add value to the business, we need to make some structural changes – beginning with representation.

JK: A recent customer audit touched on this. They were weighing up the possibility of embedding a Quality post in each project, even if costs couldn’t be recouped directly.

Human vs Machine Intelligence JK: What about Quality management linked to the use of artificial intelligence? Where is Merck with all of this?

HN: We’re seeing some limited representation in areas such as image analysis where use of AI is quite advanced. As to real ‘decision making’, to date I'm not aware that we are using AI in this in this way. But, if we did, I think the Quality considerations would be similar to today. Either you train the human being, or you train the algorithm, so if it doesn't work the measures to take will be the same. There has to be clarity around what the algorithm is doing.

JM: There could be an opportunity with individualised/personalised medicine and Quality Management – to keep track of oversight and do this more cheaply/ less manually? Along the lines of a digital twin. Let's say I'm doing an experiment and wearing Google Glass, which recalls previous activity and outcomes and will flag up when current activity is diverging too much from original parameters, for example.

If AI can be applied as a learning tool, I do see potential for collectively improving capability by identifying near misses and so on. In manufacturing there is more of a culture of celebrating this kind of thing, but in R&D we’re a long way behind so it’s perhaps more a case of whether culturally we're willing to accept the technology within the workforce.

Adapting Quality to Processes for Personalised Medicine JK: With the growing emphasis on personalised medicine, what are the implications for Quality Management?

HN: Here, you’re manufacturing very low quantities of a product which applies to perhaps just one individual or a small group of people. Quality management then becomes a much bigger undertaking because you’ll have as many quality control measures as you have personalised products.

JK: Would that then strengthen the case for intelligent automation? To manage all of Spring 2022 Volume 14 Issue 1

Regulatory & Marketplace the additional tests and test protocols that will be needed?

HN: That would complete the circle quite neatly. It’s actually automation and machine learning that led us to the point of having personalised medicine. Using the same technologies to help with the testing workload would make sense.

Poll Question 2 – Cost Optimisation in Quality In the second spot poll, attendees were asked about the drive to optimise the cost of Quality management. The desire to optimise costs was high: half of attendees said they expected the cost of Quality activity to keep rising.

Containing the Rising Costs of Quality Management JK: Should companies just accept that Quality costs will rise as data and parameters increase, or become better at reducing effort and containing cost?

PB: With huge pressure on the industry to reduce the cost of medical drugs, companies do need to contain costs wherever possible.

Whereas the cost of Quality wasn’t really an issue before, that mindset has changed with personalised medicine. Also, from a health insurance perspective, as outcome-based reimbursement becomes more established, the cost of Quality does become a factor.

JK: Does anyone focus on the potential business benefits of Quality – for example in driving insights for future products, preventing recalls, ensuring the supply chain delivers as expected, and so on?

JM: That's the Holy Grail and lots of companies recognise that Quality is an underutilised competitive lever. But I don’t know of any company that's really leading the way here. People are cautious about investing currently: it’s more a case of business as usual – updating the QMS, putting in that new CAPA management system, etc. There’s certainly more that can be done.

Next Steps Between Now and 2025 JK: What concrete steps should be taken by 2025, to move closer to where companies need to be?

HN: At a corporate level, a big one is to connect individual quality systems across the value chain to enable seamless data transfer. So you would have your CAPA system, your RIM system, your supplier RIM system all acting more or less as one system. Merck sees a big advantage here wwww.international-pharma.com

and has initiatives to drive standard data exchange formats for exchanging Quality information at a system level, removing the need to send PDF files around and retype/ scan information into each system.

PB: I agree that we need to be working with structured data that’s exchangeable across company borders. Blockchain could help here, enabling a trusted chain of data, but the right foundations are needed and this is no small step. We need to break things down into smaller initiatives.

JK: Do you see the ‘document’ going away?

JM: No. The way we access and interact with them is here to stay. But we should connect Quality systems, and a Chief Quality Officer function will be important.

Embedding Quality people in the key R&D teams will happen. Achieve that, and you might be piloting more real-time data exchange with the regulators by 2025.

James Kelleher Dr. Heiner Niessen Dr. Heiner Niessen, Head of Application Technology Quality & Compliance – Merck. After leaving Academia with a PhD in Molecular Biology & Biophysics, I joined the Silicon Valley Biotech Company Applied Biosystems and assumed various roles from IT expert through Sales and Project Manager in laboratory information management.

Later I moved to the German Biotech company QIAGEN as Alliance manager responsible for quality and supply for industry customers. In 2017 I joined Merck KGaA Darmstadt, since 2019 in the role of Head of Application Technology Quality & Compliance.

Peter Brandstetter Peter Brandstetter is a Senior Manager for Technology Consulting at Accenture in Zurich, Switzerland. A respected authority in IT-enabled transformation in life sciences, he has more than two decades' experience of solving complex IT challenges for pharmaceutical companies globally – gained across senior life sciences consulting/IT roles including Life Science Central Region Lead at CSC, Senior Managing Consultant for GBS Life Sciences at IBM, and Senior Manager at PwC. Peter specializes in quality management and quality assurance in manufacturing and R&D, enterprise content management, and R&D (clinical data management, preclinical, R&D Lab, R&D collaboration and project management), as well as computer validation.

James Kelleher, CEO, Generis. After graduating from Cambridge University, James initially pursued a career as an opera and symphonic conductor, before turning the closely related field of content management in Life Sciences, initially working at GSK before setting up Generis. For the last two decades he has focused on Regulatory and Quality within Life Sciences, working with customers such as Bayer, Merck KGaA, Pfizer, BMS, Gilead, AstraZeneca and Otsuka on a range of implementations across these disciplines.

James Man James Man,Director, R&D Advisory, Syneos Health Consulting. With over 20 years' experience in the pharmaceutical and life sciences industries, James Man, Director, R&D Advisory, Syneos Health Consulting, has led a wide variety of projects across R&D during his 14 years as a management consultant. Recent areas of specific interest include supporting a large global biopharmaceutical design and implement a clinical lab QMS and a small biotech build a modular QMS as it starts to get ready for clinical trials. James is experienced in leading transformational projects in Clinical Development, Medical Affairs and R&D Operations He excels in facilitation, communication, change alignment and stakeholder buy-in around operating model design, process reengineering, governance, patient centricity and performance management. He has authored several white papers including 'Enhancing productivity in biopharmaceutical R&D'. James holds a PhD from the University of Bristol.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 15

Regulatory & Marketplace

Reasons Why Flexibility is the Secret to Pharma Success in 2022 Ben Wylie, Senior Project Manager, at ChargePoint Technology, looks back on key learnings from 2021 for cleanroom pharmaceutical manufacturing.

He explores why flexibility is key overcoming sterile processing and efficiency challenges to achieve market success in 2022.

Looking Back on 2021 Obviously, 2021 in the pharmaceutical space was dominated by the ongoing COVID-19 outbreak. We saw a number of key medical innovations across the globe to help us save lives and, hopefully, bring an earlier end to the pandemic than might be achieved without intervention.

A key example of these advances is the unprecedentedly rapid development, approval and commercialisation of the first two messenger RNA (mRNA) vaccines approved for human use – the Pfizer/ BioNTech and Moderna vaccines1 – which have become the workhorses of the global vaccination campaign. Other vaccines have been approved for global use, such as the Oxford/AstraZeneca vaccine, which uses a well-established viral vector platform, as well as others produced by developers in Russia and China. Now, booster vaccines are being developed to tackle new variants of COVID-19, such as the Delta and Omicron variants.

New immunotherapies have also been approved to treat COVID-19 patients hospitalised by severe symptoms. Two monoclonal antibody (mAbs) treatments were approved for emergency use by the US Food and Drug Administration (FDA) this year.2,3 They received full approval by the UK Medicines and Healthcare products Regulatory Agency (MHRA) in 2021. More mAbs treatments are joining the development pipeline later in the year. Real-time research by doctors in the field has also identified existing treatments capable of having a positive impact on the health of patients with serious COVID symptoms.

This is just a brief snapshot of all of the treatments and developments to tackle COVID-19 over the past 12 months. The speed 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

of development and commercialisation of these advances, however, would not have been possible without the decision by a large number of pharmaceutical firms to engage the development and manufacturing support of contract development and manufacturing organisation (CDMO) partners.

The rapidly expanding global market offers exciting opportunities for CDMOs looking to acquire new customers and expand their business into new treatment areas and markets. However, it poses challenges too, arising from the surging worldwide competition.

Whether developing vaccines, new immunotherapies, or updating existing drug products, pharmaceutical companies were able to benefit from CDMOs’ existing capacity, specialist manufacturing infrastructure and experience. With all of this support and guidance, they were able to bring their discoveries to clinical trial, to the regulatory approval stage and onwards to full commercialisation in record time.

It can be a difficult task for existing CDMOs in particular to differentiate their offering from that of competitors to attract new drug developer customers, while at the same time ensuring maximum efficiency and productivity. Many CDMOs feel the pressure to respond to burgeoning demand for specialist and high-value projects like vaccine or immunotherapy manufacturing, by investing in dedicated production infrastructure. However, they may not need this equipment once the project has come to an end, resulting in wasted investment, or costly work to upgrade these lines for new projects in the future.

This reduced time-to-market is not the sole benefit of this collaboration between drug developers and CDMOs during the COVID-19 pandemic. Working with CDMOs eliminated the need for pharmaceutical companies to invest capital in sourcing and installing new in-house manufacturing equipment, reducing both the cost and the risk of developing their cutting-edge vaccines and drugs. It allowed developers to focus their efforts on their core competency – creating innovative and revolutionary new therapies.

Learning Lessons for 2022 With all of this in mind, it is no surprise that a major learning from 2021 and the COVID-19 outbreak for so many drug developers is that outsourcing is a beneficial part of the development and manufacturing process. In 2022 and beyond, we can expect to see this collaboration establish itself as the norm across the international pharmaceutical industry for an even wider array of other treatment sectors.

As a result of this renewed and increased interest in outsourcing, CDMOs across the world are experiencing significant and sustained growth, which is projected to continue through 2022 and over the next half decade. Valued at $130.8 billion in 2018, the CDMO sector is expected to more than double in size by 2026, reaching $278.98 billion, growing at a CAGR of 10% over the forecast period.4

Flexibility is a Must to Meet Future High Customer Demand It is vital for CDMOs to seek out new approaches to updating their existing offering to enable them to draw in high-value new customer relationships.

Agility is key to attracting customers, while minimising financial waste. A flexible production line in particular can allow CDMOs to conduct line changeovers to meet new production needs quickly and efficiently, minimising downtime and cost.

Achieving such flexibility can be a challenge, however. A production line must feature technology, equipment and components specially designed to minimise downtime, from maintenance and, product changeovers.

For vaccines, mABs and other biopharmaceutical projects, flexibility is even more of a challenge. Due to the fact that such treatments are often administered parenterally, their production lines have special cleanroom requirements to maintain an aseptic processing environment. As such, flexible cleanroom production line must also have the capability to streamline washdown procedures, without compromising on sterile integrity.

Spring 2022 Volume 14 Issue 1

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 17

Regulatory & Marketplace To meet these goals, equipment and changeable components must be easy to install and remove when needed, to reduce the risk of delays and optimise the amount of time the line is up and running.

On top of all of this, it is important to implement measures to better understand the performance and status of essential equipment and any critical parts in order to accurately predict when and where maintenance is needed to reduce downtime.

Advanced Single-use Equipment can Help in 2022 There have been considerable enhancements in the world of Single Use (SU) technology in recent years that mean it is well placed to help CDMOs meet new flexibility demands in 2022 and beyond.

SU equipment is specially recognised for its flexibility and ease of use. It considerably simplifies cleaning and validation procedures, helping to minimise production downtime.

This is a particularly crucial benefit for sterile processing lines and cleanroom environments. Sterile versions of disposable components can help maintain aseptic integrity in line with the latest regulations, such as the upcoming updates to Annex 1, without requiring extended washdown protocols.

Moreover, by simplifying cleaning procedures, SU technology can help enhance containment to safeguard line operatives from coming into contact with potentially toxic materials, such as highly potent active pharmaceutical ingredients (HPAPIs). SU equipment can also be used to maintain optimum sterile containment during the transport of pharmaceutical ingredients and drug formulations within and between manufacturing facilities.

Advanced SU technology has been designed to be simple to install and remove by employees with no additional training requirement. There are examples of SU components that can be implemented on existing production lines without the need for upgrades to equipment. All of this means that it is easy to integrate such equipment on existing lines, streamlining the time and cost of implementation.

Looking at SU under the Microscope There are a number of SU components that have the potential to significantly improve production line flexibility for CDMOs in the future.

18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

One key example is the disposable split butterfly valve (SBV). Reusable versions are well established on the production lines of both drug manufacturers and CDMOs, and are widely utilised as a space-saving alternative to isolator decontaminated units.

SBVs can allow the contained transfer of powders, including drug substances and drug products, into and out of process equipment during manufacturing processes.

Two principal parts make up an SBV: an active component fitted to production line equipment, and a passive part that attaches to a filling container. When fitted together, these two sections enable product to flow from the line to the container via their interior surface. As a result, the product never comes into contact with the environment outside the processing equipment, optimising containment and maintaining aseptic integrity.

The new generation of SU SBVs feature a disposable version of the passive component that attaches to the filling container. These alternatives provide the same high level of aseptic containment during processing but offer the potential to considerably improve manufacturing efficiency. This is because the passive component can simply be disposed of between fillings, reducing cleaning and washdown requirements. As a result, the product changeover process is simplified, enhancing productivity.

There are specialised aseptic SBVs available that can further enhance sterile integrity while boosting efficiency. These feature functions such as SIP (steam in place), autoclaves, or even offer the ability to bio-decontaminate across the disc surfaces.

Such functions can eliminate any areas of concern to ensure sterility during product transfers.

Another disposable line component that can significantly enhance efficiency is the SU ChargeBag. These can be fitted to the disposable passive half of a SU SBV to enable the contained, sterile transfer of powder between each manufacturing stage, as well as between different facilities.

SU ChargeBags further ensure contained and sterile integrity during development, manufacturing and technical transfers while minimising cleaning requirements to streamline the product changeover process.

Both of these SU components are manufactured within an ISO6 cleanroom environment and are sterilised before being used via gamma radiation. As a result, SU technology is suitable for use by CDMOs

to meet customers’ sterile processing needs across vaccine, mABs and other biopharmaceutical manufacturing projects.

Complementary Approaches to Maximise Flexibility There are other advancements in production line technology that can act as an ideal complement SU equipment to enable CDMOs in optimising the flexibility of their development and manufacturing technology in 2022. “Smart”, or intelligent, monitoring systems have the potential to significantly reduce production downtime while optimising sterile integrity or containment.

Incorporated into production lines, this advanced equipment can deliver real-time information on the use of manufacturing components at every stage of the manufacturing process. This can allow line operatives to identify where maintenance is needed before they impact on performance, giving them the insight they need to plan maintenance schedules proactively, rather than reactively.

There are other benefits to this real-time line monitoring for CDMOs. Real-time data on the usage of key components can enable line operatives to automate the creation of audit trails, enabling them to proactively manage validation programmes for their cleanroom lines. This can help CDMOs to support their customers in demonstrating compliance with regulatory requirements, proving they are taking every step to safeguard the health of both employees and end-patients.

Advanced smart monitoring tools can also show real-time data on an online dashboard that can be viewed on mobile devices on the move or on computers in remote locations. This means that operatives can monitor, analyse and even compare production performance in different facilities.

Flexibility is Key to CDMO Success and Growth in 2022 Outsourcing has now firmly established itself as a fixture in the pharmaceutical sector.

As the last year or so has demonstrated, working with outsourced partners can deliver considerable value to pharmaceutical companies, increasing the speed of delivery for drug development projects, as well as helping to optimise quality for the end product. As such, it is no surprise that the CDMO sector has enjoyed such robust growth and is expected to continue to expand into 2022 and beyond.

Spring 2022 Volume 14 Issue 1

Regulatory & Marketplace

However, as demand for CDMOs’ services increases, we can expect competition to grow in turn. Competitors will look to expand their own share of their existing markets, and even enter new territories, seeking to disrupt the local market with their own unique capabilities to attract customers.

Taking this into account, CDMOs must act now to find new ways to enhance their services and make sure they continue to differentiate themselves from rivals.

themselves from competitors, proving to customers that they are the best placed partner to support them in delivering their project needs, whatever they are.

Agility and flexibility of manufacturing infrastructure and operations is vital if CDMOs are to deliver this market differentiation. In addition to being able to support customers with their challenging aseptic or HPAPI projects, CDMOs need to demonstrate that they can deliver a wide array of project volumes and turnaround capacity when it is needed. This can allow CDMOs to distinguish

REFERENCES

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As a result, agile and flexible CDMOs will be able to support drug developers in achieving their development goals in the New Year and play a key role in contributing the pharmaceutical industry’s growth over both the short and long term.

1.

2.

3.

https://ec.europa.eu/research-and-innovation/ en/horizon-magazine/five-things-you-needknow-about-mrna-vaccine-safety https://mb.com.ph/2021/11/15/doh-crafts-policyallowing-hospitals-lgus-to-buy-ronaprevedrug-on-their-own/ https://www.drugs.com/history/sotrovimab. html

4.

https://www.fortunebusinessinsights.com/ contract-development-and-manufacturingorganization-cdmo-outsourcing-market-102502

Ben Wylie Ben Wylie is the Senior Product Manager at ChargePoint. He joined ChargePoint in 2005 and is responsible for the dayto-day and strategic management of the product portfolio, including the development of the ChargePoint single-use solutions. Ben has 14 years of experience in Pharma with a focus on marketing and product management of powder processing and containment handling.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 19

Regulatory & Marketplace

Accelerating Asia’s Digital cGXP Transformation with Industry 4.0 Technologies Across Asia, pharma’s leaders are working hard to accelerate their Industry 4.0 digital transformation and, in the process ensure current Good Practice (cGXP) compliance. In a recent IDC InfoBrief: ‘’Good Manufacturing Practices for Asia/Pacific Pharmaceutical Companies: Accelerating Transformation with Manufacturing 4.0” sponsored by Cognizant, IDC analysts found Asia’s digital transformation is accelerating in response to post-pandemic market dynamics. How can Asia’s drug manufacturers throttle up digitisation efforts effectively? Cognizant’s Kenneth Teo offers insight into IDC findings as well as fresh strategies on how the region’s leaders can improve operations by adopting digital technologies.

The Asia-Pacific region’s dominance in the global pharmaceutical manufacturing sector is growing stronger. According to BioSpectrum Asia Edition analyst Hithaishi C. Bhaskarto, global pharmaceutical companies, especially those with a presence in China, India and Japan, are focusing on optimising value creation across AsianPacific (APAC) markets via innovation and growth. Because of the growing demand for pharmaceuticals, governments of the most prominent economies in Asia are under increasing pressure to leverage the most current, effective business models and technologies to deliver the pharmaceuticalbased healthcare their societies expect.1 The APAC pharma manufacturing industry is driven, notes Bhaskarto, by the increasing uptake of modern healthcare and improving access to modern pharmaceutical-based treatment.

Key Pharmaceutical Manufacturing Trends Post-pandemic and Beyond In its June 2021 InfoBrief, IDC’s analysts noted regional reactions to the social, economic and market conditions that confronted the pharmaceutical industry in the region because of pandemic. According to IDC, three important trends emerged: 1. Global supply chain vulnerability must be addressed strategically 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

2.

3.

Incentives are needed to increase manufacturing footprints to meet global/regional demand Manufacturing of more pharmaceuticals should move local to better serve home markets

These three trends all point to a growing need for advanced digital and analytical infrastructures to meet the business continuity and growth challenges of companies operating in the region.

While these are regional challenges, they have significant global impact. According to McKinsey, in the past two decades the worldwide value of pharmaceutical goods traded has grown sixfold, from $113 billion in 2000 to $629 billion in 2019.2 Amid this growth, notes McKinsey, supply chains have become increasingly global, complex and opaque. More companies are outsourcing production to contract manufacturers, adding new modalities (such as cell therapy), and exploring novel ways to reach patients.

For some products, this results in supply chains that are so complex that they start in Asia and circumnavigate the globe twice.

A tremendous amount of pharmaceutical commerce is conducted in the Asia-Pacific region and anything that disrupts supply chains can have globally disruptive effects.

Embracing Digitalisation and The Cost-savings and Security Benefits That Come with It In a recent DIGICONasia Perspective, Fredholm Best, Asia business lead for digital safety systems company HIMA, asserted the pharmaceutical industry is undergoing rapid change, especially in light of the COVID-19 pandemic. He notes that advanced digital capabilities in areas like systems integration, track-and-trace supply chain transparency and deep learning are beginning to help the industry optimise its supply chain, improve safety and develop new drugs.

While it is true people depend on pharmaceuticals to treat illnesses and improve the quality of their lives, their manufacture is a global enterprise. India alone produces approximately 20% of the world’s supply of generic drugs and with any supply chain that is so dispersed, there

is tremendous opportunity for manipulation by bad actors.2 Timely Opportunity to Transform Biomanufacturing Digitally With the Asia-Pacific region seeing growth in both small and large molecule drug manufacturing, innovator companies and contract development and manufacturing organisations (CDMOs) are introducing new capacity to the region. For instance, of manufacturing capacity globally, it’s estimated CDMOs provide nearly 60% and most in the industry expect that number to continue to grow.3 BioSpectrum reported a similar impact: “APAC [Asia-Pacific region] has witnessed never before venture capitalism and M&A amidst the pandemic which is a highly positive sign of a prospect in healthcare deliveries across the region.”2 Journey to 4.0 Transition Even though pharma, in general, has been slow to digitise operations in a transformative, holistic sense, Asia-Pacific’s manufacturers are benefitting from the industry’s experience so far. Many in the industry attribute the industry’s cautious uptake to the fact that many early adopters did not have access to the open secure cloud, or the interoperable, more affordable smart systems now available.

Developing new manufacturing sites without legacy systems constraints is also helping Asia accelerate digitalisation. For example, in China, all new sites are being built with accessible, interoperable cloudbased technologies rather than repurposing legacy sites, which means they can be designed with industry 4.0 in mind.3 Asia: Embracing Pharma’s Manufacturing Future Bearing in mind cGXP, the pharmaceutical factory of the future seeks to assure overall operational effectiveness (OEE) by integrating the data streams from operational, information and data analytics and eliminating data silos within the organisation. It also must create the means and networks to connect external partners and data sources to facilitate scheduling, Spring 2022 Volume 14 Issue 1

Regulatory & Marketplace asset operations and identification of quality issues in real time.

By embracing Industry 4.0, it is possible to find savings in terms of operational productivity and efficiency, and to drive risk and uncertainty out of countless operations and processes. Digital transformation also creates highly collaborative data and information sharing that ensures reliable supplies of quality products reach patients in need. IDC analysts outlined several use cases in their InfoBrief presentation: •

Scheduling in Real-time. Production scheduling and sequencing are completed in an analytic model that is directly connected to execution.

Through the real-time assessment of current demand and available capacity, operations and production schedules are continuously and intelligently resequenced.

•

Dynamic Material Supply Transparency.

A more flexible and dynamic process allows for material requirements to evolve as the R&D process progresses.

This must include the ability to identify alternative material options that may outperform initial selections or provide contingency options during periods of disruption.

•

Predictive Equipment Monitoring and Diagnostics. Machine-learning algorithms that build an accurate predictive model of potential failures that can be used to alert maintenance teams in real time. Maintenance resources can then be optimised through a tiered support structure, depending on the issue, type of asset, criticality and so forth.

•

Automated Root Cause Identification and Mitigation. Connected quality metrics can create an analytic model that supports the automated analysis of quality anomalies with the ability to identify and mitigate root quality processing issues in an automated way.

•

High-fidelity Molecule Discovery.

Precision data acquisition and management supports pharma innovation and the more efficient discovery of new compounds and formulations. With high integrity data comes the ability to identify, catalogue and simulate (at the molecular level) the therapeutic and commercial potential of compounds,

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•

as well as model multiple use-case opportunities for individual molecules.

of the enterprise and the perseverance to follow it to the end.

Data-driven Digital R&D Collaboration.

Through collaborative platforms, data-driven insight can increase the efficiency and accuracy of commercial research and development (R&D) and deliver great value to any organisation.

This results in more efficient, costeffective R&D operations, increased development program effectiveness and, ultimately, faster go-to-market timelines for high potential compounds.

To assure more successful implementation, Asia’s leading drug manufacturers should also seek to engage transformative partners that can help implement a full technology stack. Similarly, the industry should carefully consider engaging industry expertise to address technology and GMP compliance requirements – accurate scoping and implementation are key here.

Accelerating Asia’s Digital Future For any drug manufacturer, the journey to digitalisation may seem long and the outcomes uncertain. But, like any journey of significant discovery, it starts by understanding where to start and which direction to go in. That requires a strategic roadmap, leaders who know the topography

It is equally important to ensure there is dynamic and pervasive sharing of data across information silos to create collaborative workflows. Finally, the enterprise should exploit platforms that capture and analyse patient data, R&D data, market data and operational data – the kind that creates actionable information to support quality innovation, and better patient outcomes.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 21

Regulatory & Marketplace

Case Study: Major Pharma Player Drives its Manufacturing 4.0 Roadmap In IDC InfoBrief, analysts presented a case example of a global healthcare company that digitally transformed its operations to be better at delivering quality and value to patients.

According to IDC, the company wanted to increase operational and capital efficiencies, including overall equipment effectiveness (OEE), across the company’s 20-plus sites.

The company was hoping to achieve early wins to demonstrate to the organisation and shareholders the value of the investment and help sustain the momentum of its digital transformation. Their intention was to focus on implementing the foundational digital technologies effectively and then, building on the expected efficiency gains, support the company’s long-term business planning, drug

development strategies, and deliver continuous improvement to products and processes.

•

Building a Roadmap to Digital Agility As part of its digital transformation journey, the company built a digital transformation roadmap that allowed it to undertake a series of projects focusing on both data use and systems innovation. The aim was to add value and operational agility while building a framework for future implementation.

•

The company’s digital transformation roadmap yielded: • • •

future digital transformation initiatives that will integrate R&D and CMO partners.

Wide-scale digitisation across the enterprise, with automated data acquisition and electronic batch record systems enabling more efficient compliance processes and record-keeping, plus task automation for manufacturing sites.

Advanced analytics, from neural networks and digital dashboards to increased data integrity and improved operational and asset performance management on site.

According to final IDC data, the pilot’s respiratory product’s manufacturing lines avoided $255 million in capital spend with the scaling of pilot technologies resulting in an additional $184 million in operational cost savings.

Manufacturing Excellence System (MES) implementation Asset management driving operational and capital efficiency and OEE Data blueprinting, data pipeline generation and design to underpin integration between sites, products and service teams, and to facilitate

Overall production speed improved by 21%. The increased capital efficiencies resulted in reduced downtime and increased yield, said IDC, delivering an OEE improvement of 10%. Automation of manual records, documentation, and logbook entries save man-hours and enable tighter controls around products and digitised compliance processes, while decreasing cycle times for order preparation and overall time to market (from R&D to medicine delivery).

REFERENCES 1.

2.

https://www.biospectrumasia.com/news/41/ 17825/pharma-industry-to-spend-4-5b-ondigital-transformation-by-2030.html https://www.digiconasia.net/perspectives/ pharma-4-0-cheaper-safer-and-better-drugsthrough-digital-transformation

Kenneth Teo Kenneth Teo is the Asia Leader for Zenith Technologies, a Cognizant Company.

Kenneth has nearly 2 decades of experience managing business P&L, sales and client relationships. He has worked with Cognizant and Zenith since 2013 and has held a variety of roles across the life sciences, manufacturing and retail industry.

22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Spring 2022 Volume 14 Issue 1

Development and manufacturing

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 23

Drug Discovery, Development & Delivery

Roundtable: The Continuing Evolution of Bioinformatics in the Pharma Industry In life sciences research, advances in instrumentation, new types of measurements that are now possible, and improved computational tools, are generating not only significantly more data than ever before, but also more diverse modalities and higher resolution data. The positive effect is that we now have evidence to inform ever more comprehensive models of disease, disease progression, and health, at both the individual level and for the population as a whole.

Moreover, pharma and biopharma organisations can leverage the new ‘mountain’ of available data to open up the potential for them to expedite the discovery and delivery of new, more effective, safer therapies for patients. As far back as 2013, McKinsey & Company1 spoke about the importance of having data that are consistent, reliable, and well linked. An ability to manage and integrate data, from discovery to real-world use after regulatory approval, is now seen by most as a fundamental requirement that allows companies to: • • •

human genome and how it varies between individuals. John Quackenbush, Professor at the Harvard T. H. Chan School of Public Health, who specialises in using massive data to probe how many small effects combine to influence human health and disease and has also founded a number of influential companies such as Genospace, explains: “It’s been incredibly exciting to have been working in a field that has been transformed so fundamentally – and which is still undergoing massive change.

Technology is advancing at such a pace that today we can develop datasets that give us a foothold in addressing questions that were unanswerable even two or three years ago.”

of all human diseases.’ But it didn’t work out like that, because biological systems are more complex than that, which in turn requires enormous datasets.”

The bioinformatics field is continuing to expand, according to Professor Quackenbush, and in a different direction to what scientists would have predicted. “What’s fascinating is that things haven’t evolved in the way some thought they might. When the first human genome was sequenced 20 years ago, people were saying ‘now we’ve identified all the genes we’ll be able to find the root cause

The Biobank Revolution Biobanks typically aggregate genetic information such as WGS (whole genome sequencing), WES (whole exome sequencing), and SNP (single nucleotide polymorphisms) with a range of other data on the same individuals: health records like GP data, hospitalisations, diagnoses, prescriptions, MRI (magnetic resonance imaging), lab

With progressively more sparse data at hand, the challenges in connecting, searching, and analysing within and across multiple datasets continues to grow. As digital transformation is fast-tracked by many, pharma companies must ask how they can make sure they have data organised and rapidly accessible in a scalable, easy to use, computational platform that is future proofed to meet requirements that we cannot predict today.

Derive maximum benefit from technology and computational advances Implement infrastructure that is fit for purpose, cost effective, and easy to use across the enterprise Support clear industry goals faster, derisking routes to the clinic and market approval using informed innovation, data to drive decision making and improved efficiency, for example.

In this roundtable, we speak with leaders in bioinformatics about the challenges facing the pharma industry today as they look to turn data rapidly and efficiently into knowledge, and knowledge into understanding and commercial success.

Data is the Currency of Computational Biology The revolution in DNA-sequencing technologies in the last 25 years means that there is now an abundance of data about the 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Spring 2022 Volume 14 Issue 1

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Drug Discovery, Development & Delivery

results from biochemistry and haematology, and patient-reported information such as family history, behavioural history, and socio-demographics are all included.

For example, the UK Biobank, which stores data from around 500,000 patients in the UK is a repository that presents a great source of public data. Martin Hemberg, Assistant Professor of Neurology, Brigham and Women’s Hospital and Member of the Faculty, Harvard Medical School, located at The Evergrande Center for Immunologic Diseases, explains: “I see biobanks as simply increasing the number of opportunities available to us. Perhaps more exciting still is the opportunity to combine data sets and data types and see more than you could see with just one modality.” Hemberg’s work focusses on developing methods for analysing single-cell RNA-seq data and he’s primarily interested in computational genomics and developing methods and models to help understand gene regulation.

Thanks to computational biology, we’ve got a lot better at defining diseases in terms of what’s going on at a molecular level, says David De Graaf, CEO of Abcuro, 26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

a biotechnology company developing immunotherapies for autoimmune diseases and cancer. “And that’s important because patients don’t come into the clinic and complain that their PI3 [kinase] hurts, for example. We need to continue to progress findings at the molecular level, with these new datasets available, and make connections through the whole chain – from identifying symptoms, to understanding the molecular basis of disease, through to drug discovery. That’s the grand aim – there’s a lot we still don’t know, for example, why patients don’t always benefit as expected from gene therapy. There’s a lot of questions that still need answering, and computational biology could support with that.”

able to take externally curated content and understand it in the context of your own experiments. Then there’s the concept of making a link between patients with a similar molecular phenotype. And finally, where computational tools could make a big difference is being able to extract value from studies that haven’t worked. People don’t always think about the fact that 99% of the money in the pharma industry is spent on things that end up going wrong. But I don’t believe it’s right to simply forget about that work – we should bring it together and gather insights from it. I think all of these things have the potential to be huge drivers in accelerating drug discovery and development.”

Despite advancements in genomic research, there are still barriers that organisations face to support their ongoing disease studies and many inefficiencies with current computational approaches. De Graaf comments: “a huge inefficiency is that it has typically been harder to find old data – I think that computational tools that annotate relevant data, and allow you to search across it, could really pay off.” He continues, “Another opportunity is being

If the industry can expand its computational toolbox to deliver rapid insights more efficiently, with technology platforms that can handle large-scale heterogeneous data, then further advances in drug discovery can be made.

Single-cell Changes the Landscape Again For many in the field, the bioinformatic landscape has been altered significantly by the ability to collect and analyse data Spring 2022 Volume 14 Issue 1

Drug Discovery, Development & Delivery from single-cells rather than aggregated cell populations, or organ systems. Single-cell RNA sequencing (scRNA-seq) allows ’omics analysis, notably genomics, transcriptomics, epigenomics and proteomics at the singlecell level and enables, for example, the identification of minor subpopulations of cells that may play a critical role in a biological process. It can also provide an ultra-sensitive tool to clarify specific molecular responses to therapy and pathways and thus reveal the nature of cell heterogeneity. The Sanger Institute commented in a 2020 blog post2 that: “The volume of single cell data that will be generated will exceed the volume of genotype sequencing data by orders of magnitude. While the human genome has 20K genes, there are 300 different cell types in the human body comprising 37 trillion cells. Previously, scientists would take billions of cells together and measure an average of gene activity. Now, it is feasible to measure each cell’s individual gene expression profile.”

Martin Hemberg notes the change he has seen in his research where this technology has helped to transform results: “Specifically, in terms of single-cell analysis, new technology development is really driving the field – I have to keep my ear to the ground to understand these new technologies and how they can help us solve day-to-day problems we have. For example, I recall that when the costs of cell isolation and sequencing RNA started to fall, researchers took advantage, new protocols emerged where pooled samples were sequenced ‘in bulk’, and the results were deconvoluted to identify individuals. The amount and complexity of the data increased dramatically. In 2016, the problem did not exist, then around 2018 the first publications came out relating to these new experiments, and we started looking at enhancing analysis methodology.”

As such, scientists must remain aware of how quickly the landscape can change as data evolves. Hemberg continues: “What’s become obvious over the years is that a difficult computational challenge can be totally solved by a better assay – or, conversely, a new assay can throw up a new, interesting and challenging bioinformatics and computational problem. The moral is clear: you need to be nimble.”

The ‘Grand Challenges’ – Can We Solve Them?

The abundance of data now available is wwww.international-pharma.com

unprecedented but, without the right tools, its potential value will remain unrealised.

Combining genomic data, imaging data and patient metadata with computational methods to create multi-tiered models that encompass genetic variants, transcription, gene expression, methylation, microRNAs, and more will be important going forward, says Professor Quackenbush. “Bringing all these tools together gives us a better chance of extracting insights from the fantastically complex datasets that are now available.”

To prepare for changes within the field, scientists and organisations should ensure their informatics systems can support new methods and approaches. An integrative analytics platform that streamlines translational research by reducing or eliminating extract transform and load processes, is a computational approach that many organisations should look towards if they want to transform the way they organise, store, compute, and integrate their multimodal scientific data without an army of data janitors.

As we look towards the ‘next big thing’ in pharma, accelerating scientific discoveries through the production of higher-resolution data and new computing paradigms through quantum data is set to soar. With a digital transformation already underway, quantum methods will create an increased requirement for scientists to have their data organised and accessible in scalable analytics platforms future-proofed to meet emerging requirements. It will be more important than ever that organisations are ready to adapt to change in the coming years to enable further bioinformatics-driven breakthroughs.

With thanks to John Quackenbush Ph.D., Martin Hemberg, Ph.D., and David De Graaf, Ph.D., for their valuable insights on some of the bioinformatics challenges faced by the pharmaceutical industry today.

REFERENCES 1.

2.

Mckinsey&Company. 2021. How big data can revolutionize pharmaceutical R&D. [online] Available at: <https://www.mckinsey.com/ industries/life-sciences/our-insights/howbig-data-can-revolutionize-pharmaceuticalr-and-d> [Accessed 14 December 2021].

Mapping the Human Cell Atlas – charting the body’s cellular world, Sanger Institute (2020/04/08) https://sangerinstitute.blog/ 2020/04/08/mapping-the-human-cell-atlascharting-the-bodys-cellular-world/#:~:text= 20%2C000%20dimensions,may%20use%20 to%20varying%20extents

Zachary Pitluk Zachary Pitluk, PhD., VP of Life Sciences at Paradigm4, has worked in sales and marketing for 23 years, from being a pharmaceutical representative for BMS to management roles in Life Science technology companies. Since 2003, his positions have included VP of Business Development at Gene Network Sciences and Chief Commercial officer at Proveris Scientific. Zach has held academic positions at Yale University Department of Molecular Biophysics and Biochemistry: Assistant Research Scientist, NIH Postdoctoral Fellow and Graduate Student, and has been named as co-inventor on numerous patents.

Email: zpitluk@paradigm4.com Web: www.paradigm4.com

Marilyn Matz Marilyn Matz is CEO and co-founder, along with Turing laureate Michael Stonebreaker, of Paradigm4. The scientific analytics solutions company enables scientists and data scientists to transform their research with an integrative analytics platform that powers massively scalable analytics and machine-learning. Prior to Paradigm4, after completing a MS degree at the MIT AI lab, she was one of three co-founders of Cognex Corporation, now a publicly traded, global industrial machine vision company, where she was Senior Vice President and Business Unit Manager of its Vision Software Products Group.

Marilyn was the recipient of the sixth annual Women Entrepreneurs in Science and Technology (WEST) Leadership Award; a co-recipient of the SEMI industry award for outstanding technical contributions to the semiconductor industry; and a 2020 NACD Directorship 100. She also serves on the Board of Directors of Teradyne, a leading supplier of automation equipment for test and industrial applications.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 27

Drug Discovery, Development & Delivery

Improving Outcomes for Gastric Cancer Patients via a Novel Oral Daily Dose Chemotherapy Formulation, Oncoral Gastric cancer is the fifth most common cancer, with around one million annual incidences worldwide,1 and it represents the fourth most common cause of cancer deaths.2 High incidences of the disease in Asia (Figure 1) mean that screening in countries like Japan have made survival rates better than in Western countries, where the disease is often already advanced by the time of diagnosis. The five-year survival rate in the US and Europe is only 20%, making it a key target for drug development.

The gastric cancer drug market is growing rapidly and is expected to approach USD 4 billion by 2029 according to GlobalData.3 This growth is fuelled by several factors, including an increase in the overall incidence, as well as higher treatment rates and extended treatment duration.

For patients with recurrent or advanced gastric cancer, the prognosis is poor, which underlines an urgent need for improved treatment options. Today, chemotherapy is a mainstay of treatment, and is associated with toxicity and limiting side-effects.

The chemotherapy agent, irinotecan, is proven to be effective in the treatment of several gastrointestinal cancer forms. The injected version is approved for treatment of colorectal and pancreatic cancer in the USA and Europe, and for metastatic gastric cancer in Japan. Although irinotecan is currently not approved for treating gastric cancer in the US and in the EU, there is offlabel clinical use. It is also recognised in clinical guidelines (ESMO, ASCO, NCCN) in monotherapeutic or combination treatment regimens for advanced gastric cancer.

Irinotecan has been studied and is being used in clinical settings today in many different solid tumour types. However, it is typically administered every third week via intra-venous (IV) bolus infusion in high doses. With this type of administration, most patients experience gastrointestinal and haematological side-effects, approximately 30% of which are severe or life threatening (grade 3 or 4).4 A tablet formulation of 28 INTERNATIONAL PHARMACEUTICAL INDUSTRY

irinotecan would enable frequent, low dose administration – also called metronomic chemotherapy – a dosing strategy which appears beneficial in a wide range of tumours.

In order to create a better treatment option for patients, Ascelia Pharma is developing a novel patented tablet formulation of irinotecan for daily dosing at home, called Oncoral, which is currently being prepared for Phase 2 clinical development. Daily oral dosing of irinotecan has the potential to play a role in the treatment of various cancer types and, while the initial indication for Oncoral is gastric cancer, it may offer the potential for future use in other types of cancers as well. As gastric cancer is relatively uncommon in the US and Europe, there is the potential for Oncoral to have an orphan drug designation.

Oncoral Mode of Action Until now, no previously tested oral irinotecan formulations have entered Phase 2 due to issues concerning poor solubility and interpatient variability in bioavailability.

The formulation of Oncoral is based on irinotecan in the free base form being solubilised in a hydrophobic lipid system.

The system is formulated into an enteric coated tablet to avoid release in the stomach, as stomach pH may influence the bio-absorption of irinotecan. The tablet releases the irinotecan immediately in the duodenum, avoiding protracted release so that the dosed irinotecan is dispersed before the next dose, to avoid

drug accumulation and ensure high bioabsorption with low variability.

After oral administration of Oncoral, conversion of irinotecan takes place in the liver to the active metabolite SN38, which is 100–1,000 more cytotoxic than irinotecan.

SN-38 reaches the tumour through systemic circulation and inhibits Topoisomerase 1 to exert its cytotoxic effect via prevention of DNA replication. Following metabolisation, SN-38 is converted to the water-soluble but inactive metabolite SN-38G. Advantages of Daily Dosing With Oncoral, researchers are exploring the possibility to give gastric cancer patients irinotecan in daily doses – metronomic chemotherapy – with the potential for better efficacy and an improved safety profile.

Efficacy After oral administration, approximately five times more irinotecan is converted to the active metabolite SN-38 compared to IV infusion.6 Several non-clinical and clinical studies provide proof of concept for metronomic dosing, including improved patient outcomes.7,8 In one study of patients with metastatic refractory breast cancer, overall survival improved from 20% with irinotecan dosing every three weeks, to 32% with weekly dosing (Figure 2).

Frequent dosing may optimise the chance that tumour cells are exposed to SN-38 during the susceptible S-phase of the cell cycle, maximising anti-tumour effect. In the Oncoral Phase 1 study, clinical benefits

New incidence cases

Cumulative risk 0–74%

Mortality

Cumulative risk 0–74%

East Asia

656,349

2.63

435,211

1.7

Northern America

29,772

0.48

13,391

0.19

Western Europe

28,490

0.66

17,755

0.35

Figure 1: Table showing the numbers of gastric cancer incidence and mortality statistics by region.5 Data taken from the Global Cancer Observatory, owned by the International Agency for Research on Cancer (IARC)).

Spring 2022 Volume 14 Issue 1

Drug Discovery, Development & Delivery

Figure 2: Study comparing irinotecan dosing every third week vs weekly dosing.8

with stable disease were observed even in patients that previously received IV irinotecan.

Safety/Tolerability/Convenience Frequent low dosing, avoiding high peak plasma levels, may reduce toxicity and complications compared to high-dose IV infusions. Oral daily administration also brings the opportunity to adjust dosing quickly in case of acute toxicity, offers convenient administration for patients, and is expected to be a cost-effective treatment alternative. In the Phase 1 single agent study,6 Oncoral was well-tolerated, and the haematological toxicities were only mild to moderate, grade 1 or grade 2.

Pharmacokinetic data showed consistent daily exposures during treatment at days 1 and 14 and no drug accumulation (Figure 3).

SN-38 interpatient variability was in the same range as after intravenous administration.

Combination Therapy Shows Promise Taiho Oncology’s LONSURF® is indicated in the EU and US as monotherapy for the treatment of adult patients with metastatic gastric cancer including adenocarcinoma of the gastroesophageal junction, who have been previously treated with at least two prior systemic treatment regimens for advanced disease. LONSURF is an oral compound consisting of a thymidine-based nucleoside analogue, trifluridine, and the thymidine phosphorylase (TP) inhibitor, tipiracil, which increases trifluridine exposure by inhibiting its metabolism by TP. Trifluridine is incorporated into DNA, resulting in DNA dysfunction and inhibition of cell proliferation.

Figure 3: Pharmacokinetic plasma profiles of irinotecan, SN-38 and SN-38G on day 1 (mean values + SEM, n = 15).

Graphic used under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).6 wwww.international-pharma.com

The combination of irinotecan and LONSURF has been tested in animal models which showed that the combination almost stopped the tumour from growing and gave INTERNATIONAL PHARMACEUTICAL INDUSTRY 29

Drug Discovery, Development & Delivery better results than administering both irinotecan or LONSURF as monotherapies [Figure 4].

• • •

Around 100 patients Metastatic gastric cancer Randomized controlled, multicenter, multinational study

Oncoral + Lonsurf Vs. Lonsurf Primary: Progression Free Survival Secondary: Response rate, PK, Safety and Overall Survival data in a follow up analysis Q4 2022–2024

survival, pharmacokinetics, safety, and tolerability.

TAS-102: LONSURF CPT-11: IV irinotecan TAS-102 + CPR-11: LONSURF + IV irinotecan Figure 4: Efficacy study in an animal model of gastric cancer, Relative tumour volume (RTV) of KM12C human colorectal tumour of KM12C-bearing nude mice. Mice were randomised according to tumour volume on day 0. Mice were treated with the 0.5% hydroxypropyl methylcellulose or TAS-102 (150 mg/kg), administered orally twice daily from days 1 to 14. Irinotecan hydrochloride (CPT-11) (40 mg/kg) was administered intravenously alone or in combination with TAS-102 on days 1 and 8. The tumour volume and body weight were measured twice a week. The values indicate the mean ±SD (n=7). The horizontal dotted line indicates an RTV of 5.9

Oncoral Clinical Development now in Phase 2 The development of Oncoral is supported by a Scientific Advisory Board of leading oncologists, who support the position that a daily tablet formulation of irinotecan could be a valuable additional treatment option for cancer patients, especially in later disease stages.

The Oncoral Phase 2 study, for which the IND was approved in December 2021, is a randomised controlled multicentre all-oral combination study in patients with advanced gastric cancer. Run in collaboration with Otsuka’s Taiho Oncology and led by the International Coordinating Investigator, Professor Josep Tabernero, former President of the European Society for Medical Oncology (ESMO), it will compare Oncoral administered in combination with LONSURF (trifluridine and tipiracil) filmcoated tablets for oral use, compared to LONSURF alone.

The primary endpoint of the combination study will be progression-free survival, which is standard for an oncology Phase 2 study. Secondary endpoints will include response rate, overall 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summary Gastric cancer patients often face late diagnosis and poor outcomes, due to limited treatment options. The opportunity to introduce metronomic chemotherapy with irinotecan in combination with other effective compounds in an oral tablet, opens up the possibility of better efficacy, and a more convenient and cost-effective treatment regimen with an acceptable safety profile.

4.

5.

REFERENCES

8.

1.

2.

3.

World Cancer Research Fund International (www.wcrf.org) World Health Organisation (Cancer (who.int)) Gastric and Gastroesophageal Junction Adenocarcinoma – Epidemiology Forecast to 2029’ 2020 (https://store.globaldata.

6.

7.

9.

com/report/gdhcer248-20--gastric-andgastroesophageal-junction-adenocarcinomaepidemiology-forecast-to-2029/) Camptosar prescribing information World Health Organisation https://gco.iarc.fr/ today/data/factsheets/cancers/7-Stomachfact-sheet.pdf (2020) Kümler et al. Cancer Chemother Pharmacol.

2019 Jan;83(1):169-178: Oral administration of irinotecan in patients with solid tumors: an open-label, phase I, dose escalating study evaluating safety, tolerability and pharmacokinetics Furman et al, Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children,1999 (https://pubmed. ncbi.nlm.nih.gov/10561220/) Perez et al. J Clin Oncol 2004: Randomized Phase II Study of Two Irinotecan Schedules for Patients With Metastatic Breast Cancer Refractory to an Anthracycline, a Taxane, or both Nukatsuka M et al. Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, with irinotecan hydrochloride on human colorectal and gastric cancer xenografts. Anticancer Res. 2015 Mar;35(3):1437-45. PMID: 25750295.

Carl Bjartmar Carl Bjartmar, MD, PhD, has been Chief Medical Officer at Ascelia Pharma since 2018 and has a long and solid track record in late-stage orphan drug development.

He has previously served in senior roles at large international pharma companies such as Lundbeck, Sanofi and Genzyme, where he gained extensive experience in clinical development, in particular the development of novel therapies for rare diseases. Before joining Ascelia, Carl was most recently Chief Medical Officer for the Swedish biotech company Wilson Therapeutics.

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Drug Discovery, Development & Delivery

The Enigma of Topical Biologics Development

Traditionally, most marketed drugs, irrespective of their route of delivery, have had relatively low molecular weights. Nowhere has this been more markedly true than in topical drug delivery. Historically, it was thought that to successfully permeate healthy skin, molecules must be of less than 500 Daltons, and must be moderately lipophilic (log P 1.0–3.5) with a low melting point and high potency.

These rules, of course, were driven by the need to overcome the natural barrier function of the skin, which is designed to protect the body from physical, mechanical and chemical insult whilst further providing a barrier to endogenous water loss. The barrier function of the skin largely derives from the non-viable, thin (10–30 µm) cornified outermost layer, the stratum corneum. When intact, the stratum corneum provides the protective effects described above but also severely limits passive drug delivery across and into the skin.

To date, 93% of approved topical products contain actives of below 600 Daltons, with the remaining 7% all being within the range of 600–1,000 Daltons (Citeline, Pipeline Database). Furthermore, these larger molecules (500–1,000 Da) are generally for use on skin that may have a compromised barrier function because of localised disease such as psoriasis or atopic dermatitis. Prime examples of this are the calcineurin inhibitors, pimecrolimus (810 Da) and tacrolimus (804 Da), that are used to topically treat atopic dermatitis.

Dermatology is rapidly developing in terms of understanding of genetic associations with diseases, the consequences of gene mutation on protein expression, and small molecule signaling and metabolomics.

Through these advances, molecular disease markers are supporting clinical decisionmaking and differentiation of disease subtypes. As a result, personalised and precision-targeted therapies tailored to an individual’s pathophysiology are becoming more common. Consequently, emergent 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

classes of active pharmaceutical ingredients are growing from small organic molecules to biomacromolecules such as monoclonal antibodies.

These recent developments in drug discovery and medicinal chemistry, and the advances in genetic therapy and diagnostics, have resulted in an increasing number of new drugs that are macromolecular and biologic in nature, with molecular weights above 1000 Daltons. This is reflected in how the number of biologics in the top ten drugs (by sales revenue) has increased over the last 5 years. It is important to note that the classification of a ‘biologic’ is a general term and can be used to reference proteins, peptides, antibodies, oligonucleotides, etc. where characterisation

by Log P and molecular weight may be an oversimplification. For passive delivery to and across the complex barrier that is the skin, other physicochemical properties like molecular volume and conformational structure may also be key discriminators which, along with potency, may ultimately determine the chances of success of a topical biologic. Whilst rates of penetration into and permeation through skin of these macromolecules may be extremely low, their extremely high potency may still elicit pharmacological activity.

Despite the generally held view in the scientific community that the passive delivery of biologics through intact skin is a significant challenge and that this is clearly reflected in the market, there are several instances in the published scientific literature claiming the successful topical delivery of macromolecules. Nevertheless, the potential for such biologics to be delivered topically across the skin rather than by injection remains a highly debated subject, and the lack of any marketed topical products where the active has a molecular weight of over 1000 Da. certainly supports the view that topical biologic delivery may not be possible.

Whilst an in-depth discussion of all the published scientific literature that claims the successful topical delivery of macromolecules is not appropriate here, a critical evaluation of much of

this literature suggests that some of the methodologies used are misleading and contain experimental artifacts that may be responsible for reaching the conclusions made. For example, many researchers have used animal models, such as rodents and/or minipigs, either in vitro or in vivo, to assess the passive delivery of large molecules. It should be noted that several of these studies have been shown to be misleading based on experimental design and validation, and/ or a lack of controls. The current lack of translation of such studies into successful clinical trials and/or marketed products further supports the current scepticism and has led to a large commercial and academic effort to find ways of disrupting the barrier function of skin through the use of physical and/or active techniques such as abrasion, microporation, magnetophoresis, ultrasound, iontophoresis, or the use of microneedles.

Companies engaged in this type of research and development have come and gone in quite large numbers over the last twenty years, with hundreds of millions of dollars of speculative investment being spent with, as of now, little or no return.

Nevertheless, the fact remains that some studies that appear to demonstrate the passive delivery of certain biologics to the skin cannot be so simply dismissed, with hypotheses around such delivery being linked to biologic specific physicochemical properties, structural conformation, potency and the lack of understanding of the barrier properties of diseased skin.

Hyaluronic acid is a hygroscopic macromolecule widely used in topical formulations (Brown and Jones 2005). Recently, its uptake into human stratum corneum has been studied using Raman spectroscopy (Essendoubi et al. 2016). This polymer with molecular weight 20–50,000 Da penetrated into the stratum corneum and was visualised in the deeper skin layers, apparently in violation of the 500 Da rule.

Short-interfering RNAs (siRNAs) offer potential tools to treat common skin disorders, but as negatively charged, hydrophilic and typically large (13–14 kDa) molecules, their topical delivery is Spring 2022 Volume 14 Issue 1

Drug Discovery, Development & Delivery challenging. However, using a range of penetration-enhancing strategies, including conjugation to SPACE-peptide coupled with an ethosome-based carrier, allowed delivery of the peptide into mouse skin (Chen et al.

2014). Whilst naked siRNA does not appear to effectively enter the stratum corneum, chemical moderation not only improves RNA stability but can facilitate uptake into the tissue (Hedge et al. 2014).

Aptamers are a relatively new class of oligonucleotide-based molecules that can specifically bind to target molecules including proteins or other cellular targets.

Aptamers have been approved for the treatment of macular degeneration and new aptamers are in clinical development for cancer, haemophilia, anaemia and diabetes.

Recently a new first in class RNA aptamer inhibitor of IL-23 for the topical treatment of psoriasis was developed and optimised (Lenn et al. 2018). The 62 nucleotide (20 kDa) aptamer had a high affinity and specificity for human IL-23 cytokine, and the use of a well-established, validated in vitro human skin model was shown to penetrate into and through intact human skin without physically disrupting the stratum corneum. The

biological activity from this topical delivery was confirmed in living ex vivo human skin shown through suppression of several key cytokines (IL17 and IL22) that are linked to clinical efficacy.

Whilst the primary research described above shows the potential for the dermal/ transdermal delivery of macromolecules, no single biological topical skin product has yet been approved for passive delivery across an intact barrier, despite the investment of millions of dollars into their development.

This highlights the need for investment in, and regulatory acceptance of, new methods for early testing and de-risking of the development pipeline for topical biologics.

In recent years, there have been a number of novel pharmacological (PD) disease models developed using fresh human epithelia. Relatively simplistic skin infection models have existed for some time and are advantageous when working with larger, more complex biomacromolecules.

For example, in a model where an organism is grown on agar beneath excised human skin (providing the barrier function), a simple zone of inhibition study can provide a biomarker

for permeation and antimicrobial activity. This avoids the need for analytical methods (HPLC, LC-MS etc), which can be tricky with large biologics. More recent advances in these skin infection models utilise the ability to grow and culture organisms on or under the skin and accurately recover and quantify viable organisms after treatment. In these models, an organism most relevant and causative of the infection is introduced and grown under controlled conditions. The location of the organism within the skin can be controlled such that it closely resembles the clinical presentation. In addition to this, the barrier properties of the skin can be replicated and the ability of the drug or formulation to exert its pharmacological effect is then assessed using the measurement of a biological marker in the form of ATP, a direct indicator of cell viability, PCR or direct viable counts. This model has been advanced into living ex vivo skin which allows one to explore the effects of infection and consequent inflammatory responses from a range of local cell types for multimodal mechanistic studies.

The ability to maintain ex vivo surgicallyexcised skin alive in culture for over a month has opened up the ability to create

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Drug Discovery, Development & Delivery complex disease models (e.g. rosacea, acne, infected eczema, seborrheic dermatitis and infected wounds) where treatment effects may take more than a week to further derisk the development process for topical products including biologics. Although, as is common with other models, ex vivo human skin used in this manner lacks cell migration (infiltrate) and clearance from the circulatory and lymphatic system. Unlike models such as reconstituted human epithelium, it will contain resident immune cells (lympohyctes, dendritic cells and Langerhans cells) which have been shown to secrete inflammatory cytokines in these models. In addition, these explants can be artificially stimulated with specific mixtures to elicit biological responses, allowing the exploration of specific disease states. For example, the release of chemokines, antimicrobial peptides and keratinocyte differentiation biomarkers associated with clinical psoriasis can be analysed for changes in gene expression and protein production. Other areas of promise include other inflammatory skin diseases (e.g. acute and chronic atopic dermatitis), multi-mechanistic skin diseases (e.g. acne and infected dermatitis), wound healing, skin ageing, damaged and environmentally stressed skin as well as various skin infections (bacterial and fungal).

With increasingly sophisticated and sensitive assays being developed for varied macromolecules and given their high potencies and specificities (requiring low dosages at their therapeutic sites), it appears likely that greater numbers of these therapeutic agents will be developed for topical delivery in the coming years.

However, the mechanism by which these

agents could passively traverse the stratum corneum barrier remains unclear. Whilst delivery of these macromolecules through intact skin remains problematic, given their potency and that the skin barrier integrity is often compromised in diseased states, opportunities still exist to design topically applied formulations for these agents.

The topical delivery of biologics is clearly far from simple, and the technical and commercial landscapes of its history are both complex and controversial. The question as to whether large (and often very potent) biologics can be delivered to/through the skin effectively enough for clinical relevance remains unanswered.

Nevertheless, by understanding this history, and deploying a pragmatic approach through the use of healthy and diseased human skin in-vitro permeation and penetration testing systems, in combination with skin disease pharmacodynamic models, it is possible to more effectively explore development in this space. Used together, these models provide an early understanding of the potential chances of success in later, more expensive, clinical evaluations.

REFERENCES 1.

2.

3.

4.

Brown, M.B. and Jones S.J., (2005). Hyaluronic acid: a unique topical vehicle for the localised delivery of drugs to the skin. J.Eur. Acad.

Dermatol. Venereol. 19: 308-318.

Chen, M., Zakrewsky, M., Gupta, V., Anselmo, A.C., Slee, D.H., Muraski, J.A., and Mitragori, S., (2014).

Topical delivery of siRNA into skin using SPACEpeptide carriers. J. Control. Release 179: 33-41.

Citeline. Pipeline Database, <http://www. citeline.com/products/pipeline/> (2014).

Essendoubi, M., Gobinet, C., Reynaud, R., Angiboust, J.F., Manfait, M., and Piot, O. (2016).

5.

6.

Human skin penetration of hyaluronic acid of different molecular weights as probed by Raman spectroscopy. Skin Res. Technol. 22: 55-62.

Hedge, V., Hickerson, R.P., Nainamalai, S., Campbell, P.A., Smith, F.J., McLean, W.H., and Pedrioli, D.M., (2014). In vivo gene silencing following non-invasive siRNA delivery into the skin using a novel topical formulation. J. Control. Release 96: 355-362.

Lenn, J., Neil, J., Donahue, C., Demock, K., Tibbetts, C.V., Cote-Sierra, J., Smith, S.H., Rubenstein, D., Therrien, J-P., Pendergast, S., Killough, J., Brown, M.B., and Williams, A.C., (2018). RNA aptamer delivery through intact human skin. J. Invest. Dermatol. 138: 282-290.

Marc Brown Marc Brown, PhD, CChem, FRSC co-founded MedPharm in August 1999. He has been the guiding force behind all of MedPharm’s scientific developments and intellectual property. He has been Professor of Pharmaceutics in the School of Pharmacy, University of Hertfordshire since 2006 and has visiting/honorary professorships at the Universities of Reading and King’s College London. He has over 200 publications and 26 patents describing his work. His research interests lie mainly in drug delivery to the skin, nail and airways. To date, he has been involved in the pharmaceutical development of over 55 products that are now on the market in Europe, America and Japan. Prior to MedPharm he was an academic in the Pharmacy Department at KCL.

Dr. Jon Lenn Jon Lenn, Chief Technology Officer, has direct responsibility for MedPharm’s operations in the United States based out of Durham, North Carolina. Since joining in 2015 he has led MedPharm’s development of cutting edge performance models for assessing penetration and activity of clients’ products targeted towards key biochemical pathways.

He has over 15 years’ experience in developing dermatological projects with Connetics, Stiefel and GSK and has been directly involved with the development and approval of 8 products. He received his PhD on the topical delivery of macromolecules from the University of Reading.

34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Spring 2022 Volume 14 Issue 1

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Clinical and Medical Research

Study Coordinators Speak Out on Trial Site Diversity: 4 Ways to Move the Needle In recent years, consensus has grown around the concern that clinical trials in the United States are neither adequately inclusive nor diverse. For example, the latest data shows that nearly 75% of patients who are enrolled in industrysponsored clinical trials in academic medical centres and community hospitals are white – as compared to 58% of the general U.S. population. These realities are reflected in trial performance and outcomes of approved medicines in the general population – a population only partially represented in the research.

That means that medicines are not being created for everybody.

While this isn’t new, the COVID-19 pandemic and the corresponding race for vaccines and treatments has shone a spotlight on the problem so bright that it can no longer be ignored.

In their recent study of more than 3,400 trial sites, the Centre for Study of Drug Development at Tufts University highlighted the critical need for sites to reflect the patient communities they serve. The study found that the race and ethnicity of clinical trial personnel is highly correlated with the race and ethnicity of study participants – which suggests that patients are more likely to participate in studies where their race or ethnicity is represented among site personnel. Unfortunately, two-thirds (68%) of the staff at academic centres and community hospitals are white, as are 56% of the personnel at private physician practices and dedicated trial sites.

Race and ethnicity are just two of many critical factors that contribute to trial inclusivity. Additional factors include time, flexibility, and cost. Thankfully, study sponsors are beginning to recognise these factors and make commitments to implement needed changes to the trial process, but these changes are rarely made in consultation with clinical trial site personnel. This is a mistake.

Study coordinators and other site staff stand on the front lines of every trial. These 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

personnel understand what it takes to enroll patients, establish trust and appreciation, and inspire retention. The real-life experience and wisdom of these unsung heroes hold the key to unlocking the door to greater inclusivity in clinical trials. “Most of the hands-on work of clinical trials is handled by study coordinators,” said Brenda Reese, Chief Commercial Officer at Javara Research. “Study coordinators typically have high emotional IQs and take time to connect with patients. Plus, they support recruitment, onboarding, screening, and much more. We would not have research today without them, so we need to involve them more in our industry wide efforts to improve trial inclusivity.”

To that end, we spoke with study coordinators at Elligo Health Research to uncover four ways to help move the needle on trial site diversity.

1. Reduce the Time Commitment Required to Participate Time commitment is the primary issue preventing inclusivity in clinical trials, said Annabelle Bitterman, clinical research coordinator at Elligo Health Research.

Annabelle worked in a women’s trial studying endometriosis that required monthly visits, which ended up requiring upwards of three hours each when factoring in transportation. “Women would sometimes bring their kids, and Sarah or I would entertain them,” remembered Bitterman.

“Given the time commitment, often their biggest struggle is finding childcare while going to these appointments, plus having a job that is inflexible about taking off.”

Of course, time off and job flexibility are luxuries that many women do not enjoy – especially women in lower socioeconomic circles, the very populations these trials are often attempting to study.

What could open these trials to a more inclusive population? Visits at the patient’s home or even virtual visits by video conference or phone are helpful solutions, said Bitterman. “For instance, in one recent women’s health study, the protocol had built-in flexibility, so we had no in-person

visits after the initial in-person screening.

All other visits had the option of being virtual or in-person. It’s not surprising that we have 100% patient retention 12 months into the study.

Decentralised, technology-enabled options should be provided to patients whenever studies can allow for them.

2. Prioritize Flexibility in the Protocol Design and Trial Process Closely related to time commitment is flexibility – the ability for a study’s design and process to accommodate the real-life needs of its participants.

“We try to make our studies as flexible as possible so we can allow anyone to join,” said Bitterman, “whether that is doing most visits remotely, providing free childcare for in-person visits, increasing availability of staff during off-hours via telehealth, or allowing weekend visits.”

Bitterman described the flexibility her clinic built into a recent ablation study. In this case, no in-person visits were required after the initial in-person screening, unless patients were having issues after the procedure. Twelve months in, the trial had retained 100% of its patients.

3. Make Accommodations for the Socioeconomic Status of Target Participants In addition to time commitment, many potential patients are dissuaded by the financial realities of trial participation.

Site Qualification Specialist, Sarah Grover emphasised the need to consider the socioeconomic status of the entire population that the study could access and accommodate for the financial needs of that population. This could mean making sure there is more funding for transportation or leveraging clinics that are along bus routes – thereby removing the barriers before patients even get to the protocol.

Free healthcare is another enticing draw. “For a birth control trial,” said Grover. “I asked the clinic to advertise that they would get free birth control and free healthcare to those women who Spring 2022 Volume 14 Issue 1

Clinical and Medical Research Both Grover and Bitterman underscored the need for this level of diversity for clinical trial staff – especially among Principal Investigators, the majority of whom are white. These PIs come in and answer additional patient questions, meaning they are another important layer of trust.

“This is why I’m involved in research, despite the negative history,” said Grover.

“I am a safe place for patients to ask these questions. And when I make them feel more comfortable, patients benefit from a great opportunity to access high-quality care and even life-saving medical treatment.”

Moving the Needle Study coordinators already know what the Tufts study confirmed: clinical trials are neither as inclusive nor diverse as they need to be. There is much work yet to be done, but the unsung heroes working directly with patients know exactly where to begin. The approaches and techniques that study teams often employ naturally get to the heart of human-centred design that considers the entirety of the participant, not simply their collection of symptoms that make them eligible for the trial. By adopting more thoughtful, human-centred protocols around time, flexibility, cost, and staffing, clinical trials can better serve their intended populations – thereby bringing lifesaving therapies to the patients that need them, faster than ever before. wouldn’t have as much money or access to insurance.” They did the same at a sister site for a uterine fibroid study, advertising to women that they would provide free healthcare. In both cases, the incentives worked.

“These patients,” she said, will often bring up black Americans’ dark history with clinical research. “And, as a black American, I understand what they are asking. So, I can allay their fears in an empathetic, delicate, and convincing way.”

4. Establish Trust with Local, Familiar Faces Lastly, as reflected in the Tufts study, diversity can be dramatically improved by ensuring that onsite staff reflect the populations they are seeking to serve.

The resulting comfort and trust have an undeniable impact on patient recruitment, participation, and retention.

Grover also emphasised that she possesses the background and understanding to provide these patients with a more comprehensive overview of trial risks, knowing their specific pain points and fears.

Altogether, this helps patients open up and trust her.

One way to achieve this, said Grover, is by expanding study locations: reaching out to clinics that are not typically doing research, perhaps in rural areas or in parts of cities that patients trust.

But perhaps the most important way is to diversify onsite clinical staff, confirmed Grover, who has seen first-hand her ability to establish trust with black patients. wwww.international-pharma.com

She has witnessed the same easy trust in relations between staff and patients of other races or ethnicities, as well. “All of our women’s health sites serve as back-ups to each other, so we have access to thousands of patients. It is a relatively diverse group, and they all rotate to clinics as needed.

The level of comfort patients have with our site coordinators is great – especially when connecting Latino patients with a Latino study coordinator.”

Mary Costello Mary Costello has spent over thirty years in the healthcare and clinical research fields, working in commercial leadership roles with large organizations including Covance, Thermo Fisher, and, more recently, supporting the growth and expansion of eClinical Solutions and Elligo Health Research. Costello has served on several industry advisory groups and is a founder and board member of BioAustin. At Medable, she serves as Head of the Site and Investigator Network and is passionate about ensuring the site’s voice and experience help shape improvements to the clinical research industry.

Email: mary.costello@medable.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 37

Clinical and Medical Research

Tackling the Challenges with Decentralised Trials

Patient-centered digital clinical trial success depends on engaging patients in new ways and managing massive volumes – and new forms – of data.

Decentralised clinical trials (DCTs) have existed for years in different shapes and forms. Pfizer's 2011 REMOTE trial1 was the first to achieve acclaim. While many clinical leaders praised DCTs, primarily because of the promise of more patient convenience, some companies found them too complex to use across all trials.

Fast forward to the COVID-19 pandemic, where disruptive changes came swiftly.

"Every company had started to dip its toes into the digital world, but COVID-19 pushed us all into the proverbial pool. We had to come up with solutions quickly to keep our studies afloat, now it's forcing us to be a little bit more forward-thinking," said Lorena Gomez, senior director of global study start-up, PRO management, and digital implementation at AbbVie.2 Restrictions to in-person patient visits and other challenges with access accelerated the implementation of new tools and

technologies to keep trials moving forward.

The pandemic also unveiled many of the challenges of traditional clinical trial models, including the fragmented use of digital, stand-alone applications.

As a result, sponsors and CROs are evaluating ways to optimise studies for the long haul. While DCTs have been a hot topic across life sciences, the need for patientcentricity will likely lead to a hybrid approach that combines decentralised and site-based functions while maintaining some human engagement within a digital framework.

Figure 1 specifies key distinctions between the various words now being used when describing modern clinical trials.

"It's going to be important that we collaborate as an industry to understand how that patient journey and site relationship is going to change. Historically as partners, we've always brought trials to sites. Now, we're going to find a way to bring patients to trials," said Mark Morais, president, clinical operations and commercial solutions, Labcorp Drug Development.

Data and Patients are at the Core of Transformation To reach the patient-centric trial goal,

companies are evolving their digital strategies to make trials more patientfriendly while improving connectivity with research sites. Some organisations are establishing a foundation for digital trials by automating data aggregation, harmonisation, and cleaning. Together, these steps are critical, especially as the amount of data flow into, out of, and between databases grows, including information from monitoring devices, sensors, and wearables that are capturing real-time patient data.

"We need to think about the impact to sites, protocol design, and patients – especially in terms of what we're capturing and how. We have to let digital drive simplicity as we potentially increase the disparate data sources," says Morais.

"Data management was once an invisible function, but it is now at the centre of everything. Data has become the new currency," said Mayank Anand, vice president, global head, data strategy and management at GSK. Promises Fall Flat, While Expectations Increase Findings from Veeva's Digital Clinical Trials Survey showed that although the industry

Figure 1 shows different paths to patient centricity (Source: Veeva Systems) 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Spring 2022 Volume 14 Issue 1

Clinical and Medical Research

Figure 2. Barriers to Patient- and Site-Centric Trials (Source: Veeva Systems)

has made progress in modernising clinical trials, there are still many issues from the rapid deployment of technology. More than 280 clinical leaders responded to the survey, showing only 27% ran DCTs before the pandemic. Now, 87% are working with DCTs or soon plan to, while 95% expect to increase their use of DCTs over the next year.1 While DCTs hold the promise to address common challenges around patient recruitment, trial timelines, and total costs, realising the full benefits will take some time. Less than one-third of respondents experienced lower costs or reduced trial timeframes using DCTs. Only 56% of sponsors and CROs said that moving to DCTs has improved the patient experience. In contrast, about half say DCTs have placed a greater burden on patients, many of whom were not entirely comfortable using digital applications.

Almost all respondents (99%) acknowledged that DCTs had technical and organisational difficulties (Figure 2), with 70% mentioning research sites' adoption of new technologies as the number one challenge.

There is a technology disconnect between sponsors and sites, with some sites reporting2 their staff spend 70% of their time on manual processes like emails.

Currently, the average site uses at least a dozen different systems3 to collect and capture study information. The result has been a mixture of individual point solutions and a combination of passcodes, portals, logins, and access codes. wwww.international-pharma.com

Notably, 59% of sponsors and CROs view internal change management as one of the key DCT challenges.

Life Sciences Takes Action Critical to addressing the most pressing challenges with DCTs, the industry needs to bring the sponsor operations-based "back office" to the site- and patient-facing technology "front office." Taking action to address the fundamental problems with data standardisation, management, integration, and patient outreach will be paramount.

A platform-based approach can help put an end to the silos that limit collaboration between study stakeholders. For example, eliminating paper-based processes by connecting clinical operations, sites, and patients will lower clinical trial costs and timelines by 25%.

Most survey respondents are already actively addressing these obstacles.

•

66% of CROs and 53% of sponsors are increasing their support of clinical research sites

•

CROs led sponsors in the adoption of specific measures, with 54% improving data sharing and collaboration (vs. 38% for sponsors)

•

54% are addressing system interoperability issues caused by the rapid deployment of eClinical technology to support DCTs, compared with 29% of sponsors.

Regarding change management, respondents are increasing their organisation's efforts to update SOPs initially written for traditional trial models to align with new digital environments and educate employees with role-specific communication and training.

Patient Centricity Redefined Organisations need to critically evaluate their definition of patient centricity to determine the best healthcare approaches and digital solutions to use. Each decision can vary by trial variables like indication and age group differences and the regulatory requirements that outline what can and can't be done in each country.

While some patients may prefer to have data collected in person at a clinic, others may choose to have it done during a telehealth visit or prefer to enter it themselves on a smart device. These options could also apply to the same patient at different times throughout the study.

Keeping a Touch of Human Engagement Human touch and interaction are still needed for clinical trials on the patient-facing side and to analyse and optimise data. Using applications to collect data and connect with trial participants delivers patient convenience and execution speed, but it doesn't make up for human-to-human interaction. Studies that include strategies for both digital engagement and in-person patient care can ensure patient centricity and compliance.

Patient centricity is a call to action for data managers and scientists. These teams INTERNATIONAL PHARMACEUTICAL INDUSTRY 39

Clinical and Medical Research interpretation by an electrophysiologist.

This is just one example of many where a cross-functional approach between health care professionals and data scientists will be critically important.

Keeping the patient focus at the forefront, enabling better data management in trials promises to improve overall agility and visibility into clinical data. "With technology and data, we must address how we plug in to bring simplicity and a connected architecture," says Anand.

Once the industry moves past some of the current challenges, modern clinical trial models promise to accelerate the delivery of new therapies. For now, more work lies ahead as companies advance toward trials that are digital and connected. Morais added, "We're creating a great amount of learning.

We need to take those learnings and share it as part of that end-to-end strategy and allow it to influence what we do next."

REFERENCES 1.

2.

3.

4.

5.

Pfizer, Pfizer Conducts First “Virtual” Clinical Trial Allowing Patients to Participate Regardless Of Geography, 2011 Applied Clinical Trials, Addressing Digital Trials, 2020 Veeva Systems, Veeva Digital Clinical Trials Survey Report, 2020 Applied Clinical Trials, Improving Information Exchange in Clinical Trials, 2019 BioSpace, New CenterWatch Inc. Study Finds That E-Clinical Technologies Are Increasing Investigative Site Work Burden And Performance Inefficiencies, 2016

Rick Van Mol

now have an opportunity to play a more strategic and visible role in early trial design and protocol development.

Traditionally, the easiest type of data to manage is content that was manually 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

entered and is comprised of a simple yes-orno answer. This results in a single data point flowing through the system. However, it is more challenging to work with data captured during continuous monitoring, such as with an electrocardiogram, which requires

Rik Van Mol is the vice president of R&D strategy for Veeva Europe, responsible for the Veeva Vault R&D suite of applications with a focus on the European market. He has nearly 20 years' experience in business/ IT consulting and regulated content management in the Life Sciences/ Pharmaceutical sector. His experience has been built in assisting clients through complex transformational programs across the Life Sciences value chain, including clinical, regulatory and manufacturing/supply chain areas, for some of the world's largest companies.

Spring 2022 Volume 14 Issue 1

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 41

Clinical and Medical Research

Evolving Clinical Trial Landscape Requires Quality Focus

The strive to deliver the very best outcomes sits at the heart of clinical research. Arguably the mechanism for delivering that “perfect” outcome rests squarely on the shoulder of a single key principle – quality. Quality permeates all areas from study design, to data collection, to successful publication, and many more.

The idea of quality includes a vast array of perspectives gained from the evolution of trends in the development of quality management practices. For example, Good Clinical Practice (GCP) is regarded as the ethical and scientific quality standard for conducting a trial and applies to all steps in the process that combine for a successful trial conclusion. The GCP role is to ensure that the clinical trial data and reported results are credible and accurate and that the rights, integrity, and confidentiality of the trial subjects are protected.

Clinical research has become increasingly complex with even small nuances potentially having a big impact on outcomes. Globalisation, outsourcing and increasing regulatory demands are all affecting clinical trials and their quality. Artificial Intelligence (AI) and machine learning (ML) are contributing new ways of discovering and acting on data management in clinical trials, particularly discovering any anomalies in the data.

Concurrently, wearables and mobile technologies, along with cloud technology and related platforms, enable the collection of frequent, specific, and multidimensional data but can pose new challenges to collecting and distributing quality clinical trial information. Clinical trial participants are often using these devices in a remote way that requires diligent work on the part of the clinician to ensure data is properly classified and disseminated throughout the appropriate channels. Social media is a rapidly increasing data source for clinical research, but the quality and ultimate validity of the information reported continues to be a concern for many.

42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Investigator sites and Institutional Review Boards (IRBs) have been under increasing scrutiny by the European Medicines Agency (EMA), the UK’s Medicine and Healthcare products Regulatory agency (MHRA), and the U.S. Food and Drug Administration (FDA) when it comes to quality. To meet the regulatory expectations, sponsors and CROs (Clinical Research Organizations) need to improve quality by developing systems with specific and exacting standards for each clinical trial process.

This article will review best practices for achieving quality by addressing challenges focused on the all-important but rapidly growing complexity of managing the distribution of critical safety documents and the processing of Individual Case Study Reports (ICSRs) and aggregate reports to sites, Ethic Committees (ECs), IRBs, and others in the reporting chain.

Quality Systems Require Many Touch Points Quality systems have many touch points including personnel roles and responsibilities, training, policies and procedures, quality assurance and auditing, document management, record retention, and reporting and corrective and preventive action. With an objective to improve quality, newer inspection approaches such as riskbased inspections, surveillance inspections, real-time oversight, and audit of sponsor quality systems have become a focal point.

As one example, the FDA has partnered with Duke University to implement the Clinical Trials Transformation Initiative1 in order to conduct research projects on design principles, data quality and quantity including monitoring, study start-up, and adverse event reporting. This public-private partnership is intended to drive adoption of practices that will increase the quality and efficiency of clinical trials.

Minimising the Potential for Human Error Rejection of clinical trial data after an inspection is ineffective and even worse, wasteful in time and cost. A better approach to avoid post-inspection waste is to change the process from focusing on inspectionbased quality improvement to focusing on

proactively determining and finally deploying specific, automated, and documented processes for quality management. Once these business processes have been defined and potentially redesigned, the often errorprone human element is greatly reduced.

For example, when key processes for safety document distribution require multiple steps that involve constant manual intervention, often using systems and tools that were not designed for that purpose, undetected small errors can combine into large scale problems. An automated process provides structure and a degree of rigidity which means that the documents are getting to the right people at the right time, every time. By monitoring with a central dashboard, the process is transparent and controlled.

Globalisation of clinical trials has put added pressure on quality measures.

When, for example, six sites with thousands of participants are running in multiple geographic areas and time zones, it is almost impossible for manual intervention processes to assure the vigilance necessary to meet rigid – and varying – regulations for delivering error-free and on-time safety information.

Quality in Roles and Responsibilities Quality also permeates the development of specific roles and responsibilities of the teams managing and monitoring the trial sites – and there can be various people involved – including but not limited to, the principal investigator (PI), Study Manager, Site Mangers, Clinical Research Associates (CRAs), et al.

Again, globalisation causes challenges in maintaining clear oversight of processes Spring 2022 Volume 14 Issue 1

Clinical and Medical Research when working with a variety of people often with different skill levels or experience in clinical trial management. The methods and degrees of monitoring vary from one clinical trial to another depending on the degree of risk involved and the size and complexity of the trial. While sponsors and CROs want to make sure that the teams in charge are well-qualified, it’s not always possible to recruit the levels of expertise needed to assure the most clear and transparent outcomes. Some team participants may be contract workers/freelancers and Site Managers may be simultaneously working on several different trials. This can present the Study Manager with that uncomfortable question “how confident are you in the validity of data from ALL your sites?” Let’s not forget that it is the study manager who is ultimately responsible for safety document distribution. Manual assembly of this information is labour intensive, costly, offers opportunity for errors and often lacks documented audit trails.

Automating the safety document distribution process clearly delivers a significant advantage. Utilising a central ‘hub’ into which documentation is delivered from each site can provide a clear and transparent advantage. Such automated systems to date have provided a portal into which documents are entered which, while a significant step forward, creates the issue of access and password retention for sites.

However, the latest applications have solved this issue and allow secured, validated and auditable access for all authorised users without the need for passwords. The result is an easy-to-use single view which is shared across all the trial sites. Depending on different roles identified at each site, there is tiered access to appropriate information.

For example, a local investigator may only have access to local sites while Study Managers have access to all sites, no matter the geographic area. This empowers study team members and simplifies access to a real-time overview, significantly reducing the workload across the team and enhancing collaborative communication. For example, in a recent case, a trial team which applied

the automated interactive hub approach, in just one month, moved from struggling to deliver 20 safety documents a day with its manual system to easily delivering more than 50 documents daily via automation of the process.

Quality of Delivery and Oversight Depending on their local infrastructure and regulations, sites expect to be able to receive information according to their preferred method and the information must be blinded or unblinded depending on specific regulations. This means recipients expect to have courier deliveries, email with attachment, email with secure link, even Fax. Any automated systems that are supporting recipients must have this flexibility, not only to ensure strong adoption, but also to deliver a unified view of compliance for the sponsor. Regardless of the distribution method the transparent oversight of the activity must remain.

With a single view, on a dashboard, the hub approach illuminates all the distinct actions and rates of progress behind each specific process, which means faster and more-informed decision-making and certainty of outcome. For example, country rules that drive the safety document distribution are audit-proof. That means that the people on the team responsible are able to see to whom a document was sent, why it was sent on a specific date, and confirmation of receipt. Supporting this effort are automated compliance reports which can identify anomalies at a site, i.e., if perhaps more training is needed to assure better adherence to policies and procedures.

Quality in Execution Seeking an automated approach can often seem daunting. Will a new system fit easily into the existing infrastructure, will it easily connect to an existing safety database and CTMS and will it be intuitive enough not to cause interruptions in human adoption?

These are all significant questions. Perhaps the simplest answer is that full automation leads to a more streamlined process which

naturally enhances the availability of critical information, provides flexibility and clarity in reporting. It also reduces manual efforts, human errors, and operational costs associated with audit trails and compliance documentation. Where solutions have been successfully implemented, they have seen significant reduction in cost and resource requirements and seen much improved compliance from sites.

In short, focusing on quality in all aspects of a clinical trial is the foundation for delivering valid and compliant outcomes.

With a simple, easily implemented, automated, interactive, and central database, a commitment to maintaining data integrity and participant safety through quality guidelines provides a systematic approach to continuous process improvement.

REFERENCES 1.

https://ctti-clinicaltrials.org

John Buchan John Buchan is a Life Science Technology Specialist for pharmasol. He has spent his career in Life Sciences and Life Science technology, the latter specialising in Pharmacovigilance. Having worked in Sales & Marketing roles in major Pharma companies, John moved into working with organizations supplying technology, software and services for Life Science and Healthcare organisations across Europe and North America. He is a passionate advocate of utilising the best of technology to solve the challenges that the pharmaceutical industry faces. He is based in the southern United Kingdom.

Web: www.pharmasol.de

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Clinical and Medical Research

Real-world Data can Bridge the Gap Between Traditional Trials and a Patient-centric Future Patient safety has been the primary focus of clinical trial design since 1947 when the Nuremberg Code outlined the ethical guidelines for clinical research.

Consisting of ten points, those most directly relating to patients dictated that trials must be designed to avoid all unnecessary injury or suffering, that patients must give consent and are free to leave the trial at any point. The Code pervades all existing guidance and current world of drug development governed by ICH-GCP makes it mandatory to have all necessary steps taken by sponsors, CROs and investigators to keep patient safety as utmost priority.

The role of patients in pharmaceutical drug development then is fundamental.

In the space of just 70 years the industry has moved well beyond patient consent and is beginning to embrace patient centricity. The benefits of integrating patient centricity into clinical trial design are far reaching, helping create better trials, better medicines and better patient treatment outcomes.

Benchmark data from across the industry indicates that on average across all protocol phases and therapeutic areas, sponsors need to identify circa 10 patients to randomise one, and roughly a fifth of those randomised will drop out.1 The question is then, how does the life science sector most effectively involve patients in the drug development process and clinical trials to improve experience and therefore, sign-up and retention?

Here, Karen Ooms at Quanticate seeks to answer this question.

Challenges to Patient Centricity Randomised clinical trials have long been a central feature of the drug development process, giving us valuable information about the performance and safety of drug candidates. Nevertheless, they have shortcomings which prevent us from understanding the performance of new therapies and how patients experience treatment in the real world.

44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

It is no surprise then that many pharmaceutical companies are looking for alternative sources of data to bridge the gap between traditional trial formats and patient-centric approaches. For a growing number of developers, real-world data (RWD) is essential to their solution.

Most pharmaceutical and biotech manufacturers believe that patient centricity will yield significant long-term, mutual benefits. The 2nd Annual Aurora Project's Global Patient-Centric Benchmark Survey1 canvassed 1,282 participants consisting of employees from across the sector, spreading across 113 countries. 85% of the respondents employed by the biopharmaceutical and medical device industries agreed the focusing on patients’ needs leads to better business outcomes. However, they face many challenges to achieve their patient-centric mission. Only 3 in 10 of the participants were confident that they could deliver against patient-centric missions and just over a fifth believing that they know how to teach patient centricity to their employees.

structure, lacking a common function that connects patients from drug discovery to delivery and into pharmacovigilance and lifecycle management. This causes valuable information to disseminate and creates white spaces where knowledge is lost between departments as the therapy progresses towards commercialisation. This absence of a patient-focused function across a product’s lifecycle often impedes patientfirst thinking, especially where functions lack clarity on overlapping responsibilities for patient care.

Finally, at the clinical stage, trial data alone is not enough to develop a truly holistic understanding of the effectiveness of a new drug product: •

Difficulty ensuring adequate representation – finding enough patients to ensure adequate representation of all those who can benefit from a drug candidate is a common challenge.

This becomes magnified in studies of treatments for rare diseases, or for demographics where there are ethical concerns, such as children, pregnant people or groups where there are more likely to be comorbidities (usually the elderly).

•

Narrow inclusion criteria – the exclusion criteria in many studies will focus on patients with comorbidities and organ dysfunctions, who are under concomitant treatments or who are over a certain age limit. In the real world however no such limitations would be in place and the patients taking the drug could be elderly or have other conditions requiring treatment. While the intention is to reduce confounding factors to gather information applicable to the average patient, it means that developers don’t have a complete view of how the drug is working, how it may interact with other treatments and how it could affect other diseases.

•

Poor patient adherence – during trials, participants are often more compliant with instructions and will have greater access to support and more regular interaction with medical professionals.

So, what are these challenges?

Firstly, regulations affect sponsors’ ability to connect patients’ data across the ecosystem. Organisations must carefully balance managing patient data privacy with capturing and harnessing valuable data for optimal drug research and development.

Regulations such as the Health Insurance Portability and Accountability Act (HIPAA), and the EU’s General Data Protection Regulation (GDPR) can prevent researchers from understanding how individual trial participants interact, respond to and experience treatments.

These regulations are however essential as they ensure that personally identifiable information is never shared without permission. Currently, they also prevent data integration across multiple sources and researchers struggle to form patient treatment modalities that integrate with real-world evidence (RWE) to improve outcomes for specific patient populations.

Secondly, many companies are organised in silos around clinical, medical, and commercial

Spring 2022 Volume 14 Issue 1

Health Science Health Inspired, Quality Driven

Nitrosamine Testing Solutions The presence of the nitrosamine, N-nitrosodimethylamine (NDMA), in certain sartan API’s has resulted in several regulatory warnings and recall of contaminated products. Concerns over the presence of this class of genotoxins has now widened to include other medicines such as the well-known diabetes drug, Metformin. The US Food & Drug Administration (USFDA) and European Medicines Agency (EMA) have responded by publishing documents for the pharmaceutical industry that address requirements and limits related to nitrosamine contaminants. Pharmaceutical Manufacturers are now taking a pro active approach to risk assessment and mitigation of genotoxic contaminants within global pharmaceutical supply chains. Central to these activities is a coordinated analytical capability to identify and quantify contaminants across global geographies and regulatory zones.

Why use SGS

About SGS

SGS Health Science has considerable expertise in the method development of nitrosamine determination in pharmaceutical products. SGS has established a specific method for NDMA which can be applied to various different matrices. Alternatively, a platform method, based on trace-level detection by LC-MSMS, is also available and provides rapid and simultaneous determination of up to ten different, targeted nitrosamines. Although with more limited application, the SGS network is also able to support specialist methodologies such as GC-MSMS. Our experience in optimizing extraction allows application of these methods to drug products, API’s, and raw materials.

SGS is the world’s leading inspection, verification, testing and certification company. We are recognized as the global benchmark for quality and integrity. With more than 94,000 employees, we operate a network of more than 2,600 offices and laboratories around the world.Our conveniently located network of laboratories and clinical trial facilities offer an array of integrated services and expertise, providing you with the knowledge, flexibility and ability to scale.

By establishing these nitrosamine methods within centers of expertise across a global laboratory network, SGS can provide an unrivaled service offering that incorporates a harmonized methodological approach together with flexible management of capacity and capability requirements.SGS offers a variety of partnership models and can collaborate in such testing programs using fee-forservice to outsourced staffing models all exploiting resources of the SGS network.

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Size and diverse testing capabilities matching biologics and small molecules needs International network across America, Europe and Asia-Pacific

Contact us healthscience@sgs.com sgs.com/healthscience sgs.com/healthcommunity

INTERNATIONAL PHARMACEUTICAL INDUSTRY 45

Clinical and Medical Research

•

At home, however, patients take and manage their medications very differently – they may take their dose at different times of the day, or they may forget to take it altogether. They may even struggle when self-administering, leading to uneven dosage quantities.

Mining Rich Trial Data for Patient Truth To assess what is happening in the real world, rather than just using clinical trials to collect data, researchers are looking to use data which has come directly from the market – RWD – to provide RWE for their treatments.

Different perspectives – varying perceptions of what constitutes a meaningful impact on symptoms and quality of life among both healthcare professionals (HCPs) and patients is something that cannot be accounted for through clinical trials alone.

The US Food and Drug Administration (FDA) defines RWE as “data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than traditional clinical trials”.

Engaging People, Not Patients Becoming more patient centric in clinical trials starts by engaging patients more as individuals. If research partners can design studies focusing on outcome measures that are meaningful to an individual patient, this is a move towards becoming more patient centric.

To address the challenges above and work towards patient centricity, trial designers are increasingly: •

•

Selecting endpoints that are meaningful to the patients and easily understood. These might be characterised by levels of tiredness or pain and can be used alongside the traditional measures of symptoms or disease progression.

Designing the study with the patient experience in mind. The number of clinical visits and the time of day and clinic location all impact the patient experience. Complicated treatment regimens can diminish willing participation and jeopardise data quality.

•

Providing a report written with the patient, not the clinician in mind.

‘Plain Language Summaries’ written in addition to clinical study reports help patients understand the results of a study and improve their perception and experience of it. These are currently not mandatory but there some discussion and expectation that they will become a regulatory requirement.

•

Taking advantage of the cloud to communicate and monitor patients remotely. With the advent of smart phones, wearables and applications, it is possible to collect more actionable data in real time.

46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

This RWD includes electronic health record data, insurance claims, device data and other patient-generated information. It also includes genuine ongoing conversations between doctors and their patients about genuine day-to-day experiences of their conditions, and of their treatment.

Such data can be collated from a wide range of sources, from medical databases kept by state healthcare systems or private HCPs to records of health insurance claims held by medical insurers. Patient-generated data from wearables or medical devices used at home can also be harnessed to generate real insight into how patients respond to treatments.

Biometric experts have much greater latitude in collecting trial data. Real-time electronic patient-reported outcomes offer researchers new ways to assure patient safety and the clinical assessment of the candidate. Advances in artificial intelligence and machine learning are also helping trial designers reach out to patients and connect them to the right clinical trials.

The integration of mobile health (mHealth) tools can generate large streams of data that researchers can explore, analyse and draw conclusions from. By creating a rich data-centric environment, researchers have a more accurate picture of the patients’

reality, avoiding having to rely on patient recall, and possible bias to the data caused by inaccurate recall, or influences of patient perception.

Why RWD is Coming of Age The 21st Century Cures Act in the US and the Adaptive Pathways approach from European Medicines Agency (EMA) both evidence that regulators are placing more emphasis on patient focused drug development. And there is further precedence – the FDA approved Pfizer’s Ibrance treatment in 2019 using analysis based largely on RWD – a first for the pharmaceutical industry.2 The COVID-19 pandemic and the race to develop vaccines have also served to highlight the genuine positive impact of RWD on pharmaceutical innovation. CROs have seen demand increase for real-time evidence of treatment performance in patients hospitalised with serious cases of COVID-19, as well as information about the longer-term efficacy of the vaccines already introduced in the market Through an anecdotal lens, observational longitudinal databases of RWD allow for indepth analysis by experts. These databases contain de-identified medical records for many patients – one of the largest with contains information on more than 100 million patients – over the course of several years. This is a much larger scale than regularly used in clinical trials.

Such a wealth of long-term information allows for analyses of rare diseases, treatment pattern changes and other factors, such as treatment performance alongside therapies for other conditions.

However, unlike in clinical trials, the researcher will not be able to randomly assign patients to a given therapy nor collect all characteristics that may be of interest.

This is one reason why RWE should act as a complement to clinical trial data.

Spring 2022 Volume 14 Issue 1

Clinical and Medical Research With all of this in mind, RWD offers considerable value when used to complement clinical trial evidence to accurately measure the efficacy of new treatments.

Standardisation Remains a Challenge RWD is still in its relative infancy and the approach to collection, synthesis and interpretation is far from being standardised.

There are no global agreements yet on what and how much information is collected, how and where it is stored, and how it is analysed.

For example, on the one hand administrative healthcare databases designed to be sent to insurance companies for billing of private medical care are easy to study, because they are clean and consistent.

However, the data they contain are limited only to what are needed by the insurance company, which restricts the information they can provide.

On the other, electronic medical records (EMR/EHR) databases are disorganised, inconsistent and incomplete, as their information is collated from patient records held by multiple facilities and

sources. Nevertheless, they provide rich data that offers incredible insight into patients’ behaviour and attributes, such as lung volume or pain scores, all of which may affect their response to a particular therapy.

Summary RWD has exciting potential to truly enrich pharma’s understanding of cutting-edge new treatments. Using it as a complement to the insight gleaned from clinical trials, sponsors can overcome the traditional limitations of clinical trials in the future and help deliver ever more effective treatments that genuinely improve patients’ lives.

While regulators and the industry is making moves towards patient-centric, RWDenabled trials – a lack of standardisation both in terms of data management and in approach remains a roadblock. Customised, case-by-case approaches to analysing RWD effectively will be required for the foreseeable to ensure the full potential of data and therapies are realised. In the longer term, expertise in capturing, collating and studying RWD is crucial if pharmaceutical companies want to make sure they harness

this new source of evidence to its full potential.

REFERENCES 1.

2.

https://www.advarra.com/resource-library/ retention-in-clinical-trials-keeping-patientson-protocols/ https://pf-media.co.uk/in-depth/creatingpatient-centric-ways-of-working/

Karen Ooms Karen Ooms is Executive Vice President and Head of Statistics at Quanticate, whi is responsible for overseeing the Statistics department at Quanticate.

She is a Chartered Fellow of the Royal Statistical Society and has a background in biostatistics spanning more than 25 years. Prior to joining Quanticate in 1999 (Statwood), she was a Senior Statistician at Unilever. She earned her MSc in Biometry from the University of Reading.

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Technology

Improved Antibody Purification Process Through Use of Additives Downstream biopharmaceutical processing utilises a series of interlocking and sequential operations, including filtration and process chromatography steps, that incrementally increases the purity of the target therapeutic molecule by exploiting the physical and chemical properties of that molecule.

It is critical for therapeutic monoclonal antibodies (mAbs) to have very high purity with low product-related and process-related impurities (host-cell proteins, DNA, leached protein A and aggregates) in order to be administered to patients safely.

In the production of mAbs, finding ways to improve yields and reduce downstream processing times, while sustaining low levels of impurities, remains a critical focus area for biopharma manufacturers. This need is becoming increasingly important, in part due to the significant improvements that have been made in upstream technologies and processes. Improvements in downstream throughput have not kept a similar pace with those made for upstream, leading to potential bottlenecks in the end-to-end process.

Downstream processing typically requires several weeks to complete prior to fill-and-

finish steps. Not only does it involve multiple chromatographic and filtration steps, but depending on the specific process, more than a dozen buffers and cleaning solution steps may also be required. It is estimated that 60–80% of the total cost of producing a mAb can be attributed back to downstream processing.1 The article will outline a novel approach to improve impurity clearance efficiency of chromatographic steps by modulating the interaction of target protein and/ or impurities with ligands on the resins.

In this study, two chromatography resins were examined for the capture step of mAb purification: a Protein A resin with high dynamic binding capacity and a mixed-mode hydrophobic interaction chromatography (HIC) resin. Both were used for a capture step, and additives were screened to reduce the nonspecific binding of impurities. The goal of the study was to optimise chromatography steps and thus increase the capacity and removal of impurities such as residual HCPs, DNA, charge variants, aggregates and leached protein A. Assessing Two Different Capture Step Chromatography Techniques To study the potential advantages of the use of additives to improve downstream capture step outcomes, two different chromatography techniques that can be

used for capture step of mAb purification were examined.

The first is the protein A affinity chromatography step. In this study, a proprietary protein A resin was used as a model resin. The resin has a novel protein A ligand engineered for high specific affinity toward the Fc region of protein and features a standard-size agarose backbone for ease of use.

In this study, the importance of binding capacity and stability of the resin were analysed, as well as the use of additives to improve the protein A step; in addition, case studies of IgG purification using the selected proprietary protein A resin provided useful insights into optimising downstream capture steps.

One of the most important specifications of protein A resin is dynamic binding capacity (DBC). A resin with higher DBC can improve the productivity of the capture step while keeping the column sizes the same and minimising the facility modification, specifically for high titer cell culture processes. Figure 1 shows a dynamic binding capacity comparison of different protein A resins that are available in the market. The binding capacity is measured at 10% breakthrough of purified IgG1 using 5 milliliter columns, where we use the loading

Figure 1: Comparison of dynamic binding capacity of multiple protein A resins.

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Spring 2022 Volume 14 Issue 1

Technology condition of using 1X phosphate buffered saline (PBS).

As can be seen, the selected proprietary protein A resin yielded the best DBC performance, especially at eight minutes of residence time, with a DBC at 65 mg per mil. To demonstrate the effect of DBC on the process throughput, a theoretical number of cycles needed per batch depending on the DBC of that resin was calculated.

This comparison was based on assuming 60-liter protein A column volume with 2,000-liter bioreactor, with 5 gram per liter material titer. Using a traditional resin with 35 mg per mil of DBC, over six process cycles would be needed to purify this batch. Alternatively, use of a protein A resin with 65 mg per mil of DBC results in needing just over three cycles to purify the same amount of material, saving approximately 45% the number of cycles needed compared to traditional resin. (Figure 2) In addition to increasing productivity of the process, reduced number of cycles also allows for reduced operational risk and lower labour and consumables cost for each cycle.

Another important specification of protein A resin is alkaline stability. Protein A resins go through hydrolysis and lose capacity over time when it’s cleaned with a sodium hydroxide solution. Thus, it is important to assess the alkaline stability of the resin at a defined cleaning condition.

In this study, the proprietary protein A resin was tested using 1 mil prepacked column and cleaning the column with different concentrations of sodium hydroxide.

Figure 2: Importance of dynamic binding capacity on process throughput.

After 100 cycles of cleaning, the resin retained more than 80% of its initial capacity, regardless of sodium hydroxide concentration. This stability is important because it will dictate how often the new resin needs to be purchased or repacked in a new column. The savings in resin cost for production is proportional to the lifetime of the resin; thus, it is possible to save half of the resin cost by selecting resin with two times longer life cycle in sodium hydroxide.

The use of different additives to increase protein A resin stability was then studied. The additives included ethylene glycol, propylene glycol and sucrose at

4°C and room temperature to 1 normal sodium hydroxide at 4°C cleaning study.

(Figure 3) The best stability was achieved when 1M sucrose was added to sodium hydroxide solution, resulting in more than 90% of initial capacity being retained after 200 cycles of cleaning. In addition, the study also assessed room temperature stability data. As Figure 3 shows, a similar study was performed at room temperature, where the column was stored in 1N sodium hydroxide and 1M sucrose mixture for 24 hours. After 24 hours of storage in room temperature, the resin retained more than 90% of the initial capacity.

Figure 3: Use of additives increases alkaline stability with more than 90% of DBC retained after 200 cleaning cycles. wwww.international-pharma.com

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Technology

Figure 4: The addition of IPA, arginine and urea to the PBS wash buffer increases HCP clearance.

Together, these show the advantages of improving protein A resin alkaline stability through use of selective additives with sodium hydroxide cleaning solutions.

Another use of additives to improve protein A step efficiency is screening different additives for wash buffer to increase the host cell protein removal rate. In a study, fourteen additives were screened with different combinations and concentrations. Those additives are added to the control wash buffer, which was 1X PBS, and the experiment was performed by loading the IgG cell culture clarified fluid from the CHO cell system, with the column being washed with 1X PBS and the different additives mixture. (Figure 4) Compared to a control without additives, all fourteen additives demonstrated beneficial impact on increasing the host cell protein removal, with the most significant improvements shown with the combination of isopropanol with arginine, isopropanol with urea, or isopropanol with urea and polysorbate.

Using Additives to Improve HIC Separation Performance In addition to studying the impact of additives to the protein A step, the use of additives to increase the separation of the HIC process was also studied. In downstream processing, HIC resins have been used for both the capture step as well as the polishing step of mAb purification.

HIC processes are useful to separate the aggregates, closely related proteins and process-related impurities based on the hydrophobic interaction that is induced by the high salt concentration.

50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

In this additives study, a mixed-mode HIC media was used. It is a primary hydrophobic interactive resin that also has weak anion exchange sites of secondary and tertiary amine groups. This mixed-mode design offers improved selectivity and efficiency compared to other HIC resins.

elution buffer compared to no additive being used and the retention time of strongly retained protein was decreased by adding the additive. However, it’s important to note that, while the retention time has been decreased, the separation of four proteins is still very distinctive.

The first additive, labeled AD1, was tested at different concentrations, and the separation and retention of four proteins – cytochrome c, myoglobin, lysozyme and alpha-amylase – was analysed. For the study, a column with 10-centimeter bed height was used, and an ammonium sulfate buffer was used for binding. For the elution step, a linear gradient of decreasing ammonium sulfate concentration was used, with AD1 being added to the elution buffer, and the total elution time was 40 minutes.

To further clarify the impact of the use of the AD1 additive in the HIC process, separation factor, resolution and retention factor of four proteins at two conditions, with and without the AD1 additive, were studied. (Figure 5)

The study that achieved the best separation with the highest efficiency was when 0.85% of additive was used in the

For amylase, the retention factor is lower when the additive is used in the elution buffer. While the process efficiency is increased by reducing the retention time, the resolution and separation factors were not affected. Thus, when the separation efficiency is calculated based on the retention factor, the amylase efficiency is improved significantly through the use of

Figure 5: AD1 reduces amylase retention without affecting protein separation factor and retention.

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Technology

Figure 6: Use of additive with elution buffer improves both recovery and mAb purity.

additives in the elution buffer. This impact of efficiency improvement will magnify when the additive is used in a higher-scale process where the process time becomes more critical and more expensive as the scale increases.

additives in the elution buffer. Both the recovery and mAb purity were very good for both conditions, but both showed some improvement when the additive was used.

Recovery was higher than 99%, and the final mAb purity was 98%.

Further investigations on other additives used with the HIC resin were also conducted.

Four different additives with different molecular weights were used. While each additive required different concentrations for optimal result, all the additives showed increases in resolution and reductions in the retention factor, which will increase the efficiency of the process while not sacrificing the separation of proteins.

Additives Offer Opportunities to Help Optimise Downstream Process Steps The global demand for biologic-based therapeutics based on mAbs is expected to continually grow in the coming years. This places greater urgency on the need to find ways to reduce costs and processing times so that valuable, life-changing treatments can be supplied more readily and costeffectively to communities across the globe.

A final study using the HIC resin with additives was conducted, in this instance performing actual purification of mAb as a capture step of the process. (Figure 6) Clarified cell culture feedstock was loaded onto a 10-centimeter bed height column, and it was eluted with and without

Innovative efforts, like the use of additives to enhance capture steps, such as protein A and HIC as described above, can provide one more tool to achieve these goals. To improve the capture step of mAb purification, it is critical to select a resin with high binding capacity to increase the

process throughput. Alkaline stability of protein A resin needs to be considered to reduce the process cost.

Different additives have shown to be effective at increasing the alkaline stability of the proprietary protein A resin that was studied and optimising the host cell protein removal during the wash step.

For hydrophobic interaction resins, mixedmode HIC media process efficiency can be improved using different additives in the elution step.

REFERENCES 1.

Deorkar, N., and Berrón, C. (2019). “Key challenges and potential solutions for optimizing downstream bioprocessing production,” International Biopharmaceutical Industry 2(2) 10-12.

Jungmin Oh Jungmin Oh is a manager of new product development at Avantor. In her current role, Jungmin leads product and process development projects with multiple biopharmaceutical industry partners, including customized product development for cell and gene therapy customers. She holds a MS and Ph.D. in chemical engineering, specialising in the optimisation of a continuous chromatography system.

wwww.international-pharma.com

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Manufacturing

The Role of the Clean Room in LAL Production

The standard endotoxin test utilises a reagent called Limulus Amoebocyte Lysate (LAL). LAL comes from the amebocytes of the American Horseshoe Crab (Limulus polyphemus). It is the proteins that create a coagulation in response to bacterial endotoxin.

This test is the most widespread test of bacterial endotoxin in parenteral injections and medical accessories.

In the production of LAL, many invisible factors contribute greatly to the quality of the product. Since it is the de-facto standard for the vital detection of endotoxins in pharmaceuticals and medical instruments, the production of the reagents must be at the highest order of cleanliness. The development of clean room technology has created an environment that allows for large scale production of an extremely effective endotoxin test. As clean rooms allowed the LAL test to become a widely produced pyrogen test, clean rooms also

52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

allow for the continued development of the next generation of endotoxin tests.

Any material that produces a febrile response is described as pyrogenic. As can be imagined, many materials are pyrogenic.

However, one class is especially notorious – bacterial endotoxin. Endotoxins are the lipid A component of the LPS from the outer membrane of gram-negative bacteria. They are the main pyrogen of concern due to their small molecular weight. Most pyrogens are protein complexes and can be eliminated through ultrafiltration or deactivated through denaturisation, but endotoxins cannot be removed through ultrafiltration since they have a molecular weight in the low thousands. They are unaffected at temperatures below the boiling point of water, so steam sterilisation has no effect.

The only means to destroy endotoxins is through rapid oxidation at temperatures over 250°C. This is only possible in dry glassware, greatly limiting the ability to remove endotoxins present in aqueous materials or in plastic containers. Protection

of pure raw materials is therefore imperative in producing finished products free of endotoxin.

Pasteur’s germ theory of disease is the theory behind clean room development and the LAL test. The precursor in practice to the LAL method was the Rabbit Pyrogen Test. This test used the in-vivo injection of a sample into a series of rabbits to determine if the sample had any pyrogenic properties.

Since the immune response of the rabbit as a mammal is nearly identical to the human response, the lack of a pyrogenic response in the rabbits indicated that the sample would not produce a human febrile response. Of course, the major disadvantage of this test was the need for in-vivo tests on living rabbits.

In 1956, the horseshoe crab’s clotting response to bacterial endotoxin was first described. In a similar pathway to the mammalian clotting response to interleukins, the horseshoe crab has a clotting pathway directly triggered by bacterial

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 53

Manufacturing

endotoxins. This led to the first in vitro test of bacterial endotoxins using the clotting factors from horseshoe crab hemolymph.

This method has become the standard endotoxin testing method, gaining accuracy through quantitative methods. The current developments in endotoxin testing are the manufacture of recombinant factors for an animal-free product and the development of a human monocyte pyrogen test.

The manufacture of production-level LAL reagents faces unique challenges due to the nature of the test. The clotting pathway is a cascade that is initiated by the smallest amount of endotoxin. From the moment the sample is taken from the crab to the final sealed product, the lysate must be kept free of all contamination. Pyrogenfree containers are adequate for protecting small quantities of products. A pyrogen free container can be created as simply as heating glassware. On a small scale, the reagent is kept pyrogen free by always maintaining a sealed barrier. However, in a large-scale production, it is advantageous to not just have the interior of the containers be pyrogen-free, but to extend this level of cleanliness to the environment. This proposal, however, faces several unique challenges. Endotoxin is ubiquitous in the air, particularly in human habitation. As 54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

bacterial material, endotoxin levels are not static. Biofilms, colonies, and single bacteria that would test negative will multiply, increasing the level of endotoxins in an area that previously had no detectable levels of endotoxin. Similar problems to these are found in other industries as well such as the manufacture of medical instruments, pharmaceuticals, and the space industry.

The solution to these industries including the manufacturing of Lysate is the clean room.

The clean room is designed to produce a space free of airborne particles. Clean rooms are rated by the number of particles in the air, and these different classes are applied to specific needs based on the situation. The heart of the clean room is HEPA filtration. Surprisingly, HEPA filtration was first developed in nuclear science to be able to remove radioactive materials from the air. NASA quickly adopted HEPA filtration and clean room research. Although this may seem surprising, NASA’s reason was to prevent biological contamination in space. In fact, the largest ISO 1 clean room is operated by NASA. In subsequent years, the medical and pharmaceutical industries adopted the clean room as well. Clean rooms allow for the mass production of formulations and filling in

the LAL industry in a volume that previously would have been unattainable. Instead of needing to limit endotoxin-free substances to the interior of vessels, they can now be transferred and used by machinery in open containers in a clean room without contamination.

Several processes must be in effect for a clean room to successfully be maintained.

The clean room is not a static environment – several active processes must be maintained to keep the environment clean. There are four main causes of contamination of a clean room that must be actively removed.

The first is from people. Dead skin and respiration mean that humans are actively producing particles that would contaminate a clean room. Gowning, therefore, is a vital part of maintaining a clean room, something that if neglected will undermine the entire space. This includes creating an impervious barrier between human skin and the environment by utilising commercial PPE such as a Tyvek® suit, goggles, and a mask.

The second cause of contamination is airborne. HEPA filtration alone will not produce a perfectly clean environment.

Laminar flow and pressure cascades are what work in conjunction with the HEPA Spring 2022 Volume 14 Issue 1

Manufacturing filters to produce a controlled environment in which the air is replaced regularly. The HEPA output creates high pressure, and the clean room is then designed with progressively lower pressures leading to the exterior. By taking advantage of laminar flow, the entire volume of air from the HEPA filters at the highest pressure cascades downward to each successive chamber.

Maintaining laminar flow is vital to the integrity of the clean room. Back currents found in turbulent flow are eliminated, and because of this, many small-scale applications that cannot logistically be performed in a clean room can be performed in a laminar flow hood.

The third cause of clean room contamination is from the materials brought into the space. A clean room may have flawless gowning and air handling.

However, this cleanliness is all for nothing if one of the raw materials coming into the manufacturing process is contaminated.

There are two aspects of raw material contamination. The first is the danger of raw materials contaminating the final product. Regarding lysate, the raw material is naturally endotoxin free within the biological environment, so the main concern is keeping the lysate in clean containers.

Water and other materials added during the refinement and formulation are produced through reconstitution with water from a WFI system and careful testing of all materials coming in for endotoxin. There is also the danger that the materials will contaminate the clean room itself. It is imperative that all volatile liquids including all aqueous materials be kept covered as much as possible to prevent excessive airborne particles from being released. Of course, the purpose of the clean room is to protect the materials inside, but this ensures that any materials entering the clean room will not contaminate other materials already present.

The fourth cause of contamination in the clean room is the growth of microbes. This area is the key portion that must be kept in active maintenance. Microorganisms can go undetected and then become a problem later. Spores, a survival mechanism of certain bacteria and fungi, can survive in hostile conditions while going undetected by testing methods. Another source of microbes that could go undetected is biofilms, especially in the filtration system.

Certain bacteria will produce an embedding matrix that will sustain the colony in a state that is extremely hard to detect. No wwww.international-pharma.com

perfectly effective means to remove biofilms exist, so the means to ensure that they do not reach levels that will compromise the cleanliness of the clean room is to actively test to make sure microbial growth is not detected as well as active sterilisation even in clean rooms that do not have any positive microbial tests.

The materials that are permanently in a clean room must be evaluated as well.

The furniture in a clean room needs to be carefully selected to be made of materials that will not give off particles. The second material is the flooring and walls. Walls in a clean room will degrade and start giving off particles. Floors in clean rooms will often be sticky to hold particles that land on the floor. The curtains in the chambers will need to be maintained as well. These passive measures will help maintain longterm cleanliness in the clean room.

The clean room provides a remarkable advancement of the twentieth century in sterile manufacturing. What once started with military research and moved over to space manufacturing quickly found valuable application in medical and pharmaceutical manufacturing as well.

The specific application that I work with in the production of LAL reagents is perhaps one of the more unusual applications of the clean room. The manufacture of LAL reagents does not have a clear-cut category.

They are used and are vital in the production of medical and pharmaceutical supplies and are therefore needed to be subjected to the same levels of cleanliness as materials in those manufacturing facilities. However, the LAL is not a synthetic product. It is of biological origin and therefore the materials cannot be regulated to the extent of most pharmaceutical products. It is this origin that led the FDA to classify and regulate LAL as a biological material rather than a pharmaceutical. The preparation of the lysate for the clean room is a specific process that must keep these features in concern.

The first step in lysate production is a completely unsanitary one—the preparation of the crabs. As can be imagined, it would be completely impossible to perform this in a clean room setting. Rather, containers must be brought from a clean setting (often a laminar flow hood) with hypodermic needles that will allow the passage of the hemolymph from the interior of the crab body through a sterile passage into the endotoxin-free container. Through the subsequent steps along the process of lysing the amebocytes to extract and purify

the clotting factors, as different materials are added and materials are removed through centrifugation, it is often done in the interior of clean containers. Once the lysate reaches the formulation stage, it can be done in a facility separate from initial lysate extraction in a more controlled environment away from contamination. It is often in this step where the production is moved to a full-sized clean room setting over the laminar flow hoods. This clean room setting is where the formulation, filling, lyophilisation and then sealing of the product takes place.

The clean room has allowed production of the LAL endotoxin test that satisfies the need of the world’s pharmaceutical demand.

Every pharmaceutical injection along with the accessories and instruments need to be tested for endotoxins. The development of the clean room has enabled this vital production to meet the needs of the global medical and pharmaceutical industry.

REFERENCES 1.

2.

3.

4.

5.

h t t p s : //a ca d e m i c .o u p.co m /fe m s e c / article/61/3/509/465029?login=true https://journals.asm.org/doi/full/10.1128/ AEM.01073-09 https://journals.asm.org/doi/full/10.1128/ AEM.02167-09 https://journals.asm.org/doi/full/10.1128/ AEM.02167-09 https://journals.asm.org/doi/full/10.1128/ AEM.02565-08

Timothy Francis Timothy Francis is the Technical Specialist for the LAL Division of FUJIFILM Wako Chemicals U.S.A. Corporation. He comes into the Technical Specialist role with 5 years of experience teaching the natural sciences at a college level. He is proficient at taking the complex, technical aspects of a topic and breaking them down into clear, understandable pieces that all connect back to the big picture. He draws upon this experience to provide professional technical support and training for the PYROSTAR™️ line and to help you with your technical needs. Outside of the work environment, he enjoys backyard astronomy, disc golf, kayaking, and enjoying time with his wife as they care for their pets.

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Manufacturing

Putting your ATMP Process on the Map:

Strategies for Scaling Out Facilities to Meet Commercial Development Realities Cell, gene and tissue therapies are transforming medicine, showing meaningful efficacy in treating – or even curing – diseases once thought intractable. Known as Advanced Therapy Medicinal Products (ATMPs) these modalities exhibit the potential to cure disease by addressing its root cause rather than treating it symptomatically.

Recent approvals of ATMP breakthroughs such as Kymriah, Tecartus and Yescarta exemplify the exceptional advancements in this space. According to Grand View Research the global market ATMP’s is projected to expand at a compound annual growth rate (CAGR) of 13.2%, with market expected to reach $21.2 billion by 2028.1 These approvals have spurred a flow of investment which is expected to help accelerate the pace of development and patient access. Grand View Research notes innovators are now adopting various operation models to accelerate the autologous ATMP product manufacturing process.

A Sharp Shift to an Age-old Paradigm Autologous ATMP therapies require human cell harvesting and therefore these processes begin with the patient. The processing ideally takes place in cleanroom environments located close to medical centres and centralised healthcare systems. A patient’s proximity to the process is essential because it can significantly improve product quality and patient experience.

Harvesting cells, treating them and reintroducing them to the patient is prompting the industry to rethink how to manage the patient experience as part of the ATMP supply chain. The patient’s direct involvement as well as (for now) the manual processing involved in autologous and allogeneic production methods insert operational risk into manufacturing that will affect product scalability.

Modular Technologies Delivering What ATMP Innovators Need Cleanrooms were traditionally fabricated on site using stick-built wall-board construction 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

methods. For much of pharmaceutical plant history, the fact that this method was cumbersome to engineer and slow and expensive to construct was not an issue – as long as it functioned, was validatable and compliant. The capital expense associated with cleanrooms was seen as financially tolerable relative to the economies of scale associated with centralised large-scale pharmaceutical manufacturing facilities.

The demand for affordable, more effective drugs as well as the need to reduce the overall costs of drug development and manufacturing have all served to turn traditional pharma facility operational models on their head.

Emerging drug development business models also influenced the industry to improve the commercial implementation of complex cleanroom spaces and help make construction as cost efficient as possible. These drivers led to increasing development of modular, pre-fabricated solutions that wrap around the space to contain it as well as ease the complexities, time and cost of erecting facilities.

Modular Systems Ideal for Autologous Processing Siting Flexibility Over the past two decades the concept of modularity in cleanroom engineering and construction has matured significantly – especially to meet the evolving, dispersed manufacturing demands of delivering ATMP treatments to patients. Although cleanroom modules encompassing entire three dimensional spaces have been implemented, the ideal modularity solution in this instance refers to a componentbased wraparound facility that leverages modular architectural technology along with high-performance environmental systems, all of which are prefabricated in a controlled factory environment. These modular systems are flat-pack shipped and ready to assemble within any host building’s unique footprint, all under clean conditions. This approach is more flexible and cost effective than 3-D solutions and is higher quality with quicker validation timelines than traditional stick-built facilities. This middle-ground modular solution is proving to be the most effective way to implement repeatable cleanroom facilities across a multi-site ATMP network.

Drug delivery strategy often dictates these sites must be located near populationcenters and possibly even within dense urban environments. In these locations, what is considered suitable and available commercial building stock can vary wildly.

For these reasons and more, the wraparound cleanroom solutions manufactured by today’s suppliers, for example, are purposely engineered to accommodate virtually any viable floor plan both horizontally and vertically.

Site location is a critical element to program success but so is selecting the right host building. Fortunately, industry experience has revealed a common set of optimal building “denominators” that can help host building selection and optimise modular cleanroom installation build-outs.

(See sidebar Selecting the Best Host Building for Program Success) Since the first cell therapy was developed and subsequently approved nearly 15 years ago, ATMP drug developers along with their modular cleanroom solutions partners have learned a thing or two about building out production capacity to help launch these programs successfully in support of critical development timelines and product approval milestones: Derive a Production Plan Do you have a Demand/Supply Plan?

The forecast should be a top-down assessment, starting with the finished commercial goods demand. Integrating risk management and contingency factors are also prudent in maintaining supply continuity, which includes ongoing pipeline clinical studies.

As a project’s development crosses a threshold from early phase success to later clinical trial, so does the need to obtain a clear projection of the demand for the treatment as well as a clear validatable process (including containment) for the drug product. Commercial production requirements represent a higher standard of current Good Manufacturing Process (relative to localised protection, product traceability, cross contamination controls, etc.). Considering the high unit cost of a purpose-built, regulated facility, it is prudent Spring 2022 Volume 14 Issue 1

Manufacturing

Shown here is a cleanroom facility responsible for a CAR-T treatment that was located on the 9th floor of a 16-story building on an urban hospital campus. Presenting challenging project logistics, the existing space compressed the cleanroom facility both horizontally and vertically due to extremely low floor-to-floor heights. Hugging the all-glass exterior of the skyscraper’s custom envelope, the cleanroom facility’s modular technology allowed it to wrap around the process and protect patient material while maintaining the views of the surrounding cityscape.

to configure ATMP manufacturing operations to support the needs of this particular segment of drug development.

Whether a company makes or contracts the manufacturing supply chain, this will likely be the largest investment/commitment in the company’s history. A forecast allows a company to communicate on multiple levels with contractors, suppliers, management, and executive teams in rationalising resources needs, focusing on goal specifics, and negotiating high value contracts.

Confirm Make vs. Buy Is your post approval supply chain going to be internal or externally provided?

A second highly consequential success factor is a company’s decision and plan to manufacture internally (Make) or externally using outsource manufacturers (Buy).

Outsourced “contract” manufacturing has historically enabled the entry of many new drugs into the market. But as the industry continues to develop ATMP therapeutics, the complexity of the science and its manufacturing processes have also increased–and that includes the value of intellectual property. wwww.international-pharma.com

With the inherent evolution of these sensitive manufacturing processes, a developer and its investors may feel the best business strategy is to retain the deeper knowledge and therefore financial return from developing and building out its own process infrastructure. A build-out strategy leveraging modular cleanroom technologies with turn-key solution partners may offer distinct economies and preclude sharing intellectual property with external contract manufacturing organisation partners. On the other hand, a CMO offering a similar operational and technical template might make the best organisation to partner with if it supports successfully achieving drug program goals and timelines.

Therefore, within the context of ATMP development the Make vs Buy decision becomes a serious consideration and should be evaluated early, certainly prior to Phase III. A conservative plan might include a “bridging” strategy where a company might launch a new product from a CMO and then plan to transfer manufacturing early to a self-owned facility upon assurance of FDA product approval (and a revenue stream).

Define/Document the Manufacturing Process Have you defined your manufacturing process?

The single greatest influencing factor on the design and cost of an ATMP facility is the process’s design. It must be housed in a fit for purpose facility. Because the process is the product, designing the physical facility requires first defining the process’s critical quality attributes (CQAs) then determining its flow and floor plan relative to the host facility structure.

A process flow diagram (PFD) can facilitate fit-for-purpose objectives. When applied and qualified properly, aseptic single use technologies can effectively “close” processes. The result will simplify facility design, reduce square footage need, diminish regulatory scrutiny, increase process change flexibly, and enable product transferability or portability.

Many cell and gene therapies have inherently small batch operations, which may further leverage these opportunities. A well-documented PFD enables designers to meet clinical, commercial and development INTERNATIONAL PHARMACEUTICAL INDUSTRY 57

Manufacturing Selecting the Best Host Building for Program Success The intent is to use this facility as a manufacturing asset, to include GMP cleanroom space along with support laboratories, warehouse, and office space. The following are key areas of consideration when evaluating the suitability of a host building to accommodate a GMP facility.

•

•

• • •

Building Use Group (inherent construction of host building to accommodate manufacturing, especially if multi-tenant facility) Building Cross Section (sufficient vertical height, not only for storage but also for cleanroom HVAC infrastructure) Building Access (for both personnel and materials deliveries) Floor Loading (suitable slab to accommodate weight of manufacturing and storage) Utilities (sufficient power, water, sewer, gas, data, fire protection)

solutions have become a key enabler in the safe and effective delivery of ATMP therapies, and with each breakthrough continuing to deliver the capabilities required to achieve commercial success and better patient outcomes.

REFERENCES 1.

product needs based on a necessary capital budget estimate.

Build Cross-functional Teams Is a team identified and sanctioned?

No external consultants will ever know the technical, operational, or strategic objectives better than a company’s internal subject matter experts. Therefore, without the benefit of a cross-functional team, there is greater risk to project success. The team should minimally include members from Manufacturing, Development, QA/QC, Regulatory, and Sales & Marketing. Where experience gaps may reside, engaging consultants is a common strategy to supplement a team in gaining broad experience, completing high level tasks, and objectively challenging rooted norms.

58 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Actualise Facility Build Out Strategy with a Modular Approach Considering that it takes hundreds of experienced staff (and tens of thousands of hours) to commercialise an ATMP drug product, the sooner resources are focused on a cohesive company build-out plan, the sooner commercial success can be achieved.

As a pioneer of turnkey cleanroom solutions, AES understands that modular approaches to cleanroom deployment can deliver significant capital expense control as well ongoing operational benefits.

Modular cleanroom solutions support key ATMP development goals, timelines and objectives including regulatory agency approval milestones and process validation.

Over the past 15 years, modular cleanroom

https://www.grandviewresearch.com/industryanalysis/advanced-therapy-medicinal-productsmarket#:~:text=products%20market%20growth% 3F-,b.,USD%2021.2%20billion%20by%202028.

Grant Merrill Grant Merrill is the CEO of AES Clean Technology. He has been involved with cleanroom design and construction for more than two decades. Grant earned his BS in Mechanical Engineering from Cornell University, and built a successful career in the industrial HVAC engineering business before joining the AES team in 2001. At AES he enjoys leading multi-disciplinary teams to deliver complex cleanroom facilities to clients throughout the life science industry.

Spring 2022 Volume 14 Issue 1

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 59

Manufacturing

Emerging Challenges for Data Integrity in the Pharmaceutical Sector Processing power has completely reshaped manufacturing over the last 20 years, especially in pharmaceutical production. Businesses can now monitor, analyse and model far more data than ever before, which has led to significant advances in drug discovery and development. Automated machinery has also allowed production to expand at an unprecedented scale giving more people greater access to the medicines they need.

Running in parallel to this progress, however, has been a growing threat to data integrity – the foundation on which businesses in this sector maintain their reputations and develop new opportunities.

The previous two decades are arguably defined as much by regulatory oversights and human error as they are by technical progress. In 2019, for example, the US Food and Drug Administration (FDA) issued over 90 warning letters, extending a pattern of

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failures that can be seen across the premarket side of the industry since the turn of the millennium.

In most cases, warnings are given for similar reasons. One study that analysed FDA letters in the US between 2007–2018 found that most were issued for failing to follow and maintain correct procedures or poor documentation practices. The same study concluded that cases of required action were on the wane, and a growing number of businesses were compliant with stricter industry guidance. This is clearly positive news but also a situation that cannot be expected to remain unchanged.

Data integrity is an ongoing process, rather than a static state, and requires businesses to be aware of potential threats ahead of production.

What is Data Integrity and Why is it Important?

Data integrity is relatively easy to define but difficult to manage. Businesses across the sector are expected to follow guidance,

including companies responsible for clinical trials, research, manufacturing and distribution. Any information generated must be complete, accurate and consistent without any deviation from prescribed methods set out in guidance. It should also be collected, stored and maintained using secure methods.

The acronym 'ALCOA' can be used to better understand what's required from businesses. It stipulates that all data should be attributable, legible, contemporary, original and accurate. Beyond this, there's an expectation that data should be accessible at all times, particularly because auditors can arrive with little notice.

There are countless decisions made each day in drug manufacturing facilities, all of which can directly impact human health.

Data integrity procedures are ultimately there to ensure a company is producing a consistently high-quality product. Those with accurate information have the means to demonstrate good practice and can quickly

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Manufacturing

identify where oversights are being made, should they be flagged.

Historical Challenges Good data integrity processes ultimately build trust between industry and regulatory bodies while also helping to limit the chances of product recalls, compliance issues and damage to a business’s reputation. This idea is best seen in a lawsuit from 2018, which saw Fresenius SE canceling its $4.3 billion acquisition of US drugmaker Akorn Inc. Fresenius claims that Akorn did not have sufficient controls in place to guarantee the reliability and validity of data gathered during process development for one of its products. Once a judge ruled that Fresenius’s withdrawal was justified, Akorn’s shares dropped by 59%.

Fresenius vs Akorn is exceptional because it scuppered a significant acquisition, but the conditions which caused the deal to be called off are not unusual. Indeed, data integrity and validation continue to be a problem for many organisations in the sector, not least because ‘hybrid’ systems that exist half on paper and half digitally are still relatively common. The World Health wwww.international-pharma.com

Organization’s latest guidelines discourages the use of these systems, and says migrating to a completely digital set up should now be prioritised.

Such moves, however, are perceived to be difficult and time-consuming. A typical facility will have many machines that generate data, usually developed by different companies using different recording techniques. Many machines will not come with software. Those that do will require validation – a systematic approach required to guarantee that any process in a pharmaceutical facility will operate within specific parameters when required.

This process can take months to complete depending on the experience of those carrying out the validation and whether they are following specific procedures.

Some organisations offer integration of all instruments, but this usually falls short of ALCOA requirements and can actually drag out the process as individual assessments of each connection need to be tested. Standardised software solutions are seen to be the preferred way to digitise paper-based approaches as they are tested

more rigorously and simplify the validation process, even when connecting multiple machines and instruments.

Businesses have also had to contend with a complex regulatory landscape that continues to shift. To combat the spike in compliance failings, the World Health Organization, UK Medicines and Healthcare Products Regulatory Agency (MHRA) and US Food and Drug Administration (FDA) have all issued draft guidance for maintaining data integrity. For manufacturers, these updates run alongside other requirements, such as GAMP-5 issued by the International Society for Pharmaceutical Engineering, which defines good practice when using automated systems in the sector.

Emerging Problems While the move from hybrid systems is welcomed by regulators, businesses are still being flagged for data integrity shortcomings even when using newer digital systems. One of the biggest challenges that has emerged over the last twenty years relates to audit trails, particularly among companies that use software with audit trail functionality.

There is a tendency to fit and forget without INTERNATIONAL PHARMACEUTICAL INDUSTRY 61

Manufacturing revisiting the data and understanding what’s being collected and why. This can pose challenges when work is being submitted to a quality group for review.

The age of some automated systems is another critical concern, particularly for drug manufacturers. As equipment reaches a certain age, hardware and software components inevitably fail or become obsolete – this not only jeopardises the validity of some data but also the required quality of a product. However, major retrofitting projects come with their own risks, and business owners are advised to proactively manage their systems to identify when components need replacing.

This approach limits plant downtime and ultimately protects data validity, even as processing changes are made.

Access Privileges Digital systems adhering to good manufacturing practices will use strict controls to maintain the reliability and integrity of data.

This includes procedural controls, technical checks and audit trail reviews. However, many organisations fail to account for the risks associated with privileged access. This essentially grants someone the power to carry out critical administrative tasks, such as issue resolution or a change in monitoring parameters, often without traceability.

Unsurprisingly, this situation is not viewed kindly by auditors as it violates one of the

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ALCOA principles – namely, that data should be attributable.

While privileged access does not compromise a system per se, guidance is nevertheless clear that facilities should avoid reliance on so-called 'God accounts' with minimal limitations. It significantly raises the chances of human error that could lead to falsification or data falling out of specification, not to mention give disgruntled employees or inside actors the opportunity to purposely do damage.

The latter may be an extreme example but cannot be discounted in an industry known for placing high pressure on teams to produce positive outcomes for influential clients.

The solution here is to avoid using a single administrator account by splitting privileges between the IT and OT domains. This ensures one person is responsible for users and the types of data they can access, and another for the instruments and information collated on the plant floor. These individuals can then apply principles of least privilege to users in different business areas – e.g. providing users with the minimum access they need to their work for the minimum time required.

Legacy systems will not have admin splitting features built into their design, and it's difficult to retrofit a solution. Fortunately, modern data acquisition systems make this

process far easier as they can slot into a facility's existing infrastructure, allowing older equipment to continue in operation without extensive changes or validation required.

The Problem with Big Data The sheer growth of data presents another critical challenge. Thirty years ago, most drug manufacturing facilities would have used a paper-based recorder to monitor temperature and pressure, with a limited number of lines plotted on a chart. Colleagues would then measure this information against a template to ensure processes fell within set parameters. Today’s acquisition systems, however, can gather a vast range of different inputs and outputs, including flow, inlet or outlet conditions, packing and other critical environmental data. While these spreadsheets are suitable for research purposes, it also means there is a higher chance of data falling out of specification.

Consequently, manufacturers now have to be sure all this extra information is calibrated correctly; otherwise, large quantities of the product may need disposing.

Long, unstructured data sets also create added pressures for the audit trail and those responsible for them. At one time, these records were designed around significant changes like a colleague signing in to begin a batch or someone changing an alarm. However, every action must now

Spring 2022 Volume 14 Issue 1

Manufacturing are found or new functions are added later, making it harder to complete.

The cost of meeting data integrity requirements is considerable, and for some, the risk of penalties will be offset by not investing in new equipment. Yet this attitude has been shown to have farreaching complications, hitting share prices and big name reputations. Those more risk-averse may opt for cheaper systems, though these can prove a false economy when ongoing validation work drives up the overall cost.

So-called ‘off the shelf’ packages seem to offer the best of both worlds, allowing a business to quickly scale up without losing sight of its data. Though no system is ever infallible, and data integrity has as much to do with culture as it does with technology, products of this type offer a cost-effective route to compliance. This is invaluable in a time where there is a marked rise in the number of health authority enforcement actions – some of which have the potential to close doors permanently.

be recorded, including the transfer of files across an organisation’s internal network.

These small additions mean it now takes much longer to check a batch, increasing labour costs and the chances of disruption.

At one time, auditors only required notes of significant changes, such as a colleague signing in to change an alarm. However, updated guidance seen in '21 CFR Part 11 Electronic Records; Electronic Signatures – Scope and Application' now force colleagues to go through an audit trail to corroborate every change that has occurred during the production of a batch, no matter how inconsequential.

This level of detail is undeniably good for robust data collection. On the other hand, updates to guidance can significantly impact a plant's competitiveness, increasing the time needed to check a product. It will also drag out the investigation process should an error be flagged.

One way through this problem is by adopting systems that request a reason for change. Date and time stamps have long been part of audit trails, as have user accounts, but a clear way to explain colleagues' actions has been lacking. A hightemperature alarm on a freezer, for example, wwww.international-pharma.com

may go off during production because someone left the door open too long.

Traditional approaches to data acquisition would log this event in the audit trail but not offer any extra information. This makes the prospect of identifying and eliminating possible issues far more complex.

Newer modular systems that offer a more controlled summary of events, however, will help to speed up checks and encourage a more diligent approach to data integrity.

Users that enter a dash or full stop in one of the entry boxes would soon be identified, encouraging them to provide a more complete explanation the next time they are prompted.

Culturing Compliance Engineering systems and ensuring they’re compliant can often cost more than specialist instruments used to create products. Manufacturers need to know their programmable logic controllers are working correctly, but they also need to be sure the information collected by a SCADA system is accurate and reliable. This issue only gets more complex when businesses opt for proprietary systems with a high GAMP level, as this will require extensive validation work that can take months. Worse still, the entire procedure will need repeating if problems

These are just some of today's challenges and opportunities for data integrity in drug manufacturing. It could be argued that some of the measures discussed are unnecessary, especially given how compliance appears to be improving over time. That said, it would not be outlandish to suggest that guidance will soon become law. As such, it would be prudent for organisations to move towards more adaptable systems that promote best practices without significant disruption.

Peter Cusworth Peter Cusworth is Industry Development Manager for Yokogawa’s Controls and Instrumentation Division. Throughout the last 20 years, he has worked closely with the industry’s most recognisable names to engineer systems that improve production while also promoting best practice around data acquisition and control. Peter has been central to the development of Yokogawa’s SMARTDAC+, a GX/GP paperless recording platform that has been designed to tackle data integrity challenges in research, development and production environments.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 63

Packaging

Automation in Pharma Packaging – When and When not to Invest?

The pharmaceutical and biotech industry has expressed clear imperatives when it comes to automation. According to Pharmaceutical Manufacturing’s Smart Pharma survey, in 2021 88% of pharma manufacturers believe their company will choose to immediately automate processes if given the option and approximately 90% said they had already begun broader transformation efforts. However, the survey also revealed that the technology vendors who responded perceived that the purchase orders just weren’t there to support the assertions made by their clients – automation is an option, but few companies are purchasing the technologies.1 Through the lens of a contract packer, this discrepancy may be explained by understanding that it simply isn’t possible or desirable to automate all or every part of packaging lines despite the benefits it offers.

Here, Boy Tjoa, Director of Operations at Tjoapack, explores the ifs and whys of when to automate packaging lines and how to balance the design and flexibility of lines to serve all the needs of different customers.

Balancing Flexibility and Speed Some of the core aims when automating the pharmaceutical packaging process are to programme the whole process of a production run, walk operators through their involvement (managing changeovers being a vital process where utilisation can be lost and gained) and measure efficiency on the line – recording output rates and material usage. The overall effect is to derisk, accelerate and increase reliability in what is the essential final stage of getting a drug product to market.

However, as an overarching truism, the further that businesses automate their lines, the less flexibility they may have. For both manufacturers and their contract partners this can create more problems than it solves.

It is essential that contract partners strike 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

a balance between realising the efficiency and reliability potential of automating lines with the ability to serve their current and prospective clients. Despite the industry’s push for automation, it must be acceptable for businesses to choose not to automate where this would not offer any real value but potentially limit their services and therefore capacity. Many fully automated lines can only run one product format with tight specifications (an OSD of certain shape or size, for example) – where this line is handling significant volume of one product then the automation is often justifiable, where there are multiple changeovers required to pack numerous small volume products, the automation may become restrictive.

The packaging design and flexibility of the products handled, costs and the space available within facilities must all be carefully weighed to ensure that any changes to packaging lines are universally compatible with the business’s offering.

There is a lot of reliable legacy equipment in a packaging environment. This equipment is not easily to replaced. Also, for many manufacturers, when they switch to a different make, or brand or manufacturer of equipment, or even a different model within the same manufacturer, they also have to change all their tools. In some instances, there are a lot of lines where there is more value in the tooling than the equipment is worth. Not only would there be a significant capital expenditure requirement then, but a lot of engineering resource as well to create and validate any new tooling. This makes it very difficult to make a business case and justify switching when there may only be marginal gains made through automation versus a significant outlay.

The square footage available in pharmaceutical plants comes at a premium because of the regulated demands associated with controlling the environment. Many new or expanded facilities invest in oversizing their production rooms to factor in the potential for future automation. Established facilities often don’t have this luxury and need to ensure that every piece of factory real estate used fully realises any potential value.

Products Dictate Automation Potential Invariably the purpose of automation is to maintain a certain, typically higher speed on a line while reducing operator involvement. Where there is complexity in packs, this normally limits line parameters.

For example, if there are a wide variety of feeding stations to manage a complex package, this lowers overall automation potential. Conversely, a simple one vial in a box presentation can run much faster and more efficiently with a higher degree of automation.

Market trends, current and potential products, business plans of a contract packaging organisation and the broader needs of its manufacturing clients will all factor into the decision on where and how to automate. Where a business is operating in both the clinical and low-volume commercial space handling oral solids, perhaps handling specialty drugs, there will typically be a lot of manual feeding involved.

The challenge to automation here is that there are so many different tablet sizes and shapes and very little standardisation. This makes automating a feeding system quite complex and while there are some solutions available, they are relatively costly and often cannot handle the full range of shapes.

It may not be cost effective to automate the feeding system in this scenario and it can hamstring the ability to manage a broader portfolio of products – essentially reducing available capacities for smallerscale products.

Future proofing against other innovation trends is also a key consideration. The global pharmaceutical packaging market accounted is expected to reach a value of $144,233 million by 2027, registering a CAGR of 6.1% from 2020 to 2027 1 with smart or intelligent packaging driving some of this growth.

The mass adoption of QR-enabled packaging, which aims to increase health literacy and patient compliance, is evolving with the application of Near-Field Communication (NFC) technology. Chips are being built into packages that allow recipients to use their smartphone to link Spring 2022 Volume 14 Issue 1

Packaging to connect. Wireless electronic components that allow tracking of drug usage as soon as a tablet is ejected from a blister is also on the rise.

The integration of this intelligent technology into packaging has the potential to greatly improve supply chain performance and patient experience but requires additional packaging processes that may prove difficult or too costly to automate for many companies.

Conversely, automating fill/finish (labelling, inspection and packing in this scenario) has become a virtual necessity when it comes to packaging injectables whilst maintaining sterile integrity in the final process stages is essential and simplified by removing operator interaction.

There is also a lot more standardisation in this space as most pharmaceutical companies use one of a fairly small range of vial sizes and the pre-filled syringe space is similarly well defined.

Making Better Use of Labour Resource It is increasingly difficult to find operators and skilled labour – particularly in Western Europe. This is driving companies to invest more in automation because they need to be able to run machines with fewer people.

Simultaneously, machines are becoming ‘smarter’ and more integrated into processes and there's a lot of focus on human-machine interfacing within the industry presently.

This can simplify the operator’s role and increase reliability. Further, swapping the employee out for a dependable robotics asset not only contributes to compliance, but allows the re-tasking of valuable, skilled employees to more significant tasks. This also contributes to the security of the product by reducing the number of operators potentially in contact with it and the opportunities for diversion.

Again, balance is essential as certain classes of pharmaceuticals require secure locations operated solely by trained and vetted employees – as it stands these mandates can negate full automation.

Robotics As mentioned above, robotics are increasingly regarded as valuable assets when implemented appropriately, most often to replicate the repetitive actions that would traditionally be performed manually. Pick and place handling for example is where robotics can be introduced to syringe lines. wwww.international-pharma.com

Another use case for automated robotics is the bulk changing of materials – i.e. adding new foil rolls, cartons, and leaflets.

There are some production lines where investment in this technology is justified due to the sheer volume of product being packed and the associated repetitiveness of the task. However, as mentioned above, when exploring the differing requirements of small-run OSDs, the changeover between runs (loading different materials) would still need to be conducted by an operator and would most likely negate any automation benefit.

Automating Beyond the Line Away from packaging lines, there is a lot of scope to automate operations. Automatic guided vehicles for warehouses for example can be introduced anywhere where there's an internal logistics need. This removes some of the human transporting of materials to and from production suites and the lateral movement of warehoused, finished product. Significant value can be added here as it frees up operators to allow them to focus on more meaningful tasks.

Overcoming Automation Challenges One of the fundamental benefits for pharma manufacturers when it comes to outsourcing packaging is the vicarious investment in innovation and improvement. When CPOs invest in equipment, in this instance automation, the efficiencies, reduced risk and reliability gained is shared across the customer base.

Where they offer more consultative services to implementing a packaging process, they can more confidently assess and design something that meets the manufacturers requirement – whether that be fully or part – automated or not at all.

Summary Ultimately, it is a contract packaging organisation’s (CPO) role to help bring products to market safely and to maintain

stable supply through whatever means are most appropriate, efficient and robust.

Automating where there is no value or where it can hamper capabilities is not advantageous to the industry.

Automation will no doubt continue to develop further to the point where most processes are automated in some form.

However, the pharmaceutical industry is justifiably conservative and keeps a wary eye on risk and cost, when and where there are certainties that an automated and or/ robotics solution will have a positive impact on both then investment and progress will be made.

REFERENCES 1.

2.

https://www.pharmamanufacturing.com/ articles/2021/smart-pharma-survey-resultspharmas-digital-prowess-put-to-the/ https://www.alliedmarketresearch.com/pharmaceutical-packaging-market

Boy Tjoa Boy Tjoa is Managing Director Tjoapack NL. He is responsible for the full order to ship process. This includes Production, Warehouse, Supply Chain, Planning and Procurement. In addition, he is responsible for Technical Services and IT departments. During his studies, he worked part-time for Tjoapack. This role was expanded to a full-time position in 2017. As Manager of Technical Innovations, he was responsible for the implementation of Serialisation.

He later took over IT and Technical Services and became Director of Systems Engineering in January 2018, before becoming Director of Operations in 2018.

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Packaging

One Thing After Another – The Pathway Towards Successful Serialisation Serialisation of pharmaceutical products is vital to eliminate counterfeiting and increase patient safety, yet such a complex addition to the packing line can cause significant challenges. Mark King, Head of Technical at Essentra Packaging explores the benefits of outsourcing serialisation.

Pharmaceuticals will always be attractive to counterfeiters. They are relatively inexpensive to produce and easy to make look convincing. The regulation and enforcement infrastructure to protect against counterfeiting varies considerably worldwide; even in developed nations the penalties are an inadequate deterrent to organised criminals.

According to the World Health Organisation, counterfeit pharmaceuticals represent up to 30% of sales in some parts of Africa, Asia and Latin America, averaging at around 10% across developing nations. In developed countries, it’s still estimated at 1%.

Given the risk of unregulated drugs getting onto the market and being prescribed to patients, counterfeiting is a global public health issue. Combatting the problem is therefore an ethical – as well as, increasingly, a legislative – matter. Beyond that, there are notable commercial reasons to limit the impact of counterfeiting. This doesn’t apply merely to the income lost to

66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

illicit third parties but also the long-term reputational damage to any brand prone to counterfeiting.

Serialisation plays a significant part in fighting back against counterfeiters, by bringing product authentication to the level of the individual pack. The European Falsified Medicines Directive (EU FMD) in 2019 has cemented widespread adoption and implementation in Europe, while the USA, Russia and China all have their own pathways towards serialisation.

The Challenges of Serialisation Implementing a successful serialisation process is understandably complex and can give pharmaceutical manufacturers a number of challenges. It is precisely because it is difficult to implement that it can be so effective in separating genuine products from counterfeit imitations.

It should be obvious from the very nature of serialisation that it will have an impact on the efficiency and performance of packing lines. Adding serialisation has three notable impacts. Firstly, it slows line speeds, because printing and validating serialised codes takes time – ultimately constraining output and efficiencies. Secondly, this problem is exacerbated during peak demand because in-line packing machines are constrained by the speed of applying serialised codes; put simply, they cannot keep up. Thirdly, serialisation increases downtime during batch changeovers.

Bear in mind that these are merely the issues when things are going well. What happens when there’s a problem on the line? Serialisation equipment is complex – it can break down and require servicing, leading to supply chain disruptions and downtime that affects output. Likewise, an improper serialisation line setup can lead to increased wastage due to crumpled cartons, dust build-up, invalid codes and printing quality inconsistencies.

All of which creates a sizeable headache for manufacturers. The biggest question is whether the additional investment can be justified. Sometimes the capital expense of serialisation, combined with the reduction in output and packing line efficiency, complicates the decision to invest in serialisation equipment on in-house packing lines. Moreover, even where customers have made the investment, it can be the case that they cannot print certain codes to the quality required.

Benefits of Outsourced Pre-serialisation In the light of all of these challenges, the possibility of outsourcing some, or all, of your serialisation needs becomes more attractive. Not only does it remove the need for investment, but it also delivers a scalable solution that can adapt to changing requirements.

The key concept to understand is that outsourcing of the serialisation process essentially refers to pre-serialisation. All

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Packaging of the codes are generated and printed onto the carton prior to going onto the packing line. This maximises your full in-house line speed capacity, as well as reducing the stresses caused by capacity changes or changeovers between pack formats. In the event of any issues on the packing line, it also means you have a trusted dual, or back-up, source supplier.

Crucially, by outsourcing to a reputable partner who specialises in pre-serialisation, the quality of the codes is assured – both from the viewpoint of being well printed and in terms of secure data management, with everything verified and validated.

Considerations When Outsourcing It’s important to note that there is no one-size-fits-all solution here. There will be a huge variety of pack formats, code positions, substrates and even code types to consider.

Let’s take the last point. The EU-standard 2D matrix code will probably be the most familiar. In Russia, however, a superficially similar but far more complex crypto code is used, whose 2D matrix code can carry up to 88 digits. Meanwhile, China prefers a linear code 128 instead of the 1D GTIN EAT code. The complexity of the Russian and Chinese codes can cause issues in the customer packing lines, making outsourcing more likely.

Managing these variations requires several complementary capabilities. The first is the choice of print method. Depending on the serialised code requirements, carton position, complexity and substrate material, the supplier can use different types of coding to suit the application.

The other major consideration is managing the data to ensure compliance. It’s therefore vital to understand the proof points of your outsourced partner in terms of software, infrastructure and governance.

As a rule, you want to make sure the following can be achieved: • • • •

Each code is unique and not duplicated, nor can a deleted one be chosen by accident.

Codes cannot be activated until cartons are packed.

Obsolete serialisation cartons are destroyed with codes added to a customer list where requested.

Customers can produce reports where required.

wwww.international-pharma.com

How to Implement a Pre-serialisation Strategy The first step in any outsourced relationship with an established supplier is to understand the customers’ specific requirements. Technical experts should visit your site, listen to what’s needed and identify the necessary actions. This includes the types of codes, data transfer and quality requirements, alongside the specifics of the pharmaceutical and its packaging.

By reviewing your existing capabilities and identifying any gaps, this enables a supplier to develop a project plan that is fit for purpose. Essentially, this process creates a clear set of operating plans to be shared by across teams, delivering an effective checklist that outlines your needs: code formats, printing methods, likely volumes and lead-times.

At this point, the introduction of a secure transfer and data management platform is key. This relieves administrative pressure from your team, to provide secure data transfer and high quality, consistent verification and validation reporting. Any data management system should also be adapted to meet any existing processes for data transfer, so customers don’t have to change their existing operations.

After transferring data, it’s essential to test the quality of printing and positioning of codes on your packaging. Verifying that the code is readable by both machine and human, as well as validating codes against the data source so they can’t be used again, is also essential.

Once a project is implemented, it is vital to keep tracking the performance and support clients whenever they face a challenge.

Outsourcing in Action Consider this example of how outsourced pre-serialisation can bring benefits to customers.

A customer is having difficulty printing Chinese and Russian Crypto codes that achieved the required grading. This is due to the laser serialisation technology the customer uses in-house, which is not suitable for creating 1D or 2D codes with a large quantity of information and/or a small printing space.

An evaluation process identifies that utilising Drop on Demand and digital

printing technology will deliver the required quality meeting the grading standard, even for small codes. The client’s packing line efficiency is increased by outsourcing the supply pre-serialised cartons, meaning the customer only needs to pack and check the codes.

This leads to significant increases in output for the customer, simply by outsourcing the serialisation, expanding their packing capacity by millions of units with no additional capital investment.

The Pathway Towards Successful Serialisation It’s clear, then, that outsourcing your serialisation requirements is an effective way towards easing the complexities involved in the process. It is important to find a secondary packaging supplier, who understands the variables that are involved in implementing pre-serialisation and the positive impact this process has on packing line efficiencies and output.

For those companies looking to implement or refine their serialisation strategy, in a way that supports productivity while also ensuring the security of data and the safety of patients, pre-serialisation offers the ideal solution.

Mark King Mark King has over 30 years' experience in the print and packaging industry, primarily servicing the Health, Beauty and Pharmaceutical sectors. Having worked in various technical roles focused on front end packaging systems and process development, Mark has more recently formed a market leading Prepress solution that is now being adopted across the Packaging Division.

Other areas of expertise include Colour Management, Operational performance benchmarking and development of our strategy for digital printing capabilities for our labels and cartons facilities. Mark and his team's focus is to engage with the broader Essentra team on Technical projects, ensuring our customers get the highest levels of service to support our strong Innovation and Sustainability agenda.

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Logistics & Supply Chain Management

A Robust Product Delivers a Reliable Solution to the Pharmaceutical Cold Chain Secure transit packaging is crucial to protect temperature critical pharmaceutical deliveries. Martin Hawes, Global Head of Product Development at Tower Cold Chain, explains how solutions that are built to last mean that some are still in active use after 15 years.

At its simplest, logistics is the art of getting a product from A to B. When it comes to the pharmaceutical cold chain, however, nothing is ever this simple. Factor in the high value of pharmaceutical goods, their perishable nature and susceptibility to temperature changes, the urgency of demands from healthcare practitioners to meet patient care and the numerous (often uncontrollable) complexities of the supply chain, the reality is more like getting from A to Z. What can go wrong in transit? Containers, and their contents, might get damaged.

Drugs may be subject to temperature excursions that render them ineffective.

And so many stakeholders are involved that managing these elements is further challenged and the risks increase. Just to take one leg of the journey, the IATA reports that 52% of all temperature excursions occur whilst a shipment is under the control of an airline or within the airport environment.

The impact of this on the pharmaceutical industry is substantial. According to the Institute for Human Data Science, the biopharma industry loses approximately $35 billion annually as a result of failures in temperature-controlled logistics.

container, optimised for temperature control.

Said container needs to be robust enough to withstand the rigours of international air freight. It should be as lightweight as possible, to minimise its impact on the overall cargo payload. And it should maximise volumetric capacity, to enable as many products as possible to be shipped at one time.

The materials used for achieving a consistent temperature will depend on whether the container uses active control (i.e., requiring an external power source) or passive control. There are pros and cons to both approaches, but from the pharmaceutical brand’s viewpoint, the critical issue is reliability, so it makes sense to base a decision on what will effectively de-risk the process.

And then there’s the wider issue of sustainability. Given the growing ethical and legislative pressure to be environmentally responsible, it is worth considering the impact a solution might have. All of the points above – light weighting, volumetric efficiency, minimising wasted product – play a significant role in sustainability. Likewise, consider whether the solution is single-use or whether it has been developed with reusability in mind.

If we’re to summarise this as a checklist, the solution should be robust, reliable and reusable. And that starts with getting the product right.

Clearly, this is a situation that nobody wants – but nor is it one that any pharmaceutical manufacturer should be worrying about. The baseline requirement for pharmaceutical logistics is that goods arrive on time, undamaged and with no temperature excursions. It’s here that the choice of the most appropriate cold chain solution makes all of the difference.

A Robust Product For those operating in this sector, the critical objective is to improve the quality and consistency of pharmaceutical deliveries across a global market. This means thinking carefully about how to keep the internal contents of the container within a specific temperature range for a defined transportation time, without any requirement for active control (typically over 120 hours). The most common controlled temperatures are ambient (15 to 25°C), chilled (2 to 8°C), frozen (-15 to -25°C) and deep frozen (-60 to -80°C).

Understanding the Variables Transporting pharmaceuticals requires a

At the centre of this equation is the product, which relies heavily on the choice

68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

of materials and components. Key criteria in any product development are quality, longevity, and performance.

Structural integrity is critical as is protection against temperature excursions.

For this reason, an ideal solution is to combine outer containers constructed primarily from rotationally moulded polyethylene wall sections which, when cooled, are filled with a structural insulation foam to form a tough composite sandwich construction with high thermal barrier properties and exceptional rigidity.

This combination of rotational moulding and structural insulation foam offers the ideal balance between simplicity and long life, offering substantial protection from external shocks or impacts over an extended period of 10+ years.

Such a system is designed to hold a number of blow-moulded polyethylene plates containing phase-change materials (PCMs) to control the internal temperature and protect the contents from external extremes. These completely enclose the contents to ensure the product is fully protected with a homogenous controlled temperature within the container.

Another consideration is whether a container system offers modular design, which means that the main structural components can be reconfigured to produce up to 12 sizes of shipper to fit differing aircraft types and ISO pallet combinations. To add to the efficiency of a modular system, it’s even better if every configuration requires just one size of PCM plate. How pharmaceuticals are to be transported is likely to vary considerably, so any solution must cover a wide range of transport systems including courier and articulated road vehicles, multimodal containers, and both narrowand wide-bodied aircraft. In every case, the emphasis is on high volumetric and weight efficiency, so it's worth comparing the tare (or unladen) weight of a container against payload volume to find the right balance.

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Logistics & Supply Chain Management

and double EU or US pallets in the larger sizes. If the system is modular, even better – because the same structural components can produce multiple shipper sizes to fit differing aircraft types and ISO pallet combinations, requiring just one size of PCM plate regardless of configuration.

Using a solution like this brings significant sustainability benefits due to the virtual elimination of product waste. An entirely reusable system with long life, for example, delivers excellent life cycle environmental performance, particularly compared to singleuse systems.

In addition, a robust design provides practical benefits to the supply chain.

Containers can be moved or handled by forklift trucks; they are stackable; and they are designed for road, air and sea transport.

Some designs also incorporate two doors allowing loading and unloading from either side – a feature that has significant advantages for logistics providers operating in restricted spaces.

This should be supported by a global network of hubs, located to provide proximity and agility for operations. As well as reducing lead times when a container is required, these hubs also support from a sustainability viewpoint by reducing the mileage when empty, i.e., when being transported to and from the hub.

Crucially, this bi-opening functionality doesn’t compromise the container’s ability to fully encapsulate the product load space with phase-change materials, delivering more homogenous temperature control of the product load area without the need for any air circulation system. As a result, a container can be loose loaded allowing more product, increased capacity and better volumetric efficiency.

Beyond the obvious sustainability advantages, reusable passive shippers afford the lowest cost solution when compared to alternative systems. In the White Paper ‘The Total Cost of Shipping,’ reusable passive shippers were compared to single-use passive shippers and active shippers, on a range of cost factors. The reusable option was, respectively, 9% and 34% less expensive than the alternatives.

A Reliable (and Reusable) Solution A robust product on its own isn’t enough, and the true performance of any solution cannot be assessed without understanding its wider benefits.

Maintaining Robustness in a Challenging Time As outlined above, the right system brings many features which save customers money and allow a far higher percentage of drugs to be delivered in compliance. This benefits both patients and the pharmaceutical companies that supply them.

Does the system minimise the need for human intervention in the process? Once loaded, packed with PCM plates and closed, can a product be safely transported without ever needing to be opened?

That said, given the current climate, amidst the ongoing pandemic and disruption to the global supply chain, it is vital that the pharmaceutical cold chain sector continues to innovate.

Yes – but only if both the ambient and internal product temperatures are continually monitored and stored for the duration of the shipment in an integrated data logger.

Any temperature excursion can be flagged precisely.

Arguably, there’s little that needs changing. While industry demand has dramatically increased, customers’ needs in essence have remained the same. They continue to require robust, reliable and reusable cold storage solutions, to provide

70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

effective temperature sensitive control in the pharmaceutical supply chain and other life-science goods.

Nonetheless, there are always marginal gains to be made – whether that means improving volumetric efficiency, thermal barrier protection, light weighting, or the design and performance of PCM plates.

The key, of course, will be to integrate such improvements without impacting on the (literal) strength that current offerings bring to the market.

Everything else is a matter of adding further value, to help the pharmaceutical industry navigate through these challenging times. No matter what the complexity of the cold chain, customers need to be reassured that product will arrive undamaged and fit for purpose.

Martin Hawes Martin Hawes is Global Head of Product Development at Tower Cold Chain. He is an internationally experienced and commercially focused Operations, Engineering and Manufacturing Director with a passion for responsible business.

Martin has achieved significant success in high volume manufacturing and asset management environments in global companies, working in the food and beverage packaging, toys, pharmaceuticals, building, consumer products and cold chain sectors. An innovative thinker and business leader, he has designed, developed and led corporate strategy for innovation, manufacturing, engineering, energy and carbon management.

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Logistics & Supply Chain Management

Purchase or Rental Temperature-controlled Packaging for Pharma Logistics – One Size Doesn’t Fit All Cold chain packaging and logistics perform an integral part in the safe shipment of pharmaceutical payloads worldwide.

To ensure efficacy of high value, life giving pharmaceutical products requires high performance cold chain thermal shipper solutions.

Whether purchased or rented, temperature-controlled packaging is a crucial component within the cold chain. The industry of cold chain logistics requires specific, specialist handling end to end as well as adherence to regional regulatory compliance criteria when shipping products from manufacturer to end destination.

The worldwide pharmaceutical cold chain logistics industry is vast and continues to be an area of significant growth, with projected global biopharma cold chain logistics spending in 2022 predicted to be $19.1bn to support an estimated global biopharma cold chain product sales in 2024 forecast to be in the region of $440bn.1 The pandemic has accelerated market growth with an increase of temperaturesensitive pharmaceuticals being transported across the globe and the continuing requirement for worldwide shipments of COVID-19 therapies, vaccines and boosters.

There are key considerations to be taken into account when selecting suitable shipping solutions for temperature sensitive payloads, including the type of thermal packaging needed, insulation required its quality/thickness/weight of Phase Change Materials (PCMs)and qualified durations.

However, there is also the question of whether to purchase packaging or rent while acknowledging that one size or solution doesn’t fit all shipping scenarios.

Current Market Trends Currently the sector is seeing a rising rental requirement which is not limited to 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

bulk shipments but applies also to parcel payload packaging as companies continue to outsource their cold chain. They want to own fewer, or zero, boxes or eliminate managing the associated requirements of maintaining owned thermal packaging products. Other ways of utilising temperature-controlled packaging include long term leasing or payper-use options. These options also remove the need to purchase, manage and maintain a large fleet of product.

Companies are increasingly looking to enlist the services of thermal packaging vendors who own the packaging products companies require for their pharmaceutical shipments.

Selected vendors can manage the responsibility of conditioning and repairing packaging products, which means companies only need to pay a per trip fee.

Rental is a good option for both bulk and parcel shipments with applications available for higher volume commercial pharmaceutical transportation options as well.

Whatever option is selected, be it to buy, single trip rental or longer-term lease, there is a corresponding emergence of advancements in associated track and trace capabilities. What we are seeing is the development of more advanced software platforms within the industry that are continually being enhanced. This is in response to the requirement, whether it is COVID-19 vaccines or cell and gene therapies being shipped, that there is a need to know the exact location and accurate temperature throughout the journey of the shipment.

All packaging products, whether rented or purchased, need to be high-performing and reliable to ensure they mitigate any potential temperature excursions on the journey from manufacturer to clinic or patient.

Therefore, when selecting a temperaturecontrolled packaging supplier they should offer a broad range of products and support services for both purchase and rent.

Any selected suppliers should also have a global footprint with an extensive network

and infrastructure in place worldwide, including where key pharmaceutical hubs are located. Any selected supplier also needs to be able to offer a broad range of solutions to meet customers’ varied needs, alongside an associated fleet of products with an expansive network in place to offer consistency and availability globally.

Power of Purchase Opting to purchase temperature controlled packaging means the product can be used immediately or added to stock for the future deployment of pharma payloads, which provides greater flexibility.

If the packaging product is reusable, it can be utilised to make multiple trips.

The purchaser will need access to conditioning equipment and processes required to ensure the packaging continues to comply with global regulatory requirements.

These necessary maintenance measures make sure the packaging product continues to perform properly, providing protection to mitigate any potential temperature excursions on future journeys.

From a financial perspective, once an investment has been made to buy boxes for pharma shipments; after it has been used it will then need to be stored. So, as well as taking into consideration capital costs, there is the need to take into account any storage space and inventory costs.

Purchased products will also require additional costs and services which means some companies will need to invest further to be able to deploy their packaging product. If storing owned products within a facility, which may suddenly be required for shipments, the packaging product will need to be conditioned and prepared properly, ready for use.

In addition to this there are logistics costs to consider and if deploying reusable packaging products, track and trace capabilities will need to be in place to ensure monitoring of the product can take place and the product can be successfully returned.

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Logistics & Supply Chain Management With the increased durability and with it, the extended life of modern shippers, some purchasers may need to carry out additional requalification of the product to ensure its performance to the required level over the lifetime of the asset. Purchasers need to understand life cycle performance, the likely return % of the product, cost of maintenance (damage to packaging, coolants, insulation) track its obsolescence and ultimately end of life asset removal and replacement.

Reusable packaging, whether owned or rented is still less costly in the long run due to the significantly lower costs per trip than single use packaging.

Rental Rewards Renting a temperature controlled shipping container provides the flexibility to chose the service and application that best suits a customers’ requirements, logistics profile and budget.

Rental is a major growth area in the sector currently as customers increasingly look for

74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

suppliers who can provide everything for them from packaging products, as well as manage the product’s deployment, logistics and monitoring.

This is the key advantage of the rental / leased option. The asset management aspects are removed and placed in the hands of the system provider, who have to ensure they have the staff and infrastructure, with the correct skill sets, to implement a successful rental programme.

The system provider also has to ensure that they have a range of ‘fit for purpose’ thermal shippers available to rent, as the success or failure of the rental programme depends on assets being available.

Rental programs offer a number of advantages including spreading the cost over time while delivering the performance needed for global pharmaceutical payload requirements. Rental can be more cost effective especially if a company makes regular shipments on a regular route or plans to make high volume shipments.

Another reason some companies opt for rental is because they don’t necessarily have the time or resource to arrange everything themselves when shipping their highvalue products. Enlisting the services of a temperature-controlled packaging vendor can offer access to a broad portfolio of products, a one stop shop, as well as providing all associated services.

The benefits include not having to make any capital investment upfront or maintain and manage the packaging products because specialist providers are doing that on the customers’ behalf and managing any associated risks.

Rental and leasing options provide all the benefits of access to thermal performance technology with greater flexibility to help lower the cost-per-use, alongside experiencing payload volume efficiency and lower distribution costs.

Thermal packaging vendors specialising in rental systems provide a menu structure

Spring 2022 Volume 14 Issue 1

Logistics & Supply Chain Management which companies can select from. There is often an option to rent a product and the company can carry out its own conditioning, packing of the product and deploy it, providing a leasing option within the market.

An alternative option is for companies to relinquish responsibility to the packaging company. This means after acquiring a rental asset everything else is provided by the packaging vendor. This can include conditioning, packing of payloads, any associated monitoring required alongside the deployment and return of the hired packaging product.

Rental options provide access to packaging products and cold chain logistics services when they are required, mitigating the need to provide capital for purchased packaging products and the need to store products within warehouse space when not in use.

Sustainability and Reuse Rental is a reuse program in itself. Rental packaging customers don’t have to concern themselves with the logistics of returning a rented product or the end of life of that product and sustainability thereof because as they don’t own it, therefore those responsibilities lie with the company who are renting out the products.

It is also the renting company’s responsibility to provide transparency linked to reused products. Increasingly operators utilising and operating within the pharma logistics space require assurances that products are reused and are sustainable to ensure the products credentials align with any sustainability goals or polices the customers’ company has.

There is an increasing requirement for packaging vendors to provide details to demonstrate how their products are reused, alongside plans for the products’ end of life, whether it can be recycled or key components can be reused.

Importance of Infrastructure While there are advantages to opting for the rental option to rent or lease is not always appropriate for every location or shipping situation. Rental requires logistics networks that guarantee the recovery of the shipper. This works better within mature and existing shipping/pharma lanes, which have the necessary infrastructure to support shipments and well established wwww.international-pharma.com

logistics networks including within the US, Europe, Europe to Asia or US to Asia.

Issues can arise when shipping pharmaceutical payloads to more remote locations, for instance if deploying a consignment of vaccines from Europe or the US to the Republic of the Congo. In such circumstances rental options are not as feasible due to the remoteness of some regional locations which do not have the necessary infrastructure in place for return logistics.

Spiralling costs could be a barrier for return logistics when shipping to more remote regions which don’t have established return lanes or where it is deemed too expensive to retrieve shippers.

This was highlighted in the early stages of the pandemic when commercial airlines ceased flights and planes, which would ordinarily have provided cargo space for returning shippers, were grounded due to the global lockdowns.

The industry initially saw a spike in the deployment of single use products when aircraft were first grounded as companies couldn’t guarantee they could get their product back, however that trend has since reversed and rental requirements reinstated again.

The pandemic response wouldn’t have worked as well using a rental model because no single supplier owned an appropriately large inventory fleet necessary to provide the hundreds of thousands of boxes required to deploy the many millions of vaccines and therapies being shipped worldwide.

Conclusion Whether opting to purchase or rent, the transportation of temperature controlled, time-sensitive pharmaceutical payloads pose challenges.

To meet pharmaceutical manufacturers’ requirements and achieve regulatory compliance, it is vital to utilise established lanes. An integrated supply chain with predictable and repeatable shipping and receiving performance is imperative whether utilising rental or purchased shipper solutions.

Deploying shipments via established lanes helps to ensure pharma payloads maintain integrity throughout the cold chain. To achieve this the sector continues to implement improvements.

IATA’s CEIV Pharma program demonstrates how the industry is increasingly focused on improvements, building and reinforcing a network of certified pharmaceutical trade lanes, to meet consistent standards and delivery of pharmaceutical handling excellence throughout.

Its creation of a globally consistent and recognised pharmaceutical product handling certification reflects the cold chain collaborators consensus to continue to improve pharma logistics worldwide.

We will continue to see such improvements to existing networks including increased availability of flights offering more options to use single use or return rental shipper solutions.

Ultimately, whether renting or buying packaging products, when selecting a temperature-controlled packaging vendor for pharma logistics, the extent of their global network and the scale of the fleet of products provided should be a critical consideration.

REFERENCES 1.

https://www.statista.com/topics/4321/coldchain-logistics/#dossierKeyfigures

Paul Terry Paul Terry is Sales Director – EMEA for Peli BioThermal. Paul has over 20 years experience of commercial sales; sales team management and long-term strategic planning. Since Paul joined the organisation in 2013, Peli BioThermal have experienced significant sales growth throughout their comprehensive single/reusable parcel and bulk shipper products, which have been specially developed for the pharmaceutical and clinical trials market. Increased growth has also been achieved through the company’s Credo on Demand bulk rental programme, which makes use of the businesses extensive Global network.

Email: paul.terry@peli.com

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Transport Risk Assessment and Verification – from Theory to Practice Legal and regulatory requirements, including GMP and GDP guidelines, require that medicinal products should be stored and transported in a way that the delivered product maintains its quality and integrity and remains within the legal supply chain during storage and/or transportation. Storage and transport need to be described in the Pharmaceutical Quality System and the principles of quality risk management should be used for designing and managing these activities.

While the respective requirements appear to be well implemented for storage facilities in the pharmaceutical industry and the supply chain, observations in audits and inspections as well as frequent questions concerning transport requirements demonstrate that consultancy on this topic is highly valued.

The following discussion is based on the requirements described in the EU Guidelines on Good Distribution Practice of medicinal products for human use; however, the GDP Guidelines for active substances, the GMP Guidelines and similar regulations contain comparable requirements for the respective areas within or outside of the EU. Transport as “Mobile Storage” Transport is nowadays often referred to as “mobile storage”. However, compared to storage in warehouses, there are many more external factors that may affect product quality during transport, including, but not limited to: • • • • • • • • •

environmental factors (climatic zones, temperature, humidity, light, vibration…) mode of transport (air, sea, road) delivery routes transport duration number of transits holding times vehicles shipping containers transport temperature

76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

• • • • •

equipment to control environmental requirements (active, passive) equipment to measure environmental factors handling at airport handling at customs clearance security aspects (e.g. damage, contamination, adulteration, theft)

Chapter 9 of the EU GDP guidelines point out that it must be must be demonstrated that the medicinal products have not been exposed to conditions that may compromise their quality and integrity during transport.

The GDP guidelines explicitly request a transport risk assessment focusing on the temperature during transport as a critical factor for all medicinal products. The outcome of the risk assessment should facilitate decision-making where temperature controls have to be implemented. However, depending on the product, other factors (e.g. moisture, light, vibration, air pressure) may be considered critical for a specific product and should then be included in the risk assessment and be controlled or monitored during transport.

Such a risk assessment of the delivery routes requires not only a profound knowledge of the product characteristics (product susceptibility, stability data and subsequently registered storage conditions) but also detailed knowledge of the planned or existing delivery routes that should be assessed. A collaboration with the concerned carrier is recommended to clearly understand details of the delivery route.

According to chapter 6 of the EU GMP Annex 15 on validation and qualification, the impact of variables in the transportation process, other than those conditions which are continuously controlled or monitored, (e.g. delays during transportation, failure of monitoring devices, topping up liquid nitrogen, product susceptibility and any other relevant factors) should also be considered during risk analysis.

Transport Mapping Thus, the first step to approach a risk assessment should be the development of an initial, high-level transport mapping, describing the transport from the storage

facility at the start to the storage facility of the final recipient. This initial mapping should show intermediate storage facilities, modes of transport, transits, climatic zones and a rough estimate of timelines. The information can be visualised as a flow chart, shown in tabular form or similar.

During this step, a grouping of products with comparable product characteristics, stability and delivery routes and/or the determination of a few worst-case scenarios may reduce the number and complexity of risk assessments to be performed.

During further steps, the transport mapping can be finetuned with additional information, e.g. on vehicle types, intermediate hubs, further transits, holding times, information on environmental factors, already established controls or monitoring of environmental factors, more detailed timelines, etc. (see list above).

Risk Assessment Based on this more detailed transport mapping, a risk assessment can now be performed. A commonly used tool is the FMEA-analysis (failure mode and effect analysis). This method correlates the severity of potential failures with the probability of occurrence and the probability of detection and a resulting quantifiable relative risk score can be derived. However, other risk assessment tools can be used as an alternative (see, for example, ICH Guideline Q9).

Where transport routes are complex, it may be helpful to break them down and analyse the respective parts step by step.

Risk Mitigation/Minimisation Measures After risk analysis and evaluation, risk mitigation or minimisation measures should be derived, where appropriate. The most effective and safe transport is usually the most direct and quickest one with the least number of transits. Questions to be considered for risk minimisation could therefore include the following: Is it possible to reduce transport time and/or holding times? Can the number and duration of transits be reduced (e.g. change of transport mode, change of vehicles, interim storage, Spring 2022 Volume 14 Issue 1

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Spring 2022 Volume 14 Issue 1

Logistics & Supply Chain Management

reloading)? Can the shipping containers be improved? Do additional temperature controls (or other controls) need to be implemented? Thus, a risk assessment can also be used for the purpose of transport optimisation.

When risk minimisation measures meet their limits, it has to be decided whether the remaining risks are or are not acceptable (including the resulting consequences).

The risk assessment and its results need to be documented and communicated.

After a defined period, the effectiveness of the implemented measures should be controlled.

Transport Verification It will obviously be impossible to perform a transport validation for entire delivery routes based on the outcome of the risk assessment(s), as a validation requires precisely replicable flows and parameters, and in transport too many variables are usually involved. However, a feasible alternative approach is a transport verification that can be performed in a structured way.

As mentioned above, temperature is a significant risk factor that can affect product quality. Thus, with the focus on the temperature, a transport verification process should confirm in a pre-defined scenario, based on the outcome of the risk assessment, that the products remain within a predefined temperature range during transport. This can be done by evaluating temperature records from accompanying data loggers, temperature indicators or similar while using qualified vehicles, transport equipment and calibrated temperature measuring systems.

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Additional controls of other relevant factors can be managed analogously, depending on the product characteristics and requirements.

The transport verification process should be described in a pre-defined transport verification protocol and assessed and concluded in a respective report, confirming the suitability of the defined transport routes. Seasonal variations have to be taken into consideration; thus, a predefined winter and summer scenario should be evaluated. However, as stated in Annex 15, due to the variable conditions expected during transportation, successful transport verification does not replace continuous monitoring and recording of any critical environmental conditions to which the product may be subjected, unless otherwise justified.

Outsourcing of Transporting Activities Transport activities for medicinal products are often outsourced to carriers. The requirements mentioned in chapter 7 of the EU GDP Guidelines apply for outsourcing of such GDP activities. In Europe, carriers involved in transport of medicinal products neither hold a Wholesale Distribution Authorisation or GDP certificate (despite the fact that they also perform storage activities), nor are they controlled by the Competent Authorities. However, they have to comply with the requirements of the EU-GDP Guidelines. This should be taken into account for carrier qualification and re-qualification and subsequent carrier management.

Conclusion Profound knowledge of the medicinal

products concerned and the delivery routes are needed to execute risk assessments on transport. The risk assessment is a powerful tool for the planning of new transport routes, for optimising and controlling existing transport routes, and as the basis for subsequent transport verification.

REFERENCES 1.

2.

3.

EU Guidelines of 5 November 2013 on Good Distribution Practice of medicinal products for human use (2013/C 343/01) (https:// eur-lex.europa.eu/LexUriServ/LexUriServ. do?uri=OJ:C:2013:343:0001:0014:EN:PDF) EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 15: Qualification and Validation (01 October 2015) (https:// ec.europa.eu/health/sites/default/files/files/ eudralex/vol-4/2015-10_annex15.pdf) ICH guideline Q9 on quality risk management (January 2006) (https://www.ema.europa. eu/en/documents/scientific-guideline/ international-conference-harmonisationtechnical-require-ments-registrationpharmaceuticals-human-use_en-3.pdf)

Annegret Blum Annegret Blum is a pharmacist and has worked for 20+ years in strategic and operational areas of quality management up to board position in the pharmaceutical and biotech industry. She is an experienced lead auditor, practicing consultant and SME in the area of GDP. Spring 2022 Volume 14 Issue 1

KLINGE TEMPERATURE CONTROL The Biopharma Cold Chain Sourcebook (a leading resource to the pharmaceutical industry) recently reported: “Recent Good Distribution Practice (GDP) guidelines, to which the industry is gradually adopting, require control of even room-temperature product, which is essentially everything that is not refrigerated or frozen.

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USA: +1 717 840 4500 inquiry@klingegroup.com | www.klingegroup.com INTERNATIONAL PHARMACEUTICAL INDUSTRY 79

Logistics & Supply Chain Management

Getting More Value from Logistics Quality

Optimising Logistics Quality Management for Efficient Compliance, Competitive Advantage and Customer Value With its raison d’etre of saving lives and improving the health of people around the world, the assurance of quality lies at the very heart of the pharmaceutical production and distribution process.

Cost Of Quality (COQ) is a measure of all the costs relating to the quality of a product and its adherence to regulatory and in-house standards, guidelines and expectations. “Any cost that would not be incurred if quality were perfect”1 is a simple way of describing COQ. The costs concerned can be of several types: • • •

preventative costs e.g. training costs measurement/appraisal e.g. audit costs remedial and failure costs i.e. the costs associated with fixing defects/ deviations and all associated consequential costs such as diverse business impacts

These latter ‘external’ costs, although difficult to predict, can have huge bottomline consequences.

What Are The Costs?

In practice, the COQ can be a very nebulous sum to pin down since different pharmacos tend to follow very different costing procedures and cost-allocation policies.

accelerating M&A activity. The net result of all these confounding factors is often a hugely complex and disjointed quality management system.

Estimates of the COPQ in the pharmaceutical sector range from 25–40% of turnover3 and up to 40% of operating expenses.4 This compares to other qualitydriven industries such as semiconductors which demonstrate only 4–8%.4 Others have estimated that pharma quality costs can be 3–6 times larger than profit levels illustrating that “this is a huge opportunity that has been largely untouched thus far.”1 Indeed, analysts have stated that less than 50 percent of companies in the life sciences industry, really know what the COQ is for their organization.6 And when you drill down past GMP to GDP, the awareness is likely to be much, much less.

Certainly, GMP compliance costs are measured in the multi-million pounds per annum for a typical medium or large pharma company.7 GDP costs are often seen as a sub-set of overall GMP costs making them even harder to identify and uncouple. In fact, a recent survey indicates that just 36% of companies engaged in pharmaceutical logistics have a clear idea of their GDPcompliance costs. See Figure 1.

“Logistics networks are becoming increasingly complex as ever more environmentally astute technology is developed and demand for biologics and pharmaceuticals from emerging markets such as Asia and Africa continue to rise, and next generation cell and gene therapies are brought to the market”8 Where Are The GDP Costs?

But GDP costs are substantial. According to some sources9 the pharma industry loses as much as USD 35Bn annually just on account of temperature failures alone. This extraordinary figure relates to lost product, clinical trial loss, replacement costs, wasted logistics costs, the costs of root-cause analysis, and process remediation.

Indeed, the cost of investigation and reporting is believed to substantially exceed the cost of wasted product. For example, IATA cites the average cost of investigating a single pharma temperature excursion at USD 6,500.10 Regulatory investigations and excursion assessments are an expensive and resourceconsuming activity. And the same can be said for insurance claims for losses and damages. These can be equally time and labour consuming and come with highly unpredictable outcomes.

“It is impossible to determine the total cost of compliance accurately due to the

According to APQC2 business quality measures have: • • •

no standard definition no standard components no common calculation

With quality being a rather abstract concept invariably involving fragmented, multi-departmental processes, it is usually very difficult to put firm dollar figures against it.

Furthermore, it is a moving feast. Keeping tabs on the costs of quality is not made any easier by ever-changing regulatory requirements, increased outsourcing and 80 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 1: Nearly two thirds of the pharma-logistics sector does not have a clear grasp of its costs of GDP compliance Spring 2022 Volume 14 Issue 1

Logistics & Supply Chain Management fragmentation and complexity of the compliance universe”7 However, as we have seen, many, perhaps most, pharma companies don't, or are unable to, measure the waste attributable to GDP deficiencies.

Some of the quality-related logistics costs include: • • • • • • • • • • • • • • • • • •

Dedicated compliance staff – skilled quality team is expensive Cost of external consultants – specialised knowledge and independent expertise is expensive Cost of specialised external facilities – testing houses, cold chambers etc.

Management time – not easily quantified Validation exercises – including seasonal and recurrent shipping lane validations Shipping field trials – expensive and time-consuming Qualification exercises – equipment and packaging, calibrations etc.

Cost of equipment – protective packaging, data loggers, reefers etc.

Cost of qualifying equipment and validating processes Shipment record keeping Shipment monitoring Training IT systems development Facility upgrades Opportunity cost from diverting scarce internal resources Establishing written procedures and SOPs Cost of deviations – reporting, RCA, CAPA, product waste, delays Lost customers, delayed market penetration, regulator fines, and other market impacts in the event of quality default

Abrogating GDP quality to the supply chain is asking for trouble. Risk itself, the ability to manage risk, and the concomitant costs of mitigation and compliance are distributed very unevenly throughout the logistics chain.

Pharmaceutical companies can outsource the work, and even the risk but, at the end of the day they cannot sub-contract the responsibility. Ultimately it is the legal obligation of the pharma client, as MAH, to ensure that its logistics partners are conducting their operations safely, competently, and compliantly. wwww.international-pharma.com

“A typical excursion can take over 40 labour hours to investigate and involves input from multiple departments. Reducing that time by 10% per investigation through better collaboration efforts can save hundreds of thousands of pounds for a pharmaceutical organisation”.12 So, the answer does not simply rest in the drawing up of ‘watertight’ service contracts.

Passing all risk down the supply chain does not lead to the lowest cost and certainly does not lead to best value for the client.

And it is important to note that the highly competitive logistics industry, with its netprofit margins languishing in the lower single figures, rarely has the financial slack to throw money at unexpected problems when it comes to quality conformance.

The costs of poorly managed quality and lax regulatory compliance within the logistics chain will always end up at the door of the client in some shape or form. Usually with an enormous price-ticket attached. In this environment, the only approach to logistics quality that is going to fly in the long-term is that of a 'right first time' doctrine driven by the shipper client.

“We have thousands of excursions every year and it takes up to 25 man-hours to assess each event”.11 The Bottom Line The benefits of improved and more efficient quality control and better compliance are obvious, if somewhat difficult to ascertain in practice. One study13 of pharma manufacturing, however, demonstrated a more than five-fold return on investment in quality improvements. The overall benefits in terms of assured compliance, enhanced risk attenuation, increased customer value and lower overall costs are manifold.

Because the reality is that poor quality is one of the biggest ‘cost icebergs’ in business. The hidden costs of poor-quality management were vividly conveyed in a 201814 study which showed that the median cost of a single protocol amendment for a Phase II clinical trial amounted to $141,000 rising to $535,000 for a Phase III amendment.

As the value of pharmaceuticals continues to climb, as the latest biomedicines become more sensitive, as regulatory oversight becomes more stringent, as drugs are packed in larger containers, and as the demand for medicines intensifies in the virus-age, the

potential for risk and loss in the logistics chain is increasing sharply.

A more integrated approach to GDP compliance presents the only sustainable way of improving outcomes, reducing costs, and extracting more value in these unprecedented circumstances.

MMCS – A New Route to GDP Compliance and Standardisation One important initiative with the object of shaking up the legacy GDP compliance model with a more integrated approach is MMCS. In early 2021 BSI, the British Standards Institution, and Poseidon, the independent pharma logistics network, came together to co-develop and execute the Multi-Modal Compliance and Standards (MMCS) program which is conceived as a consensus-driven foundation for industry-wide GDP standards that is global in scope, covers all modes of carriage for bulk pharmaceuticals and provides impartial guidance on the growing maze of GDP regulations.

Aimed at pharmaceutical shippers and the entire distribution chain, MMCS is being designed to bring consistency, certainty and continuous improvement to the complex process of meeting international quality and regulatory standards for the safe, efficient and sustainable distribution of medicines, vaccines and APIs. Angus Metcalfe, BSI Group's Managing Director, Global Healthcare had this to say when the MMCS program was announced: "The entire pharma-logistics field stands to gain from this collaborative initiative which will improve quality, reduce compliance costs and promote process and technical harmonisation. A more joined-up approach to GDP compliance presents a sustainable way of improving outcomes, reducing costs, and extracting more value from logistics quality in these unprecedented times”.

The MMCS model is being designed to: • • • •

greatly simplify quality compliance processes especially from a shipper’s perspective remove huge amount of duplicated effort, overlap and repetition amongst pharma companies proactively attenuate some of the risk inherent in the pharma logistics process introduce greater standardisation INTERNATIONAL PHARMACEUTICAL INDUSTRY 81

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Figure 2: The building block of the MMCS program

•

• •

•

• • • • •

•

of player, process, product, and system including universal technical standards for key supply chain elements bring pharmaceutical companies together to minimise process divergence, aggregate volumes, share resources and collectively innovate reduce the high number of quality and regulatory non-conformancies promote continuous GDP improvement as dictated by legal statute, common sense and moral obligation provide shippers and LSPs with a common reference point for continuous improvement in quality and compliance integrate seamlessly into legacy logistics systems support and complement the need for greater sustainability when it comes to pharmaceutical logistics Provide a comprehensive GDP training support program reduce compliance costs as a result of standardisation and economies of scale create a system of shared supply chain audits to streamline risk management, vendor performance and GDP compliance strengthen physical and digital supply chain security by creating a common platform for GDP interoperability

As a universal risk management system for logistics, the MMCS will comprise multiple operational threads all configured 82 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and aligned to optimise their combined effect. Some of the more important strands of the program are: 1. Standards/Guidelines MMCS is investigating the creation of an overarching generic standard (or standards) covering pharma GDP processes and behaviours from a strategic perspective, and then underpinning this umbrella prescript with a series of technical standards as necessary.

2. Shared Audit Platform The MMCS team is currently assessing the demand and potential for a Shared Audit Platform where the industry can mutually accept independent audit results and absolve the audited parties from having to endure multiple assessments from different principals.

3. Objective Certification Conformity verification has an important role to play, and third-party certification will be another important element of the MMCS program.

4. Training GDP training is a core pillar of the MMCS program which is seeking to work closely with established training organisations and specialists to develop the necessary agenda, content and formats for differing regions and markets.

5. Supply Chain Qualification According to the MHRA* “this is one of the

highest risk areas of Good Distribution Practice”. Yet despite this risk, we have seen that the end-to-end management of supply chain GDP is one of the weakest areas of regulatory compliance.

Interested parties and professionals from across the pharma-logistics spectrum – shippers, quality practitioners, logistics providers, product/service suppliers etc. are invited to join the MMCS Consultation Cluster to be kept informed and contribute to the program’s development. To register go here: https://team-up.glasscubes.com/form/ 952a11f7-75ed-4e02-a1f7-2ff99da91046 REFERENCES 1.

2.

3.

4.

5.

6.

7.

Apply cost of poor process and product quality to life sciences industry; K. Meyer, isixsigma. com The Challenging Cost of Quality; A Heller, APQC American Productivity & Quality Center 2012 Understanding Pharmaceutical Logistics Validation in a Dynamic Environment; Mark Sawicki, Ph.D. Pharmaceutical Outsourcing, Feb 2018 The importance of COPQ for the pharmaceutical industry; John Johnson, FRSC, CChem, MIQA, NSF Health Sciences 2015 Cost of poor quality in a pharmaceutical industry: A case study; Muhammad Jawad Bhatti and Muhamamd Usman Awan, 3rd International Summit on GMP, GCP & Quality Control, Sept 25-26, 2014, Valencia, Spain Evaluating the Cost of Quality: It's Simple Math, Kari Miller, QMS Regulatory and Product Management Leader, Global Tech Solutions, IQVIA Blog, Jun 02, 2020 Reviewing the Real Costs of GMP Compliance, BioProcess International, Jun 2008 Spring 2022 Volume 14 Issue 1

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13.

GSK Vaccines, Temperature Controlled Logistics, London 2108 Cost benefit of investment on quality in pharmaceutical manufacturing: WHO GMP pre- and post-certification of a Nigerian pharmaceutical manufacturer, Chimezie

Courtney Soulsby

8.

9.

10.

11.

12.

The Challenge of compliance in life sciences, moving from cost to value. Deloitte 2015 Is the tide turning? M. Edwards, The Medicine Maker, March 2018 How to become CEIV Pharma Certified, IATA, Q4 2020 Roman Mijnhart, Senior Director Quality Global Supply Sanofi Genzyme, "A Global Approach to Reducing Temperature Excursions", Temperature Controlled Logistics, London 2108 Tackling Temperature Excursions: Risks, Challenges and Solutions; Saddam Huq, Global QA Senior Manager, Distribution & Cold Chain,

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Courtney Soulsby works as a Sector Director for the Healthcare and Life Sciences sector team for BSI (British Standards Institution). Working to understand market challenges and future needs of the healthcare sector, Courtney works with key clients and industry partners to develop holistic solutions, strategies and programs. Courtney has worked with pharmaceutical industry and their downstream logistics supply chain for over ten years – with a deep understanding the issues with regulation, compliance, quality, and other risk exposures when transporting medicines.

14.

15.

Anyakora et al; BMC Health Services Research, 2017 What is the Cost of Poor Quality in Pharma?

Artem Andrianov, Ph.D., MBA, Cyntegrity Here’s Why Poor Quality Costs You More Than You Think, T. Amirtha, Feb 2021

Alan Kennedy Alan Kennedy is a specialist in supply chain dynamics who, with his extensive cross-sector experience, is focused on bringing best-collaboration practice to pharma-logistics. Alan is the Executive Director of Poseidon, the independent pharmaceutical logistics network, which has been conceived to radically transform the transportation of pharmaceutical products by sea. This is being achieved through the application of contemporary supply chain best-practice and structured, multi-party collaboration. He regularly presents on this topic and has authored numerous papers.

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Relevance of Vaccine Cold Chains Around the World for the Effective Storage and Transport of Vaccines – Case Study by B Medical Systems Ever since Dr. Edward Jenner pioneered the concept of vaccines in the West by inoculating a 13-year-old boy with the cowpox virus and subsequently demonstrating the child’s immunity to smallpox because of that treatment, vaccines to many different infectious diseases were created over the centuries, saving millions of people. Some diseases such as smallpox, which had a risk of death after contracting it of about 30%, have been globally eradicated and others, such as measles, whooping cough and polio are among the many diseases that are now considered as rare in many parts of the world. This achievement has been possible by the large-scale vaccination programs which ensured the establishment of the herd immunity needed to stop the spread of the pathogens causing these diseases.

However, vaccination programs faced many challenges when immunising communities around the world. One of the most important ones is related to the molecular structure of many vaccines: to induce an immune response and the creation of antibodies in the person being administered the vaccine, antigens are used to simulate the actual pathogen. These antigens, because of their molecular structure, can be very delicate to environmental factors such as temperature variations and light. This became a serious problem when vaccination campaigns started targeting populations living in countries with high ambient temperatures, as the chemical components making up the doses would easily denature. This situation changed in 1974 when the WHO and UNICEF launched the Expanded Program on Immunisation and in 1979 met with Electrolux to discuss the start of the production for the first Vaccine Cold Chain units.

The Vaccine Cold Chain The Vaccine Cold Chain is the network of medical refrigerators, freezers, and transport solutions tasked to always keep the vaccines at the intended temperatures, from the point of manufacture until administration. These refrigeration and freezer units have become pivotal for the success of immunisation 84 INTERNATIONAL PHARMACEUTICAL INDUSTRY

campaigns around the world and in particular in countries with high ambient temperatures. They also developed over the years to solve problems such as lack of electricity and increasingly difficult vaccine storage temperature requirements. However, challenges remain, and Vaccine Cold Chain manufacturers such as B Medical Systems will play a critical role in tackling them.

B Medical Systems B Medical Systems S.à r.l (formerly Dometic/ Electrolux) is a global manufacturer and distributor of vaccine cold chain and medical refrigeration solutions. Based in Hosingen, Luxembourg, the company was founded in 1979, when the WHO approached the Swedish manufacturing giant Electrolux to provide a solution to safely store and transport vaccines around the world.

Across its 3 major business portfolios of Vaccine Cold Chain, Medical Refrigeration, and Blood Management solutions, the company currently offers 100+ models. B Medical Systems’ major products include Vaccine Refrigerators (Ice-Lined Refrigerators and Solar Direct Drive Refrigerators), Laboratory Refrigerators, Laboratory Freezers, Pharmacy Refrigerators, Ultra-Low Freezers, Plasma Freezers, Contact Shock Freezers and Transport Boxes. All products have integrated 24/7 temperature monitoring capabilities that further ensure that these products offer the highest level of safety and reliability.

Throughout its over 40 years of experience, the company has created innovative solutions to store and transport vaccines, blood components, laboratory specimens, and more across the world safely and reliably.

Its commitment to supporting governments, health institutions and NGOs has not only saved innumerable lives but helped communities develop and prosper.

As the established market leader in the Vaccine Cold Chain for the past decades, B Medical Systems has provided equipment to support its partners in vaccinating more than 350 million children in developing countries.

Through its long-lasting relationships with global humanitarian organisations such as UNICEF, the WHO, Gavi, Health Ministries, and more, B Medical Systems has installed more than five hundred thousand units across 140+ countries around the world

to safely store and transport vaccines, medicines, blood, and other samples.

B Medical Systems is also one of the first few companies to receive the EU MDR certification for its active refrigeration products across its medical refrigeration and blood management business lines, and one of the few companies in the world to have an end-to-end refrigeration solution certified by EU MDR, US FDA and WHO PQS. During the COVID-19 pandemic, B Medical Systems has been actively supporting governments world-wide in the establishment of their vaccine responses, by supporting the establishment of a reliable and versatile Vaccine Cold Chain able to meet any storage temperature requirement and deliver the best results in terms of safety, reliability, and efficiency.

Supporting Country-Wide Vaccinations in Central Europe When the first few SARS-CoV-2 vaccines were being assessed for approval by the EU EMA, one of the countries in Central Europe approached B Medical Systems to build a reliable cold chain to maintain any type of vaccine at the correct temperatures along the whole vaccine distribution chain. However, the setting up of such a cold chain presented some major challenges. For instance, at the time there was great uncertainty regarding the temperature storage profile of each vaccine: the governments were not sure which types of vaccines would be supplied to them and they needed to be ready to store doses requiring storage temperature profiles of -70°C (Pfizer/BioNTech), between -50°C and -15°C (Moderna), -20°C (Johnson & Johnson), and between +2°C and 8°C (AstraZeneca, etc.).

Furthermore, the number of doses that would be provided to the member states of the EU was still uncertain, and vaccine spoilage due to malfunctioning storage equipment had to be kept to a minimum.

The company B Medical Systems worked with the government of this particular country to set up a cold chain for the safe storage of all vaccines at all stages, from the central hub to the patient. With the help of the company, this government was able to identify a series of steps needed to ensure the safe storage and transport of all the Spring 2022 Volume 14 Issue 1

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COVID-19 vaccines, which can be found in the table above.

Following the steps identified, B Medical Systems provided the country enough U701 Ultra-Low Freezers for the central hub to store all the vaccine doses that had been calculated to be required, as well as enough TCW80AC, TCW4000AC and TCW3000AC vaccine refrigerators and freezers for each point of care around the country’s territory.

Moreover, RCW25 vaccine transport boxes were also supplied to transport the doses between the various points of care.

It is important to note that the equipment provided was chosen to be able to cover all vaccine refrigeration requirements for each step: the U701, with its ability to reach temperatures ranging from -86°C to -20°C, can easily be used to store both Pfizer/ BioNTech’s and Moderna’s vaccines, while the TCW3000AC Vaccine Refrigerator can reliably hold doses at a set temperature of -16°C. The TCW80AC and the TCW4000AC are dependable refrigerators capable of safely storing vaccines at a temperature of +4°C, and the sturdy RCW25 transport boxes can be used to transport doses at different temperatures with the addition of ice packs, different types of phase change materials (PCMs) or dry ice inside them. With the equipment supplied, the supported country was able to safely

store the doses received and start vaccinating its citizens.

The company’s experience from previous large-scale vaccinations for different diseases in other countries ensured that this European country had the perfect support to organise the entire cold chain infrastructure required ahead of time, including the setup of remote monitoring solutions to control the refrigerators and ultra-low freezers used across its territory, thus putting in place an extra level of security for the safe storage of all the vaccines. This, combined with the excellent equipment provided and the effort of all the healthcare workers involved in the immunisation program, ensured zero wastage of vaccines.

The government of this country was pleased to have worked with B Medical Systems and, together with Pfizer, stated the following: “B Medical Systems has helped ensure that each and every COVID-19 vaccine […] has been stored optimally with zero temperature excursions thereby ensuring zero wastage of the vaccines. This is a great achievement especially when there is news on a daily basis about improper cold chain storage and transportation around the world. […] They have also helped us solve any vaccine cold chain logistical issue in the true spirit of partnership; as we work together to jointly fight COVID-19.”

B Medical Systems’ Ultra-Low Freezers have been utilised around the world during the COVID-19 pandemic to store Pfizer/BioNTech and Moderna vaccines. wwww.international-pharma.com

Luc Provost,

CEO of B Medical Systems Mr. Luc Provost believes in a vision that fosters innovation and customercentricity. He is a hands-on leader who focuses on perfecting every customer interaction with efficiency and effectiveness.

He has a proven executive management track record and over 20 years of experience in driving sales growth. He is passionate about helping save lives by providing solutions in the remotest areas and is also a prominent speaker and thought leader in the field of medical refrigeration. Mr. Luc Provost, CEO of B Medical Systems, a global medical refrigeration device manufacturer, has been with the company for more than 20 years. He possesses a wealth of knowledge in business ownership, technology, operations, and sales and is at the core of the company’s reputation as an end-to-end medical cold chain provider. Since joining the company, he has played a pivotal role in the company’s revenue growth, geographical expansions and has signed various global commercial agreements for the company including with major corporations like Toyota. He was also instrumental in the launch of 50+ new products, many of which even created new WHO PQS standards. In his official capacity as CEO, he has travelled to 100+ countries and has worked closely with several central governments, ministries of health, international humanitarian and procurement organizations like UNICEF, WHO etc. Luc Provost holds a degree in Business and Management from University of Louvain in Belgium and has studied International Marketing at Laval University in Quebec. He is a Belgian citizen and has also worked for the Belgian Army.

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How to Save 1,000 kilos of CO2 per 333-litre Refrigerated Packaging – Thanks to the First-ever Circular Economy Pharmaceutical Packaging 2019 was a turning-point. It was the year when fears of palpable global climate change gripped society as a whole, including the worlds of business and industry. In 2020 the COVID-19 pandemic led to a second dramatic realisation.

In order to increase the resilience of global supply chains there is a radical need for greater sustainability. eutecma's objective now is to tap into the enormous potential which climate-friendly, no-waste packaging can offer the temperature-controlled transportation of pharmaceuticals.

At the end of a three-year process of evaluation and development, we have created, for example, the 333-litre PROTECT cooling box, estimated to be reusable 15 times that can save up to 1,000 kilos of CO2. This is possible thanks to the first-ever circular economy system in the pharmaceutical packaging sector. The so-called retecma Loop, which is based on artificial intelligence (AI), ensures that not a single gram of expanded polystyrene (EPS) material is lost. eutecma's drive towards increased sustainability in the temperature-controlled transportation of pharmaceuticals began in 2019. Our strategic concept could be compared with that of a bifocal lens. Just as the lens is designed for both close-up and distance vision, eutecma's development projects have followed two directions. On the one hand, the challenge was to make existing products more sustainable quickly; on the other hand, the medium-term goal was to redesign the pharmaceutical supply chain packaging radically.

systems, the customer has a choice between packaging boxes made from conventional Virgin EPS/styrofoam and others made from recycled styrofoam (Styropor® Ccycled™).

This secondary material consists of pyrolysis oil, which is produced by the world's largest chemical company BASF from plastic waste. Both innovative products improve our customers' CO2 balance significantly.

Last but not the least, we have launched an information campaign with the aim of informing customers how PROTECT packaging and ICECATCH© passive energy storage units can be used not just once but multiple times – without jeopardising the temperature integrity or the quality of the transportation.

Bifocal – The Distant View: Rethinking Pharmaceutical Supply Chain Packaging While more rapidly sustainable product alternatives were being shipped from our company headquarters in the Port of Mannheim, we were at the same time working on a "big bang". This was because, we recognised that to achieve a drastic reduction in CO2 levels and also in waste material, packaging in the pharmaceutical supply chain needs to be completely reconfigured. The fact that there were numerous requests for a "100% green and temperature-regulated packaging" indicated that customers would welcome such a development. All too often, supposedly sustainable products had turned out to be mere "greenwashing" in the marketplace. We interpreted these requests not only as confirmation that we are on the right track, but also as a challenge to fully rework the issue of pharmaceutical packaging.

Step 1: The Choice of Material We began with the question: Must temperature-regulated high-tech packaging really have to consist of EPS? Can we not assume that wool, straw and hemp are much more sustainable materials? So, we launched a two-year evaluation process, to be conducted without any preconceived views. This presented no problems to us, since eutecma is not a producer of EPS, but simply a provider, which means that we don't have to bear the burden of production and machineries. Accordingly, it would have been possible for us to switch to an alternative material immediately without incurring losses. We investigated the following materials: paper, cardboard, wool, hemp, cotton, used textiles and various plastics.

A specific phenomenon appeared repeatedly. Although materials showed many good properties during testing, ultimately the problem was that they failed to meet all the evaluation criteria. Wool, for example, is an excellent material for insulated packaging, but as PROTECT packaging had to be usable worldwide, and Australia forbids the import of wool, we had to rule out wool for our purposes.

The use of old textiles was also ruled out, in this case because all too frequently they are heavily contaminated by pesticides. A box made of straw can be pressed into any shape, but often has inferior insulation properties due to the development of moisture. In addition, it should be sealed with foil to prevent dust harming the pharmaceutical product.

Bifocal – Close Up: Rapid Successes with Sustainable Products This has resulted in ecological product alternatives which became available as early as 2020. For example, the foil composites of our ICECATCH© passive energy storage units consist of 50% sugar cane waste material.

The latter bears the quality seal "I'm green", developed by Braskem, the Brazilian producer of polyethylene based on sugar cane waste.

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Logistics – Corporate Analysis In the end, two evaluation criteria proved critical: universal formability and complete recyclability. The eutecma system comprising ICECATCH© passive energy storage units and PROTECT boxes attains a high degree of reproducibility, since the former are secured in insertion slots throughout the transportation process and consequently supply energy to the products continuously and reliably. To achieve this result with other materials, these would need to be combined with a second material. For example, paper packaging requires a thin layer of plastic to prevent the formation of thermal bridges.

However, this type of hybrid packaging is almost impossible to recycle completely.

This is because separation of the different components precedes the recycling process – and this calls for a huge amount of energy, which in turn can be saved if a monomaterial is used. Therefore, the smaller the number of components contained in the packaging, the simpler the recycling process.

Conclusion: EPS is ideally suited as a mono-material for climate-friendly, no-waste, temperature-controlled refrigerated packaging, since it fulfils a wide range of criteria. In particular, it can easily be completely recycled – both mechanically and chemically – and thus integrated into a perpetual recycling.

Step 2: The "mental paradigm shift" What would happen if from now on the used EPS packaging was no longer a waste material that had to be disposed of quickly?

What would happen if from now on used EPS packaging was valuable raw material?

Would it then not be logical to make every possible effort to ensure that the material EPS had as much "life" in it as possible? That was the initial thinking behind a strategy which is now resulting in the introduction of retecma: the first-ever AI-supported closed-loop material processing system in the pharmaceutical packaging sector. Of key importance here are the three success factors: digitalisation, regionalisation, and high-quality recycling.

clearly identifiable by way of an RFID chip.

This RFID chip indicates not only the type of element (for example: L-shaped stacking frame) and the target weight but also the number of times the element has already been used. In addition, each PROTECT Box is assigned a QR code which can be read out at the final destination by means of a eutecma app.

application. The AI-supported system performs two fully automated tests on the individual components and either one or two sanitising procedures:

The eutecma app offers the following options:

3.

1.

2.

3.

Reusing the packaging > Click to get the handling instructions depending on the duration of transport and temperature profiles Sending packaging to the Refreshment Centre > Click the address of the nearest Refreshment Centre Sending packaging to Recycling > Click the address of the nearest recycling company

Option 2 is a new and unique feature: the components of all PROTECT Boxes and ICECATCH© passive energy storage units are overhauled in eutecma's Refreshment Centres and made ready for their next

1.

2.

4.

Weight test: If the target weight is not reached, material damage is assumed, and the component is withdrawn.

Photo-optical test: If the camera detects damage, the component is withdrawn.

Ultraviolet light is used to sanitise each component.

Steam cleaning (only if required): If the camera detects severe contamination, the component is steam-cleaned.

All the Refreshment Centres operate with Artificial Intelligence, which means their knowledge increases from one day to the next. Thus, the system can distinguish between superficial scratches and defects which threaten the integrity of the product.

In addition, since the Refreshment Centres can be networked with one another across different continents, this acquisition of know-how takes on a global dimension.

The aim of the refreshment process is to ensure that the elements are reusable as far as possible.

Success factor: Digitalisation If EPS is a valuable material which should be reused as long as possible, then the packaging must not be regarded as a WHOLE; instead, it should be broken down into its component parts. Accordingly, each element in a PROTECT Box and an ICECATCH© passive energy storage unit will soon be wwww.international-pharma.com

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Success factor: Regionalisation To keep the CO2 footprint as small as possible and to restrict unnecessary journeys by empty delivery vehicles over long distances to a minimum, retecma will as soon as possible be available on those continents where the main flows of goods are destined, namely Europe (Germany), Asia, South America, North America as well as Middle East. Up until now standard practice has been either to dispose of packaging at the destination or to return it empty to the point of origin. With the retecma Loop system the procedure is different: in the future all PROTECT Boxes and ICECATCH© passive energy storage units will remain in the destination region. If the recipients have no use for them, they will be collected in the destination region and can then be transported either to the Refreshment Centre or to authorised recycling partners.

Success factor: Top-quality recycling All too often, however, discarded EPS components end up on a rubbish tip. This will not happen with eutecma's Reverse Logistic System, because part of the retecma pledge is that unusable EPS components are to undergo a high-quality recycling process. To this end we are working with certified regionally based partners who are carefully selected and audited. These regional partners ensure that by means of mechanical or chemical recycling it is possible to produce new valuable, highquality EPS raw material from EPS which had previously been discarded in a manner detrimental to the environment. This new EPS raw material can be used, for example, in the production of new PROTECT boxes.

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Conclusion: Digitalisation, regionalisation and top-quality recycling form the backbone of retecma – the first closed-loop material system in the pharmaceutical packaging sector.

Artificial intelligence (AI) supports the core process of recycling in the eutecma Refreshment Centre.

Step 3: Saving up to 1,000 kilos of CO2 with a 333-litre cooling box According to the trend study "Pharma Management Radar" undertaken by Camelot Management Consultants, the interviewees consider product packaging to be an important means of achieving ecological improvements. Nevertheless, the survey, carried out in 2020, indicated that these efforts are thwarted by the lack of alternatives. However, all that has

now changed with retecma Loop, the firstever circular economy for pharmaceutical packaging. Instead of a piecemeal solution to augment their supply chain, retecma enables pharmaceutical companies with an interest in sustainability to leverage the enormous CO2 potential. Our calculations show that with a predicted quota of 15 reuses/usage cycles the PROTECT Europallet box with a capacity of 333 litres saves up to 1,000 kilos of CO2. Similar forecasts have been made for all other boxes in the PROTECT range.

Thus, each reused PROTECT Box and each reused ICECATCH© passive energy storage unit saves energy and resources, CO2 and waste. In addition, thanks to the AI-based Refreshment Centres, retecma will soon know how many lifecycles the individual components pass through and therefore will also be able to utilise the last kilometre that is still possible with the EPS packaging.

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And even after their final usage, no EPSs are lost in the retecma system. Thanks to sophisticated recycling processes, valuable new material is produced, from which high-quality EPS products can in turn be obtained.

And what's more: eutecma will in future be doing even more to help protect the planet. We are measuring our direct and indirect emissions to determine the complete CO2 footprint which our company and our products are leaving on the planet. In those areas in which we can achieve direct effects, for example by converting to green energy, we will do so, while in those areas in which CO2 emissions are unavoidable, for example

during the initial production of PROTECT packaging and ICECATCH© passive energy storage units, we will compensate for this by specifically promoting climate protection projects.

Conclusion The time for greater sustainability in the pharmaceutical supply chain is not just ripe – it is over-ripe. For quite some time now, companies have been coming to realise that improving one's brand image is not the be-all and end-all. Ecological sustainability can also be used to make the global supply chains more robust. And this is a powerful asset in times of unexpected pandemics, sudden declarations of war and skyrocketing

inflation. That's why eutecma is now acting as a pioneer and investing substantial amounts in the introduction of retecma, the first-ever closed-loop material recycling system for pharmaceutical packaging. We are firmly convinced that only an intentional scarcity of goods as a result of strict multiple usage, supported by digitalisation, regionalisation and high-quality recycling, will make the pharmaceutical supply chain climate-friendly and waste-free. And thus, also counteract risks which threaten the pharmaceutical industry worldwide.

According to the Camelot study, this includes growing cost pressure and supplier stability – factors mentioned by 86% and 52% of interviewees respectively.

Sven Rölle Sven Rölle has been on the staff of eutecma from its earliest days. Having held various posts in the packaging industry, including SCA Packaging, he has played a key role in numerous milestones in the history of the eutecma company.

The economics graduate is Head of Sales and is in close contact with many of the global players who do business with eutecma. With his deep understanding of intelligent solutions, characterised by "out-of-the-box" thinking, he and his team are making significant strides in the development of new groundbreaking cooling systems and supporting services.

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Logistics – Corporate Analysis

Why Pharmaceutical Manufacturers and Airport Logistics Should Grow Hand in Hand While the past two years have been very turbulent in many ways, the air cargo industry has seen unprecedented growth levels, providing vital resources globally, whilst under constant pressure.

In early 2020 global air cargo volumes collapsed due to the sudden loss of wide body passenger jets, who account for 50% of total air cargo capacity globally. On top of that there was a very high demand ex-Asia for PPE, air cargo capacity was vitally needed to ship COVID-19 vaccines and now the industry is charged with the supply of the COVID-19 antiviral medicines on top of the regular pharmaceutical traffic. Yet the industry has a can-do mentality and offers a solution for any problem.

Of all the products that use air cargo, pharmaceuticals are one of the few that are not affected by regular business cycles. The global medicine market (using invoice price levels by IQVIA) is expected to grow at 3–6% CAGR through 2025, to about $1.6 trillion. The market remains very stable, whether we see economic growth or decline, pharmaceuticals are a vital commodity, and this market will remain naturally stable within the air cargo supply chain. It’s therefore safe to assume that growth within this product segment will continue to flourish in the logistics industry.

A segment that needs to grow in parallel with the pharmaceutical industry itself, working closely together, ensuring that logistics can keep up and safely deliver the product to the end user. A key stakeholder and driver in this process are the airport authorities, they should motivate the airport community to modernize infrastructure, invest in quality improvement programs and drive innovation.

However, airport communities cannot do this alone, support is needed from the pharmaceutical industry itself.

Improvements in infrastructure, certification, digitization and so on should be looked at from a joint perspective. Workshops should be organised, and partnerships should be signed at conferences. The stakeholder that matters most will reap the benefits, i.e., the patient.

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Brussels Airport's latest Real Estate developments, BRUcargo West, which houses three large pharma hubs.

The Brussels Airport Story – Listening to the Manufacturers Over the past ten years, the cargo area of Brussels Airport (BRUcargo) has been investing and innovating into the pharmaceutical airport eco-system, not only because of its ideal central location within Europe and its proximity to major pharmaceutical manufacturers, but because of its clear company-strategy on enhancing the pharmaceutical supply chain at its airport premises.

The first gap that needed to be filled over a decade ago, was the clear understanding of the pharmaceutical manufacturer’s logistics requirements. Apart from networking and building relationships at pharma conferences, the airport kickstarted a forum that invited pharmaceutical manufacturers in one room, the BRUcargo pharma shipper forum, a biannual event. In this setup, the airport was able to identify key weaknesses, listen to essential desires and where it could add innovation.

A key topic that was evident in the BRUcargo pharma shipper forums was the lack of pharma standardization in the air cargo industry. At the time there was no governing body ensuring that pharmaceutical products were handled correctly at the airport. The only existing certification at the time was the Good Distribution Practice (GDP), but this did not really apply to pharmaceuticals moving through an airport. In collaboration with IATA, Brussels Airport and other stakeholders launched a taskforce to compile and create an encompassing program that trains and validates pharmaceutical stakeholders in

the air cargo industry, better known as IATA CEIV. BRUcargo currently holds the largest concentration of CEIV certified companies globally and has implemented this program into its strategy.

Besides working on the CEIV program, investments have been made in modernizing the infrastructure at BRUcargo, again by listening to feedback of the pharmaceutical manufacturers themselves. Currently, over 35,000m2 of dedicated pharmaceutical cold storage facilities are in operation at the airport, spread across 18 different pharma hubs. Each company has full ownership of their pharma specialization and investments are made on their behalf. By having multiple pharma hubs on site, healthy competition enables innovation. Additionally, feedback was given that the transport of pharmaceuticals towards the aircraft was showing a lot of temperature deviations. As a result, the airport researched and invested in a pooled fleet of airside pharma transporters, ensuring climatized transport at airside.

To push handling quality to a higher level, Brussels Airport offers a digital platform, BRUcloud, as a solution to many inefficiencies.

For pharmaceuticals a live dashboard was created along with an extended checklist for the acceptance stage of pharmaceuticals when arriving at the airport. This way the airport ensures all pharmaceutical shipments are correctly handled as per product requirement.

In order to strengthen the cargo community at BRUcargo, a community engagement platform was launched in 2016, Air Cargo Spring 2022 Volume 14 Issue 1

Logistics – Corporate Analysis

Handling process of COVID-19 vaccines in a pharma hub.

One billionth vaccine being loaded onto a United flight to ORD, in the background you can see two Airside Pharma Transporters.

Belgium. The platform consists of an airline, forwarder and handling cluster, linked to nine steering groups who tackle everyday operational issues, launch innovative projects and promote the airport. One of these steering groups, the pharma steering group, acts as a facilitator to bring all pharmaceutical airport stakeholders in one room, and where innovative approaches to optimizing the pharma supply chain at BRUcargo are discussed and launched.

are assessing current pharma standards within the air cargo industry and how to be innovative towards the future. A current project of Pharma.Aero, CEIV 2.0, is assessing the current industry sentiment on the CEIV certification and share this feedback with IATA. A clear outliner of the project is the lack of engagement with the pharmaceutical industry within the CEIV program. How can both industries improve this and navigate together to a better future?

By listening and closely collaborating with the pharmaceutical industry, the recent innovations and investments gave the airport a pole position during the COVID-19 pandemic.

Brussels Airport was the first airport to distribute the COVID-19 vaccines globally and has handled over a billion doses within a year. Additionally, the airport also became the first hub to distribute COVID-19 antiviral medicines. With this amazing achievement Brussels Airport has confirmed its position as the preferred European pharma & life sciences gateway. It gives great pleasure and pride that the airport was able to positively impact so many lives around the globe.

With a lack of engagement comes a lack of communication. Looking back at Q4 2020, the air cargo industry had a better understanding how the new Apple MacBook would be boxed and shipped than the shipping requirements of the COVID-19 vaccines. It is obvious which one should receive the higher attention. A call for better communication is being worked on, efforts are being made on local and international level. However, comparable to the days before the CEIV certification, there is no authority centralizing and fact checking the information or encouraging and facilitating the air cargo industry to collaborate closer with the pharmaceutical industry. For example, at the moment Pharma.Aero and a local working group at Brussels Airport are investigating the handling requirements and technicalities of Advanced Therapy Medicinal Products (ATMP), as this will quickly become the next hot topic in healthcare. Unfortunately, the number of pharmaceutical manufacturers present in these projects are very limited, yet the purpose is to ensure a better understanding and improving transport conditions of their product.

But it was not the airport alone who benefitted from this, by working together in the past, the pharmaceutical industry now has access to a well located and highly qualitative global hub for the transport of sensitive pharmaceuticals. It’s a win-win.

A Long Road Ahead, Together Despite all the positive results and examples given in the previous paragraph, the air cargo industry is not there yet. Brussels Airport is one of the few airport communities who actively work on a close relationship with the pharmaceutical manufacturers, and where the results have paid off, yet with plenty of work still ahead. A push needs to be made on a wider scale to promote closer collaboration between the two industries. There is no point in having a top-notch pharma hub at airport A but having multiple temperature deviations at airport B. This push is being made by organizations such as Pharma.Aero, where working groups wwww.international-pharma.com

Not only should both industries collaborate better on good communication and handling practices, but they should also jointly look at optimizing the supply chain to improve sustainability. Currently single use packaging is the norm, and on many occasions the selected packaging is overkill.

By joining forces and doing combined tests on temperature behavior and lane mapping, a more optimized packaging solution can be implemented, eliminating unnecessary

Loading process of an Airside Pharma Transporter with COVID-19 vaccines.

precautions and packaging material. Linking data and control towers can also highlight handling inefficiencies within and outside the airport, thus further reducing the waiting times of pharmaceuticals during transport, improving throughput of the supply chain and reducing unnecessary CO2 emissions by stationary trucks for example.

With the world opening up again after many lockdowns, now is the time to act.

Attend conferences, link up again, talk to your airport or pharmaceutical partners and join forces. It pays off. If you want to join the Brussels Airport collaboration platform and wish to participate in one of the pharma shipper forums, do not hesitate to reach out to the author of this article.

Samuel Speltdoorn Samuel Speltdoorn is the Cargo Business Development Manager at Brussels Airport, responsible for all pharmaceutical developments at the airport’s dedicated cargo area. He is co-chair of the local pharma steering group, chairman of the COVID-19 taskforce and is actively involved in various Pharma.Aero projects. He is a graduate of Cranfield University and previously worked for Virgin Atlantic Cargo in London.

Email: samuel.speltdoorn@brusselsairport.be

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Event Preview & Review

ATMP Hybrid Conference – An Irish Perspective The Parenteral Drug Association (PDA) is the leading global provider of science, technology and regulatory information and education for the pharmaceutical and biopharmaceutical community. Founded in 1946 as a nonprofit organisation, PDA is committed to developing scientifically sound, practical technical information and resources to advance science and regulation through the expertise of its near 10,000 members worldwide.

Conferences, meetings, and courses bring together pharmaceutical manufacturers, suppliers, users, academics, and regulatory officials to discuss and boost issues of mutual interest. These exchanges of technical knowledge, expertise, and best practices assist the advancement of pharmaceutical science and technology in the interest of public health.

Recently, the design and development of a modern health policy in the field of regenerative medicine leads to the formation of a new and integrated cognitive field, which requires systematic research and study to produce innovative answers and best practices. Advanced therapy medicinal products (ATMPs) are a new product category, which is at the heart of concern since it has to deal with diseases in which traditional medicine has proven to be ineffective so far.

The ATMPs consist of three basic categories of products: 1) gene therapy (gene therapy medicinal products (GTMPs)); 2) somatic cell therapies; and 3) tissue engineering products, as well as any combination of the above. These are products that use human cells and tissues which have undergone gene or other treatment or modification in the laboratory. The donor and the recipient of the cells/tissues may be the same individual (autologous use) or different (allogeneic use). Cell therapy and gene therapy are overlapping fields of biomedical research and treatment. Both therapies aim to treat, prevent, or potentially cure diseases, and both approaches have the potential to alleviate the underlying cause of genetic diseases and acquired diseases.

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PDA Ireland Chapter, Event Committee

Guest Speakers

Valerie Mulholland, GMP Services Ltd, MC

Guest Speakers

PDA’s Ireland Chapter organised the ATMP Hybrid Conference on the 26th of November 2021 in Dublin.

The main aim of the event sponsored by renowned organisations like IPS, Bioquell, Koerber, Pharmalex, Steris & SteriTech was an ideal meeting ground to provide comprehensive information on ATMPs, which could be applied in various regenerative medicine and tissue engineering applications. Moreover, ATMPs could be a valuable tool for the physicians for the proper administration of lifethreatening diseases, thus could be applied in personalized regenerative medicine.

An attendance of more than 250 people both in-person & remotely, gathered to discuss the importance of ATMP as the next wave of therapeutics and enhance the contribution that the biopharma sector makes to the Irish economy as well as deliver solutions to unmet and existing medical needs.

“I believe Ireland is very well positioned and with a very strong pharmaceutical and biopharmaceutical industry worth around over €140B in exports. Most of the main companies in the world manufacture here (Ireland). I think we do have all the components of what a very successful sector in the future should be”, affirms Matt Moran, Director at BioPharmaChem Ireland. Moran adds: “The Covid-19 pandemic has had a huge impact and we now have an mRNA vaccine, which is a new technology. And it is proven to be very successful in the treatment or prevention of Covid-19 through vaccination.

And what I think is very encouraging about this new technology is that it has got huge potential to be used in other therapeutic areas as well as dealing with new variants of the Covid-19.”

The event gave us a sense of returning to normality after two years of disruption.

Although the pharmaceutical industry has never stopped, social gatherings and faceto-face events which have been vital to knowledge sharing & key partnerships had come to an abrupt halt. This conference was vital to regenerate a sense of purpose in the drug discovery and development world. It was also vital to highlight the role which Ireland can play in a global setting.

“Bioquell Ecolab solutions are just delighted to be back here, to see people face-to-face again is just so important and we are so happy to support this industry.

PDA Ireland events have always been brilliant events and always well attended.

It’s just brilliant for us to get in front of Spring 2022 Volume 14 Issue 1

Event Preview & Review these people again and to reconnect.” Says Kristen McKeown at Bioquell, one of the main sponsors of the event.

True to PDA’s mission to promote the exchange of rapidly evolving information on the latest technology and regulations, the ATMP Hybrid Conference hosted topics like A Fully Integrated Ecosystem for Manufacturing Gene Therapies from Clinical through Commercialisation, mRNA Vaccines – An Overview of the Manufacturing Challenges & Bottlenecks, New Momentum for Advanced Therapies: How Regulators can help.

The event, moderated by Valerie Mulholland, started with a welcome speech from Ann McGee, PDA Ireland President, and Matt Moran, Director BioPharmaChem Ireland. Between face-to-face and online presentations, some important names of the industry gave their insights into some topics, like Bertie Daly at Takeda who talked more about the contamination control strategy for cell therapy manufacturing facility and Dr. Christian Schneider, who spoke about how regulators can help in advanced therapies, between others.

The event enabled attendees to: • Discuss business-related questions with regulators, industry, and academic organisations • Ignite conversation, collaboration, and change in how we improve access to innovative treatments by accelerating their way to the market and ultimately to patients • Gain practical knowledge on how to best navigate the complex access landscape of advanced therapies • Create solutions in various formats with plenary sessions and interactive sessions By the end the event the feedback from all the attendees was excellent. “It’s a delight to be sponsoring the PDA event.

There was a sense of joy from people, from seeing the familiar faces and some unfamiliar ones also. It was just great to be back “mentions Bernard Flynn at Elis Cleanroom. Brian O’Connor from MeiraGtx, exclaimed “It is Immediately clear from the interaction you get from before and after the presentation. People will come and chat with you. Something you can’t necessarily do online. You can’t be in person and get that face-to-face interaction” Please find more at: www.pda.org/chapters/europe/Ireland wwww.international-pharma.com

Name: Brian O’Connor, Director of Quality Assurance Company: MeiraGTx Ireland Feedback: “Thank you Kevin, and all the PDA Ireland team, for the privilege to speak among such an esteemed panel of speakers. It is clear that the development of ATMP manufacturing in Ireland has great momentum and it was inspiring to hear first-hand the details on the projects happening across academia and industry.”

Name: Niall Barron, Principal Investigator, Cell Engineering Lab Company: NIBRT Feedback: “Thank you Kevin and co at PDA Ireland. Great event and really looking forward to seeing Ireland go from strength to strength in the production and delivery of ATMPs!” Name: Christian K Schneider, M.D., Head of Biopharma Excellence/Chief Medical Officer (Biopharma) Company: Biopharma Excellence Feedback: “Also from my side thank you so much for having me in the conference. Brilliant speakers, and the conference highlighted what power the Irish ATMP life sciences community has. I really hope to learn more in the future!”

Name: Matt Moran – Director BioPharmaChem Ireland Company: BioPharmaChem Ireland Feedback: “Great presentation Bertie and Aidan – fascinating to see the challenges that you have overcome to deliver this product – a whole new ball game!”

Name: Kevin Smyth, IPS Company: IPS-Integrated Project Services GmbH Feedback: “IPS were delighted to be the main sponsor of the fantastic event. The PDA Ireland committee successfully managed to provide us with top class international ATMP expert speakers from Ireland, the UK and mainland Europe. In addition to the excellent speakers and presentations, the open floor Q&A sessions were very informative and highly interactive.

Everybody who attended this conference established new contacts and learned more about the fascinating and rapidly developing ATMP Biopharma Industry . Well done to all the organisers, presenters and delegates.”

Name: Trevor Brett, Director, Business Development Company: PharmaLex UK Feedback: “Thank you for PDA arranging such an insightful and enjoyable ATMP event: scores 11 out of 10! The talks by Takeda and Meira were totally awesome.”

Name: Catherine Jomary, PhD., Technology Lead ATMPs Company: IPS-Integrated Project Services GmbH Feedback: “Thank you very much for your kind invitation to the meeting, for introducing me to the Dublin IPS Team and to Ireland experts in ATMPs. I really enjoyed the meeting, and congratulations for the organisation!”

Name: Bertie Daly, Manufacturing Head Cell Therapy Company: Takeda Feedback: “It was my pleasure to present with Aidan at the prestigious PDA event. Great meeting with the SME’s on the panel sharing their knowledge and expertise on the various presentations. Special mention to the organizers, Aidan Harrington for providing the opportunity to present and of course Valerie Mulholland our moderator for making the event such a success.”

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 95

Advertisers Index

Page 41

Almac Group

Page 53

Aurena Laboratories

Page 84 & 85

B Medical Systems

Page 90 & 91

Brussels Airport

IFC

BSP Pharmaceuticals S.p.A

Page 17

ChargePoint Technology

Page 77

Controlant

Page 69 & 86–89

Eutecma GmbH

Page 31

FUJIFILM Wako Chemicals U.S.A. Corporation

Page 3

Gerresheimer AG

Page 11

Kahle Automation

Page 79

Klinge Temperature Control

Page 23

Krautz Temax

BC

Natoli Engineering Company

Page 5

Nemera

Page 25

Nipro

Page 35

Owen Mumford

Page 95

Pharmapack

Page 7

RGCC International GmbH

IBC

Securikett Ulrich & Horn GmbH

Page 45

SGS

Page 94

Temperature Control and Logistics – by IQPC

Page 73

THERMO KING

Page 71

Tower Cold Chain

Page 59

Trilogy Writing & Consulting GmbH

Page 33 & 47

Valsteam ADCA

Page 83

Woolcool

I hope this journal guides you progressively, through the maze of activities and changes taking place in the pharmaceutical industry

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