IBI Volume 5 Issue 2

Volume 5 Issue 2

Peer Reviewed

Understanding and Overcoming The Challenges of Flow Cytometry Accessing Greater Dimensions of Biological Understanding Through LC-MS Proteomics Advancing Cardiac Drug Discovery with Human Induced Pluripotent Stem Cell Technology Live Cell Transport The New Way of Transportation

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II INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

Summer 2022 Volume 5 Issue 2

Contents 04 Foreword TALKING POINT

DIRECTOR: Mark A. Barker INTERNATIONAL MEDIA DIRECTOR: Anthony Stewart anthony@senglobalcoms.com EDITORIAL MANAGER: Beatriz Romao beatriz@senglobalcoms.com DESIGN DIRECTOR: Jana Sukenikova www.fanahshapeless.com FINANCE DEPARTMENT: Akash Sharma accounts@senglobal.co.uk 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)20 4541 7569 Email: info@senglobalcoms.com www.international-biopharma.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 IBI will be published in Autumn 2022.

ISSN No.International Biopharmaceutical Industry ISSN 1755-4578.

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

2022 Senglobal ltd.

Volume 5 Issue 2 – Summer 2022

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06 Gerresheimer – Innovating for a Better Life Gerresheimer is a leading global partner to the pharma and healthcare industry. With specialty products made of glass and plastic, the company contributes to health and well-being.

Gerresheimer is represented worldwide and produces with around 10,000 employees wherever its customers and markets are. With plants in Europe, North and South America and Asia, Gerresheimer generates sales of around €1.5 billion. In this interview, Stefan Verheyden at Gerresheimer, introduces Gx Biological Solution, a newly established customer and biotech-oriented team at Gerresheimer. He also gives an insight into the newly launched online service tool gGuide, which helps customers find the best product solution in Gerresheimer's portfolio.

WATCH PAGES 08 What is a blockchain? Why it’s Perfect for Healthcare Applications Blockchain is a much talked about technology and is now relatively well established in the financial sector as a secure form of payments transfer – and the basis of all cryptocurrencies, which has also driven consumer adoption. But what is often less well reported is its significant potential as a transformative technology in a multitude of healthcare settings. Its immutability makes it not only suitable for traceable financial and token-based transactions, but also as an ideal tracking and security platform for both patient records and the pharmaceutical supply chains amongst a multitude of emerging applications. Raja Sharif at FarmaTrust discusses what blockchains are, the different types and why they have so much potential in healthcare settings as the technology matures.

REGULATORY & COMPLIANCE 10 Adapting to an Everchanging Regulatory Landscape Compliance in regulated laboratories isn’t static; the rules and guidance are constantly evolving to improve standards and the quality of drug products. However, the areas of non-compliance found during regulatory inspections typically remain unchanged, with the same issues being observed from year to year. The bulk of the non-compliance issues arises from breaches of basic principles of Good Manufacturing Practice and Good Laboratory Practice (GxP), requirements relating to procedural control, documentation standards, a lack of scientific investigation, training, maintenance, qualification and validation of both hardware and software. Garry Wright at Agilent Technologies analyses how the regulatory landscape has been changing.

14 Understanding and Overcoming the Challenges of Flow Cytometry Flow cytometry is a powerful analytical tool that is widely used throughout drug development in various capacities. With an understanding of the range of applications flow cytometry offers, it is clear why it is heavily implemented in drug discovery and development. Studies have the ability to detect the expression of cell surface and/or intracellular molecules, determine the proportion of cell types within a heterologous cell population, and analyse cell volume and size. However, the flexibility offered means goal-guided careful study design and a thorough technological understanding are required to define and inform panel selection, compensation, and gating in flow cytometry. Pirouz Daftarian at Crown Bioscience, explores these requirements and highlights the need for drug developers to ensure that flow cytometry studies are purposedriven in their design, to realise a world where patients get the right treatment at the right time.

INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY 1

Contents 16 How to Hire a Translation Agency Choosing the right medical translation provider can help in-house regulatory and clinical departments and contract research organisations support strategic growth while controlling costs and minimising risk. In this practical guide to hiring a translation agency, DWL, A BIG Language Solutions Company discusses eight key steps to take when choosing a vendor, ranging from assessing domain knowledge to managing liability and security.

RESEARCH / INNOVATION / DEVELOPMENT 20 Accessing Greater Dimensions of Biological Understanding Through LC-MS Proteomics Proteomics has the potential to answer vital biological questions, optimise drug development and improve clinical care. Seeing these benefits, more researchers are embracing proteomic profiling, driving demand for ever-larger proteomics studies and the high-throughput techniques needed to deliver them. But, while available affinitybased methods can provide high-throughput proteomic analysis, their specificity may be low. Luckily, liquid chromatography-mass spectrometry (LC-MS) can effectively address the shortcomings of affinity-based approaches, offering both depth and throughput of data. Dr. Andreas F.R. Hühmer at Thermo Fisher Scientific and Oliver Rinner at Biognosys, discuss the evolution of high-throughput proteomics, the opportunities presented by LC-MS, and how companies are helping researchers to use this technology to drive the advancement of clinical research and care.

26 Working in Tandem: Formulation Science and Drug Delivery Device Design The need to continue to innovate with drug delivery devices has been a focus for medical device companies over the past couple of decades. With self-administration of injectables increasingly prevalent, manufacturers must balance the use of new technologies with the need to make products as simple and user-friendly as possible. At Owen Mumford Pharmaceutical Services we acknowledge the importance of understanding the key trends in formulation science and how this may impact the development of new medical devices for subcutaneous administration. We recently conducted in-depth interviews with experts in pharmaceutical formulation science and device development from the US, UK, Ireland, Germany and India to understand where innovations will be directed in the coming years. Julie Cotterell at Owen Mumford Pharmaceutical Services examines in more detail how these twin areas must work in tandem to create optimal solutions and deliver drug-device combination products that can accommodate a wide range of patient needs.

28 Developing Stable Lentiviral Cell Lines Lentiviral vectors (LVV) are commonly used as gene delivery tools for cell and gene therapies, notably chimeric antigen receptor (CAR) T cell therapies. Like other retroviruses, lentiviruses can convert their single-stranded RNA genome into double-stranded DNA when integrating into the genome of a cell. Unlike other retroviruses, lentiviruses can transduce non-dividing and quiescent cells, which makes them highly suitable for use in cell therapy.

Corinne Branciaroli and Dr. Katie Roberts at OXGENE, analyses the development of stable lentiviral cell lines.

MANUFACTURING & PROCESSING 32 Manufacturing of Biological Tissues: Standardisation and Automation The manufacturing of biological tissues responds to major societal challenges, but it also faces major issues, especially those related to the standardisation of manufacturing processes and scale-up.

Stäubli Robotics is a leading global player in robotics, consistently delivering engineering as effective and reliable as our service and 2 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

support. Bearing these challenges in mind, the French start-up Poietis has developed the Next Generation Bioprinting (NGB) platform, equipped with a Stäubli TX2-40 robotic arm to perform 4D bioprinting of biological tissues in a faster, more affordable and more functional way.

THERAPEUTICS 34 Advancing Cardiac Drug Discovery with Human Induced Pluripotent Stem Cell Technology Despite having available treatments for most cardiac diseases there is an increasing need for more specific and effective therapies. To help drug developers advance smoothly in this process, it is important to decrease the translational gap that is leading to high attrition rates and costs. Human induced pluripotent stem cell (iPSC) technology is increasingly utilised to develop disease models that reliably mimic the diversity of patient pathogenicity and cardiac disease severity in vitro.

Phenotypic screening based on iPSC models represents a big opportunity to make cardiac drug discovery more time and cost-effective by increasing the translational power of preclinical candidates. Noelia Muñoz-Martín and Elena Matsa at Ncardia, review common challenges and goals for drug developers and how the latest innovations in iPSC technology are contributing to efficiently advancing cardiac drug discovery.

42 How Scalable Manufacture will Enable Progress for Lentiviral Therapies In the twenty years since the creation of the first effective CAR-T cells, lentiviral vectors have become valuable tools for the development of ex vivo gene and cell therapies. Two ex vivo lentiviral gene therapy products have recently reached the market, one approved for the treatment of acute lymphoblastic leukaemia and the other for beta thalassemia. The successful development of these treatments has demonstrated the potential for lentiviral therapies to treat cancer and other diseases. Dr .

Katie Roberts at OXGENE, explains how scalable manufacture will enable progress for lentiviral therapies.

SUPPLY CHAIN MANAGEMENT 44 Live Cell Transport – The New Way of Transportation A new generation of active temperature-controlled and CO2 conditioned transport devices are challenging the existing cell shipment methods. In routine cell culture transport protocols, it is commonplace to thaw, plate and recover cryopreserved cells.

When using this method, some cells survive the transport quite well, while others either do not survive the transport at all, or they come back from a near-death experience- not quite the same afterwards. Cells that are exposed to suboptimal life-sustaining conditions encounter severe stress and have a reduced survival rate. Dr. Corné Swart at Cellbox Solutions GmbH explores the new way of live cell transportation.

48 Preparing Biopharmaceutical Downstream Processing Supply Chains for Resiliency Post-pandemic From monoclonal antibodies (mAbs) that treat ailments such as cancer and arthritis to messenger RNA (mRNA) vaccines to fight a pandemic, biopharma’s place in global healthcare has rarely been more prominent. By 2030 the global market for biopharmaceuticals is projected to reach $856.1 billion and expand at a compound annual growth rate (CAGR) of 12.5% from 2021 to 2030. In response to the increasing number of infectious diseases around the world antibody development is also fuelling tremendous growth in the biopharmaceutical manufacturing sector. Hans J. Johansson at Purolite Life Sciences looks over supply chain resilience for bioprocess resins and future-proofing downstream bioprocessing.

Summer 2022 Volume 5 Issue 2

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Foreword Flow cytometry is a technology allowing multi-parametric analysis of thousands of particles per second and helps to adequately identify or functionally characterise complex cell populations of interest. It is often used in basic research, discovery, preclinical and clinical trials.

With the increasing proportion of biologics in the pipeline, flow cytometry has proven itself to be an indispensable tool to asses safety, receptor occupancy or pharmacodynamics.

Flow cytometry is a powerful analytical tool that is widely used throughout drug development in various capacities. With an understanding of the range of applications flow cytometry offers, it is clear why it is heavily implemented in drug discovery and development. Studies have the ability to detect the expression of cell surface and / or intracellular molecules, determine the proportion of cell types within a heterologous cell population, and analyse cell volume and size.

However, the flexibility offered means goal-guided careful study design and a thorough technological understanding are required to define and inform panel selection, compensation, and gating in flow cytometry. Pirouz Daftarian at Crown Bioscience, explores these requirements and highlights the need for drug developers to ensure that flow cytometry studies are purposedriven in their design, to realise a world where patients get the right treatment at the right time.

understand where innovations will be directed in the coming years. Julie Cotterell at Owen Mumford Pharmaceutical Services examines in more detail how these twin areas must work in tandem to create optimal solutions and deliver drug-device combination products that can accommodate a wide range of patient needs.

A new generation of active temperature-controlled and CO2 conditioned transport devices are challenging the existing cell shipment methods. In routine cell culture transport protocols, it is commonplace to thaw, plate and recover cryopreserved cells.

When using this method, some cells survive the transport quite well, while others either do not survive the transport at all, or they come back from a near-death experience- not quite the same afterwards. Cells that are exposed to suboptimal life-sustaining conditions encounter severe stress and have a reduced survival rate. Dr. Corné Swart at Cellbox Solutions GmbH explores the new way of live cell transportation.

I would like to thank all our authors and contributors for making this issue an exciting one. We are working relentlessly to bring you the most exciting and relevant topics through our journals.

Beatriz Romao, Editorial Manager

The need to continue to innovate with drug delivery devices has been a focus for medical device companies over the past couple of decades. With self-administration of injectables increasingly prevalent, manufacturers must balance the use of new technologies with the need to make products as simple and user-friendly as possible. At Owen Mumford Pharmaceutical Services we acknowledge the importance of understanding the key trends in formulation science and how this may impact the development of new medical devices for subcutaneous administration. We recently conducted in-depth interviews with experts in pharmaceutical formulation science and device development from the US, UK, Ireland, Germany and India to

IBI – Editorial Advisory Board •

Ashok K. Ghone, PhD, VP, Global Services MakroCare, USA

•

Bakhyt Sarymsakova – Head of Department of International Cooperation, National Research Center of MCH, Astana, Kazakhstan

•

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

•

Lorna. M. Graham, BSc Hons, MSc, Director, Project Management, Worldwide Clinical Trials

•

Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

•

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

•

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

•

Catherine Lund, Vice Chairman, OnQ Consulting

•

Cellia K. Habita, President & CEO, Arianne Corporation

•

Chris Tait, Life Science Account Manager, CHUBB Insurance Company of Europe

•

Deborah A. Komlos, Senior Medical & Regulatory Writer, Clarivate Analytics

•

Elizabeth Moench, President and CEO of Bioclinica – Patient Recruitment & Retention

•

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

•

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

•

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

•

Hermann Schulz, MD, Founder, PresseKontext

•

Stefan Astrom, Founder and CEO of Astrom Research International HB

•

Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

•

Steve Heath, Head of EMEA – Medidata Solutions, Inc

4 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

Summer 2022 Volume 5 Issue 2

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Contact us healthscience@sgs.com sgs.com/healthscience sgs.com/healthcommunity www.international-biopharma.com

INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY 5

Talking Point

Gerresheimer – Innovating for a Better Life Gerresheimer is a leading global partner to the pharma and healthcare industry. With specialty products made of glass and plastic, the company contributes to health and well-being. Gerresheimer is represented worldwide and produces with around 10,000 employees wherever its customers and markets are. With plants in Europe, North and South America and Asia, Gerresheimer generates sales of around €1.5 billion. Its wide range of products includes pharmaceutical packaging and products for the simple and safe administration of medicines: Insulin pens, inhalers, micropumps, prefillable syringes, injection vials, ampoules, bottles and containers for liquid and solid medications with closure and safety systems as well as packaging for the cosmetics industry.

Gx Biological Solutions Expands Its Services In this interview, Stefan Verheyden, Global Vice-President Gx Biological Solutions at Gerresheimer, introduces Gx Biological Solution, a newly established customer and biotech-oriented team at Gerresheimer. He also gives an insight into the newly launched online service tool gGuide, which helps customers find the best product solution in Gerresheimer's portfolio.

Q: Gerresheimer established a new focus team: Gx Biological Solutions. Why was the team founded?

A: We have become one of the world's leading partners to the pharmaceutical and healthcare industries. Our broad portfolio includes many pharmaceutical packaging products – including safe drug delivery systems such as insulin pens, inhalers, prefilled syringes, vials, cartridges, bottles and containers for liquid and solid drugs with closure and safety systems. Basically, we have been serving the biologics market with our solutions for many years. However, in recent years we have observed an increasing diversification of this market, the industry leaders and their requirements. Therefore, we would like to take this development into account and strategically focus more on the specific support of biopharmaceutical companies. Hence, we have set up our Gx Biological Solutions team in a market-oriented way in order to support customers in the best possible way in choosing a suitable primary packaging material or device through our expertise and a broad range of services.

Q: What are the challenges in the field of biologics?

A: The development of proteins, monoclonal antibodies, or even cell and gene therapies are frequently accompanied by challenges that are often not apparent at first glance. Proteins, for example, are amphiphilic, surface-active molecules whose 6 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

intact glycosylation patterns are essential for their subsequent function in the patient's body. In addition, specific sensitivities to individual components or materials of primary packaging must sometimes be taken into account, which sometimes only become apparent during storage studies. Other drugs, for instance, contain phosphate-based buffer solutions, which can interact with glass surfaces over the storage period and lead to the formation of glass flakes. This risk can be avoided by using special coatings or even polymer-based packaging materials. In any case, indication- and user-specific characteristics have to be taken into account. Some diseases make it very difficult for patients to administer their medications independently at home, such as rheumatoid arthritis.

Opening a cap then quickly becomes a challenge in everyday life.

All this has a lasting effect on the choice of a suitable packaging material or device.

Q: What is unique about the Gx Biological Solutions focus team?

A: The idea of Gx Biological Solutions is to establish an interdisciplinary team with global resources and cross-divisional product expertise to advise our customers. The team supports companies during development and beyond throughout the drug product lifecycle by providing customised application and indication-based recommendations. The short-term provision of platform solutions as well as product sample quantities for early clinical studies, the performance, evaluation and interpretation of functional or laboratory tests or the development of customised solutions are thus also within Gx Biological Solutions' area of expertise.

Q: What characterizes the market as different from the regular gerresheimer clientele?

A: We are referring to a multi-layered market that is growing and thus offers many opportunities. Already, biotechnologically produced drugs account for around 40% of total drug pipeline developments. And the trend is rising. Especially due to the breakthrough of RNA-based drugs and the establishment of cell and gene therapies, the market will diversify further in the coming years. Many start-ups and medium-sized companies are already advancing the development of novel drugs as strongly as never before. The approach of our Gx Biological Solutions team is therefore to specifically facilitate access to suitable packaging solutions and medical products for these companies as well, and to enable them to benefit from our expertise. Our pharmaceutical product portfolio currently includes more than 1600 product variants from a total of 111 product families. Especially for new customers, this can be slightly overwhelming. At Gx Biological Solutions, we are therefore pursuing the approach of assigning suitable product variants to therapy and indication fields and their Summer 2022 Volume 5 Issue 2

Talking Point a few clicks thanks to a targeted question structure. The gGuide is therefore intuitive, time-efficient and at the same time flexible to use.

Q: Does the gGuide rival the sales department?

sensitivities, thus making our portfolio more transparent. In a first step, we have therefore implemented the digital product selector "gGuide" on our website. This offers all interested parties an initial overview of suitable product recommendations as well as the opportunity to contact us in an easy and non-binding manner.

Q: How does the gGuide work?

A: With the gGuide, we are pursuing a drug-centric and, above all, customer-centric approach that can address the individual needs of an inquiry. Therefore, the first question is not whether they are looking for a vial or a syringe, a plastic or a glass product.

Instead, users answer whether the product is a small molecule, a biologic or another active ingredient, such as homeopathic or phytopharmaceutical products. In fact, the focus is on the drug developed by our customers. In the following questions, the gGuide then inquires: • • • • •

A: Quite clearly, no. It even supports the sales department in its work. The gGuide is a tool for making initial contact. However, our customers can easily make a very precise inquiry, which our sales department can then process efficiently according to the requirements. Our advice is thus tailored to the individual needs of a customer inquiry from the outset. In addition, we also learn from our customers. Based on the inquiries we are given, we can obtain a even better understanding of the market and its requirements, further enhance our products, and intensify our cooperation.

Q: Which further developments of the gGuide does gerresheimer plan for the future?

A: First of all, we would like to see how the service is used and, if necessary, adapt it and integrate further functions. In the future, it would also be conceivable to delve further into the various product areas - in other words, to set up a separate selector for vials, for prefillable syringes or for the configuration of a medical device. There are definitely some considerations in the pipeline.

So, stay tuned.

about the therapeutic area in which the drug is to be used, about the way in which the drug will be formulated and administered, about the intended quantity per target market, by specific packaging configurations such as RTF® (ready to fill) or RTS® (ready to sterilise), as well as by known properties and sensitivities of the drug.

The process ends with a selection of the best fitting packaging solutions from our standard portfolio. If we are unable to recommend a product based on the selection criteria, the customer is directed to a contact form so that the request can be detailed to our team. In the subsequent step, our customers then receive more in-depth advice on the possible configurations of a product. Here, if desired, offers can be worked out based on individual needs.

Q: What are the advantages of the gGuide for Gerresheimer's customers?

A: The gGuide is not only suitable for companies in the biotech sector. Anyone who does not yet have a precise idea of what kind of packaging they are looking for can use the gGuide for a quick, non-binding consultation. Our entire pharmaceutical, biopharmaceutical and veterinary product range is stored in the gGuide, as well as the option to request customer-specific solutions. Our global expertise is thus bundled in one tool and digitally accessible to our customers around the clock with just www.international-biopharma.com

Stefan Verheyden Stefan Verheyden holds a degree in Chemistry and has been active in pharma- and biopharma industry for over 25 years. Started his career in Product Management Lab Chemicals at Merck subsidiary in Belgium, before moving into leading Sales and Business Development roles in production chemistry, raw materials and API’s at 2 major players in the industry. After 20 years he moved into the pharmapackaging industry taking over a global role as Senior Vice President at one of the players within the primary packaging industry. Moved to Gerresheimer almost 5 years ago, after heading the global syringe business for almost 4 years he has taken ownership over a newly setup unit – Gx Biological Solutions – supporting the fast growing biological market segment through dedicated expertise, system integration and solution offering.

INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY 7

Watch Pages

What is a Blockchain?

Why it’s Perfect for Healthcare Applications Blockchain is a much talked about technology and is now relatively well established in the financial sector as a secure form of payments transfer – and the basis of all cryptocurrencies, which has also driven consumer adoption. But what is often less well reported is its significant potential as a transformative technology in a multitude of healthcare settings. Its immutability makes it not only suitable for traceable financial and token-based transactions, but also as an ideal tracking and security platform for both patient records and the pharmaceutical supply chains amongst a multitude of emerging applications.

In this article we will discuss what blockchains are, the different types and why they have so much potential in healthcare settings as the technology matures.

What is Blockchain?

In simple terms, a blockchain is a shared digital ledger of transactions across disparate businesses without the need for control by any single central entity – meaning its free from any centralised control. The ledger works by grouping information into chronologically-ordered blocks or nodes (bits of information) and these are then linked and secured using the latest cryptography technology. What adds further security is that the database is distributed across a network of multiple computers, which reduces the risk of security breaches as there is no single point of failure. These platforms also safeguard data against losses by being frequently verified and distributed and any individual changes will be tracked in the blockchain itself.

This means that the entire digital record is visible to everyone who is authorised, including all the changes over its lifespan and can even includes who made any changes – the latter being incredibly important reason for its suitability as a supply chain record (i.e. its always clear who did what and when) More recently, “Smart Contracts” have been much discussed, which enables two or more parties to sign an immutable contract that is automatically fulfilled (i.e. triggering payments or the release of certain predefined information). The smart contract details the asset exchange terms and allows for total transparency and, in the case of the healthcare sector, as one example, could provide chain of custody of records.

Public and Private Blockchains The most obvious question when looking at utilising a blockchain is to determine whether they are going to be implemented as public or private blockchain platforms. In the pharma industry, unlike say the cryptocurrency space (where full visibility is vital), companies lean towards using private blockchains due to the increased security that is offered.

These permissioned blockchains require authentication such 8 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

as invitations and in some circumstances “legal” contracts to join, whereas public blockchains are open for anyone to join and see. The activities and membership within public platforms are regulated under a governance model, which can be encoded into the blockchain protocol. Public platforms are the original concept for blockchains that distributed ledger purists believe should be used as they allow greater data sharing, but for the sake of security, private blockchains are more widely used within the pharmaceutical industry.

A more recent development we have seen and one that is particularly important in healthcare settings is the in ‘interoperability’ between chains, which empowers the sharing of data amongst disparate systems. This means that old concerns about everyone having to be on the same blockchain platform are no longer a concern. Data can be transferred between different blockchain platforms.

One area in healthcare that is maturing at the similar moment at blockchain technology are advanced therapies.

And here, in these complex supply chains, where security of patient data, and tracking of chain of identity is quite literally a life and death matter, blockchains can help ease the burden and reduce complexity. The ability to securely track a sample from the patient to the pharma company where the therapy is made and back again to the individual patient is huge leap forward in an area where paper-based administration still leads. In fact, earlier this year ATMPS Ltd received the patent in the USA for the utilisation of blockchain technology in the tracking from vein to vein of advanced therapies products. This is potentially a revolutionary step for advanced therapies and will help remove many of the logistical burdens faced in their scale up and distribution, especially as many more enter the market over the next few years.

One further application we are particularly excited about is helping simplify the relationships between payors, hospitals and developers of treatments. One of the ongoing challenges here is managing all the multiple partners in terms outcomes for the patient. So even in the simplest approaches there is still a great deal of paperwork needed from the hospital to the payor (insurer in the USA or the NHS in the UK) and to the developer of the therapy but then equally between the developer and the payor. The net result is a large expensive and administrative burden on the healthcare system.

However, we can simplify these reimbursement models using smart contracts on blockchain. So for example, in the United States, blockchain could be used to enable the administering hospital to trigger the payments automatically once certain conditions (clinical outcomes) for payment have been met. This therefore means the developer will receive payments faster. But it also provides advantages for both the hospital and payor in reducing the burden of cross-checking medical records, and what a specific plan covers or not in terms Summer 2022 Volume 5 Issue 2

Watch Pages

of treatment, while also greatly increasing transparency – as their will be a single record of the therapy from ordering and tracking to outcome. And of course, from the patient perspective the chain means they will be able to more accurately plan for when to attend the hospital – as they can be automatically notified and the hospital can better predict treatment plans.

But what of the bigger picture ideas that could emerge in the medium to longer term. Blockchain is widely seen as one of the founding infrastructures that will be required to build web 3.0. And, while there are many immediate term benefits, as per Amara’s law the longer term is likely to see completely different healthcare architecture.

For example, Smart cities using the IoT (the internet of things) – which connects technologies allowing the exchange of data across devices and systems using the Internet and other various communication networks – will be able to be automated and potentially linked directly into the healthcare apparatus.

Blockchain and especially cross chains will grow in importance as the transition to these processes and machine-to-machine communication becomes more prevalent. These transactions between machines will therefore not need human intervention which allows for faster transferring of patient information and greatly benefits the healthcare sector for both professionals and patients.

Another area we believe blockchain will have an impact is in the growing use of AI in pharmaceutical discovery, genetic analysis and wider healthcare sectors – as it can ensure non corruption of data, particularly as they transfer between systems. www.international-biopharma.com

Conclusion As companies see the decrease in time and money spent on developing advanced therapies and starting clinical trials when blockchain is introduced and as regulators start mandating more full transparency from end-to-end, we will see blockchain become a norm within pharma. This adoption will be revolutionary for patients, speeding up the process to get them new medicines and technologies as regulatory approval is expediated and tracking patients progress within new data hubs. Records for devices and patients will be able to be linked for doctors and innovators in ways that were previously unimaginable in a globally centralised structure.

With the current maturity of blockchains, the ability to make processes and workflows more efficient and the cost reductions that are provided, if you are implementing new systems, the most important question to ask is why blockchain tools?

Raja Sharif Raja is the Founder and CEO of FarmaTrust and is driving the company’s vision and mission of creating innovative solutions for the pharmaceutical and healthcare industries to protect consumers of medicines and create efficiencies in the industry. Raja is a UK qualified barrister; he has been General Counsel and Board Member of number European companies, with over 20 years business experience in the global media and technology companies.

INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY 9

Regulatory & Compliance

Adapting to an Everchanging Regulatory Landscape

Compliance in regulated laboratories isn’t static; the rules and guidance are constantly evolving to improve standards and the quality of drug products. However, the areas of non-compliance found during regulatory inspections typically remain unchanged, with the same issues being observed from year to year. The bulk of the non-compliance issues arise from breaches of basic principles of Good Manufacturing Practice and Good Laboratory Practice (GxP), requirements relating to procedural control, documentation standards, a lack of scientific investigation, training, maintenance, qualification and validation of both hardware and software.

The regulatory inspection program was impacted on a global level during the COVID-19 pandemic as inspectors were no longer able to travel overseas and visit regulated companies to carry out conventional site-based inspections. As a result, regulatory authorities around the world quickly developed virtual inspection processes that utilised a combination of video technology to inspect facilities and interview staff while documents and supporting information were shared across secure digital channels.

Many regulated companies still use paper-based systems that rely on physically sharing documents and information with inspectors during a face to face, on-site inspection. The paper-based approach can cause significant difficulties when being inspected via the new virtual inspection process, which is heavily reliant on having digital documents and information readily available. Having to scan paper documents and information into digital formats is a time-consuming process and provides significant delays during a virtual inspection that may impact the final outcome. A number of regulated companies used the pandemic as an opportunity to update their Quality Management System (QMS) and move away from paper-based systems to digital workflows to future-proof their quality operations.

From an inspector’s perspective, there’s a preference for digital data as it contains additional meta data, information relating to how a piece of data or result was acquired, processed and reported. Digital data provides greater visibility of the activities performed during the analysis phase and can better determine whether any data manipulation or falsification has taken place.

Regulatory authorities around the world have not reverted back to site-based inspections even though COVID-19 restrictions have been relaxed and travel routes to foreign countries are becoming increasingly available. They are instead relying on their global network and collaboration with other regulators via Mutual Recognition Agreements (MRA). An MRA enables a 10 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

regulator in one country to accept an inspection performed by a regulator in a different country, who has been assessed and confirmed to operate to equivalent inspection standards. In the future, therefore, site-based inspections may only be deployed for “high-risk” companies with either a poor compliance record, or for novel products that are possibly first to market and may be performed by a local regulator. It is highly likely that regulators will continue to use virtual inspections for “low-risk” companies that are overseas, enabling the regulator to maintain their inspection program but focus resources on high-risk areas.

Intended Use Instrument Qualification The United States Pharmacopeia (USP) <1058>,1 which covers Analytical Instrument Qualification (AIQ), was updated in 2017 to include more detailed requirements for instrument qualification as well as connecting the requirements for software validation and data integrity.

Many regulated companies operate an Original Equipment Manufacturer (OEM) policy that relies on the instrument manufacturer to provide a qualification program. Following the changes made to USP <1058> in 2017, inspectors now want to see companies performing a detailed risk assessment around how instruments will be used as part of their GxP product test program. The “intended use” of the instruments will then define how they should be qualified to ensure the “range of use” is tested during the qualification. As a result, two companies can be using the same instrument, but they will be analysing different products and using different methods, meaning the qualification requirements will be different.

Many regulated companies are now providing their User Requirement Specifications (URS) to OEM and service vendors to request custom qualification programs to meet their specific requirements and range of use.

Software Qualification and Validation Modern software platforms are designed to be flexible and used across many different industries for various purposes. In today’s modern laboratories, a single instrument can have a variety of applications, but regulated companies expect software to be designed for their specific use to minimise compliance risk and protect the integrity of the data. Software platforms do have the ability to meet the latest regulatory requirements but that depends on the configurable options selected by the end user – compliance therefore comes from choosing the right configuration and proper use.

There is a common misunderstanding within regulated industries about the difference between software qualification and software validation. Qualification checks that the functionality of the software is working correctly once installed, and it is at this point that end users often think their software is validated. Validation, however, is a second process; testing to show that the software has been correctly configured, with all the technical and security controls, and is suitable for the Summer 2022 Volume 5 Issue 2

Qualogy is a GxP regulatory archive and is run by an experienced team whom together have over 35 years’ experience in the industry. We pride ourselves on our high-quality service creating a professional yet personalised approach to handlinig your data. At Qualogy we understand the importance of your data and therefore we do not just see a box - we value its importance.

The Archive Our stand-alone archives are designed for security and protection of your material, with temperature and humidity-control and fire protection. With multiple quality checks we ensure accuracy, professionalism and security every time.

The Service: Our experienced and trained Qualogy drivers offer a door-to-door courier service from anywhere in Europe. As a dedicated Regulatory Archive, Qualogy has exceptionally high standards and vast knowledge of the GxP regulations. We can adapt our services to support your business needs, providing a unique and efficient customer experience.

Contact us today to find out more 01933 357953 | archives@qualogy.co.uk | www.qualogy.co.uk The Archivist, Qualogy Ltd, Po Box 6255, Thrapston, Northamptonshire, NN14 4ZL

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INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY 11

Regulatory & Compliance AQbD requirements to ensure that the methods used for GxP testing are robust and fit for purpose.

regulated workflows to safeguard the integrity of the data. The confusion around these two very different steps means that companies often omit the final validation stage, resulting in significant compliance risks and GxP data potentially not being considered valid.

Data Integrity With the increased use of electronic data, it is imperative to have systems and processes in place to ensure the accuracy, consistency and safety of your data. Using digital workflows within these modern software platforms puts you in the safest position from a regulatory risk perspective. Digital workflows provide the necessary safety net for you to defend the validity of your electronic data and associated results that you may have used to bring drugs to the commercial marketplace. Many companies now perform data integrity risk assessments on software platforms being used within regulated laboratories, changing the software configuration and revalidating to close any data integrity gaps. It is these steps which will minimise future inspection risk.

Evolving Regulations Ten years ago, regulated companies only had to prove to an inspector that they had run a qualification on their instrument.

Now they need to have a customised qualification programme, based on their specific user requirements and intended use.

Laboratories need qualified and validated software, which must have data integrity controls built in. The result is good control around instruments and software and data security, but there could still be questions around methods being run on specific instruments.

Analytical Quality by Design USP reviews its general chapters on a five-year rolling basis so the next revision of USP <1058> is expected towards the end of 2022.

In January 2022, USP published a stimulus paper in Pharmacopeial Forum edition 481 titled “Analytical Instrument and Systems (AIS) Qualification, to support Analytical Procedure Validation over the Life Cycle”. This paper is currently under review by the USP expert committee to determine whether the draft chapter will become official later this year.

The major change to the USP <1058> chapter is the inclusion of Analytical Quality by Design (AQbD) to link in with USP <1220>, another USP general chapter covering The Analytical Procedure Lifecycle that was first issued in 2016.

The <1058> chapter has evolved significantly over the last 15 years. The 2008 revision only included general information relating to instrument qualification. The 2017 revision provided an expanded focus for instrument qualification to include the need to perform risk assessments and intended use qualification as well as covering requirements for software validation and data integrity. The next focus for the 2022 revision is to include 12 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

Many regulated companies have problematic methods which made it through validation processes but prove to be less reliable when used regularly as part of GxP test programs.

Inspectors want visibility of these problematic methods during regulatory inspections and are now expecting to see trend data relating to method performance. The trend data that the inspectors seek is available as digital data (meta data) within the software platforms that you are using to acquire, process and report GxP results. If an inspector observes that you have partial sequences with failed System Suitability Testing (SST) within your software, it will be a red flag that your method is not robust and may be impacting the quality of the data it produces.

This may lead to an inspection observation requesting that the method be re-developed and re-validated to improve its robustness.

Compliance isn’t Optional Maintaining a compliant and effective laboratory is getting increasingly complex. Moreover, compliance isn’t optional – failures are penalised, and non-compliance behaviour can have a negative impact on the credibility of a company. For example, warning letters are published in the public domain on various regulated body websites such as FDA Data Dashboard, Health Canada and the Eudra GMDP database.

Meeting complex regulations isn’t just top of the agenda for a select few sectors like pharma and biopharma, which may come to mind first for being traditionally regulated. Emerging industries across food and beverage, environmental and lifestyle sectors are also being subjected to increased regulations.

It is therefore essential for regulated laboratories of all sizes to work with trusted partners that have the right experience and tools to help them optimise workflows while also maintaining the highest possible compliance levels. This approach will help minimise inspection risks.

REFERENCES 1.

https://www.agilent.com/cs/library/whitepaper/public/compendiumLED-compliance-USP1058-5994-1134en-agilent.pdf, visited on 16 March 2022

Garry Wright Garry Wright is the European Laboratory Compliance Specialist for Agilent Technologies and a member of the Agilent Compliance Council. Garry worked in Regulated Pharmaceutical industry for 20 years prior to joining Agilent. His industrial experience focussed on development and implementation of Quality Management Systems, GMP training and Compliance Auditing. Garry’s role within Agilent is to provide Compliance Consulting services to Agilent and our customer network. Garry has presented topics relating to Regulatory Compliance, Data Integrity and Equipment Qualification at a variety of Compliance forums over the last 7 years since joining Agilent.

Summer 2022 Volume 5 Issue 2

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INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY 13

Regulatory & Compliance

Understanding and Overcoming the Challenges of Flow Cytometry Flow cytometry is a powerful analytical tool that is widely used throughout drug development in various capacities.

With an understanding of the range of applications flow cytometry offers, it is clear why it is heavily implemented in drug discovery and development. Studies have the ability to detect the expression of cell surface and/or intracellular molecules, determine the proportion of cell types within a heterologous cell population, and analyse cell volume and size.

However, the flexibility offered means goal-guided careful study design and a thorough technological understanding are required to define and inform panel selection, compensation, and gating in flow cytometry.

In this article, Director Scientific Engagement at Crown Bioscience, Pirouz Daftarian explores these requirements and highlights the need for drug developers to ensure that flow cytometry studies are purpose-driven in their design, to realise a world where patients get the right treatment at the right time.

The Wide Applications of Flow Cytometry Flow cytometry offers the ability to analyse the chemical and physical characteristics of thousands of cells relatively quickly.

Although flow cytometry can be used to distinguish between certain unlabelled cells, it is most often used to measure the fluorescence emission of fluorochrome-labelled reagents. These reagents are typically antibodies, cell tracers, cell trackers or conjugates that specifically bind to particular cell-associated antigens (markers). As different fluorochromes are excited at different wavelengths, many different fluorochromes can be used to specifically detect various markers within the same study. This allows flow cytometry to not only be used to study marker binding but also to differentiate and discriminate between subsets of cells by using markers known to bind to specific cell types.

Flow cytometry is inherently intricate. As well as careful selection of the best markers and fluorochromes for the study – and ensuring the instruments used can excite the fluorochromes – correctly analysing the data collected is also critical. Analysts must ensure the purpose of the study is defined, the use appropriate controls, define the validation parameters, consider signal-to-noise compensation, and have a robust gating strategy.

Recognising the Challenges of Flow Cytometry With so many considerations to be made throughout a flow cytometry study, it is imperative to pre-empt common challenges.

This is particularly important when using flow cytometry to determine potential candidates for Investigational New Drug Applications (INDs), where understanding the mechanism of action (MoA) of a molecule is vital for effective clinical trial design.

14 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

The Purpose of the Study is Fundamental to Study Design Before starting any flow cytometry experiment, it is essential that the purpose of the study and the hypotheses it is based on are clearly defined. Setting the validation parameters, designing the reagent panel, choosing a gating strategy, and many other decisions made throughout will be dependent on understanding the purpose of the study.

If these decisions are not made with the purpose in mind, an abundance of data could be collected that does not answer the original hypothesis or could potentially lead to erroneous conclusions being made. As time is often critical in IND applications, it is vital to avoid poor study design which relies on a strong understanding of the principles of flow cytometry and its limitations.

Designing the Reagent Panel Can be Complex Panel design in flow cytometry encompasses the selection of a combination of reagents (usually fluorochrome-labelled antibodies) that recognise specific antigens on the surface of cells within the sample cell population. Commonly, panel selection will use a hierarchy approach to differentiate cells, with the reagent with the brightest fluorochrome having specificity to the smallest target cell population.

By selecting the right panels, misleading or non-specific binding of antibodies to the cells in the sample population can be avoided. However, this often relies on a strong understanding and familiarity with flow cytometry, as there are many factors that will impact panel selection. Depending on the study, these factors could include the size of the antibody, how the reagent binds to the marker, and whether binding could impact other cell interactions. Binding studies may be required prior to flow cytometry to elucidate these potential interactions.

Validation Parameters will Depend on the Purpose From the onset of the study, the validation parameters should be defined to ensure that the data are credible and reproducible within and between laboratories. These parameters will depend on the nature of the study; for example, if the study uses live cells, parameters should be set to ensure the viability of cells is maintained.

As well as the markers selected to achieve the goal of the study, another aspect that is important in validation is the choice of reagents that are specific to these markers. There are many commercially available antibodies of different sizes that offer various fluorochrome intensities and it is essential that those chosen are validated. This validation should ensure that the selected antibodies do not cross-react or bind non-specifically throughout the study.

Collecting Events for Statistically Significant Results When carrying out reagent panel design, the estimated proportion of target cells within a heterologous cell population Summer 2022 Volume 5 Issue 2

Regulatory & Compliance must be considered to ensure that statistically significant data is collected.

Low frequency of the target cell population is a common challenge in immunological studies. Occasionally, the proportion of target cells in a population may be so low it will not be detected by flow cytometry. This can be overcome in some circumstances using in vitro vaccination or in vitro culture to expand these low-frequency cells. However, using in vitro expansion methods could mean the results are no longer truly representative, and the decision to use these methods will be dependent on the purpose of the study.

A Goal-guided Gating Strategy When designing the study, the gating strategy should be carefully considered with the purpose of the study in mind. Setting the gates incorrectly can mean the target cells that the study was developed to understand could be missed completely.

Fluorescence minus one (FMO) controls – where each control sample includes all fluorochromes except one – can allow for a highly accurate gate boundary to be set. Although FMO controls may not be needed in cases where well-defined positive and negative populations exist, these controls can be critical when there are rare cell populations or antigens with low expression. Additionally, FMO controls can be used to identify self-aggregation of antibodies. As setting up these controls is time-consuming it is essential that their need is determined during the early stages of study design.

Selecting and Including the Right Controls There are five main types of controls that should be included in flow cytometry studies: 1.

Instrumental controls These controls ensure the flow cytometer and its components are working as intended.

2.

Compensation controls When two or more fluorochromes are used, compensation controls are needed to correct spill over of emissions into other channels.

3.

Gated controls These controls will help to set the gate (the area on the scatter plot or histogram produced to identify and define subsets of populations).

4.

Isotype controls By using antibodies that are the same class and type as the primary antibody but lacking specificity to the target, isotype controls can be used to identify issues with the protocol.

5.

Experimental controls Negative controls should identify false positives resulting from nonspecific antibody binding using cells known not to express the marker of interest. Positive controls with cells that express the target marker can be used to identify faulty antibodies causing false negatives.

Key Lessons Flow cytometry is a powerful analytical tool that is instrumental www.international-biopharma.com

in drug discovery and development. However, the wide variety of potential applications and many factors that must be considered throughout, including panel design, determining the necessary controls, and validation, lead to many potential challenges. It is therefore important to identify those with expertise and experience in flow cytometry who can help to overcome these hurdles and to ensure successful analysis and delivers to the purpose of the study.

Pirouz Daftarian Pirouz Daftarian completed his PhD training in immunology in the Faculty of Medicine of the University of Ottawa, in 1998. Since then, he has been leading studies on cancer immunology, vaccines and inflammation, in academia, and biotech. He joined Crown Bioscience / JSR Life Sciences in 2017 and led the developing applications for IO products and as a Director of Scientific Engagement for Inflammation and In Vitro IO. Of prior experience, pirouz was with NGM Biopharmaceutical, was a faculty at Miller School of Medicine of U of Miami and a Head Scientist, Cancer Biology, at IMV Inc. Pirouz has authored > 80 peer reviewed papers, has served as a reviewer of DOD, NIH, NCI, is a reviewer for several journals, and acted as a consultant to pharma and biotech companies.

INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY 15

Application Note

How to Hire a Translation Agency

8 Steps Every Clinical Team Should Take to Find the Right Translation Partner Choosing the right medical translation provider can help in-house regulatory and clinical departments and contract research organisations support strategic growth while controlling costs and minimising risk. In this practical guide to hiring a translation agency, we discuss eight key steps to take when choosing a vendor, ranging from assessing domain knowledge to managing liability and security.

It is a familiar scenario: the portfolio manager or project manager receives a call from an internal business unit or subsidiary. Management has approved a new trial concerning multiple sites and countries that they need the start-up team to manage. Translation will be required and the budget and timeline are limited. The clinical team sizes up their options and calls their trusted sites. Do they have a local contact they could use, and how much will it cost? Will the study follow the new CTR 536/2014 requirements and be submitted in the Clinical Trials Information System (CTIS)? Have all the necessary patents been requested?

Such a scenario can cause a sharp intake of breath for even those clinical departments with a well-managed network of local partners in place. The local site may not have the necessary skills to relay the trial documentation in plain language for instance. Alternatively, it may be cost prohibitive or unfeasible to use local sites to perform translations as local sites may still be charging by the hour. Furthermore, ‘translation’ may be far down the priority list in comparison with other activities required during the study.

There can be issues of consistency or quality too. Where work is scheduled as a one-off and under time or budget constraints, how can you be sure that the translations will be understood by trial subjects or accepted by regulators?

Clinical documents might not be scrutinised until they are needed most – for example, during the ICF review and signature stage. If quality is not assured early, there is a real risk that the sponsor will pay later either through additional costs, delays to the clinical trial or a risky misunderstanding by a trial subject.

When we talk about translating plain language summaries (PLS), the use of inadequate wording or approaches can also have drastic consequences. Trial subjects and carers must understand the study requirements, the due diligence required to participate or the reasons why the drug may not have the desired effect. Lack of understanding may drive subjects away from participating in the study.

Providing Consistency Across All Operations Working with a Language Service Provider (LSP) that provides translations across all relevant medical fields, from clinical and pharmacovigilance to product registration and marketing 16 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

helps to streamline the management of translation tasks and build consistency across all translated materials.

As sponsors and CROs know all too well, translating clinical texts is not the same as translating standard documents or training materials. The influence of non-specialist language coupled with insufficient knowledge of the therapeutic area

5 Reasons Clinical Documents Require Professional Translation Support 1. Domain Knowledge Sourcing translations for global clinical trials starts with recruiting linguists with knowledge of the relevant market, therapeutic area, document types, audience and linguistic preferences. Oftentimes, clinical texts can be highly medical and these should not be entrusted to providers without domain-specific experience. Domain-experienced LSPs should be aware of, and help you adhere to, essential legislation like the EU Clinical Trial Regulation.

2. Local Knowledge Established LSPs show awareness of local linguistic nuance, familiarity with diverse document types, appropriate register (scientific or lay), as well as the need for formal certification, legalisation or notarisation.

3. Certifications of Accuracy Clinical documents require certification that translations have been accurately performed.

Certification gives those parties that rely on the documents the added confidence that the translation has met the agreed standard.

4. The Right Language To effectively manage global clinical trials, sponsors and CROs insist upon a diverse team of qualified linguists. Also essential are agile and ISO-audited recruitment processes allowing to scale at speed according to changing linguistic requirements.

5. Risk Mitigation A company’s reputation can hinge on the quality of their translated materials. Errors and inaccuracies can increase regulatory hurdles, undermine a company's strategy or cause misunderstanding among trial subjects.

In addition, having to find and correct errors introduces additional cost and takes time, meaning that both profit margins and schedules are negatively affected.

Summer 2022 Volume 5 Issue 2

Application Note introduces the risk of confusion among trial subjects or unwanted regulatory roadblocks.

As sponsors typically give each department the authority to choose their preferred language service providers, it’s common to rely on one LSP for clinical trials, another for corporate translations, another for marketing authorisation applications and another for patents, for example. While the technical expertise of the different providers is crucial in such scenarios, so too is the need to ensure security and quality across translations, and to set clear deadlines.

Using multiple translation suppliers can be not only time-consuming and inefficient but also risks undermining efforts to achieve a consistent quality standard in a cost-effective manner.

LSPs, in contrast, prioritise translation consistency and quality. They combine in-house production management with global freelance linguistic talent to offer a single trusted resource for language services, adhering to tight timeframes and pre-set budgets.

It is for these reasons that the emerging best practice among successful CROs is to unify traditionally disparate language requirements under one or two high-performing LSP. Choosing the Right Provider: A Step-by-Step Guide Today’s sponsors and CROs operate in an increasingly global marketplace. Within the Life Sciences especially there is a need for compliant and accurate translations no matter the target language. As the need for translation grows, so too do the risks and potential costs of getting it wrong. Avoid the potential pitfalls with our step-by-step guide to choosing a provider.

Step One: Identify Your Needs It may seem obvious, but if your documentation is specific to the domain of clinical research then the LSP must have proven experience with the clinical trial process and a track record of accurately translating the relevant documentation.

An experienced LSP will not only help you identify and assess the documentation you need to translate, but also help you estimate a translation budget for your entire clinical trial.

Step Two: Chart the Workflow Time is of the essence when setting up and recruiting subjects for a clinical trial or responding to adverse event reports.

Understanding the translation requirements and outlining a tailored, semi-automated workflow early in the process is crucial. The agreed workflow can include back translation, linguistic validation, certification and also allow time for all of the necessary review and approval processes.

Step Three: Match Those Requirements with Providers Does your LSP have the necessary domain knowledge, languages, and turnaround times that you and your clients need?

Not all LSPs specialise in Life Science translations, so it may be that your existing vendor struggles to provide end-to-end www.international-biopharma.com

support across your entire industry. Rather than finding this out through quality issues, be open about the needs of all departments and seek out an LSP who is competent at unifying them.

Accurately translating your company’s message (whether clinical, regulatory, advertising or training, etc.) requires in-depth knowledge specific to each domain. For example, to translate an informed consent form (ICF) or a clinical trial summary, sponsors require a translator to be familiar with the therapeutic area as well as the language and culture of the region in which the trial is taking place.

As well as the idiosyncrasies of local languages, your chosen translation vendor needs awareness of specific glossaries such as medDRA where applicable. This will impact terminology choices and understanding by the target reader. Equally important is knowledge of any technical or scientific field or discipline covered by the text.

It is also appropriate and advisable to request references from any agency you consider working with. Do not hesitate to ask for references in your same field to ensure that the vendor has relevant previous experience.

Step Four: Consider Your Security, Confidentiality, and Governance Requirements No matter the content of your documents, your translation vendor should always have processes in place to ensure the security and protection of your confidential information both in transit and within their systems. Ideally, your chosen vendor should possess ISO certification and/or SOC 2 Type II security certificates. Be sure to discuss these issues in advance of sending content to your vendor.

Step Five: Make Sure You’re Covered Initiate conversations about diverse translation requirements in your vendor selection process. Your vendor should carry public liability insurance at levels commensurate with the financial penalties that are commonplace in your area of specialisation. Request proof of coverage to ensure that you are protected against translation mistakes, negligence, and data breaches.

Step Six: Manage Costs No one wants to deal with hidden charges and unexpected costs. Professional LSPs will always provide complimentary quotes that clearly detail all costs, often itemised by language.

Any changes to the quoted costs should be communicated to you by your project manager for approval in advance of being added to an invoice.

Step Seven: Run a Test Translation If time allows, run a test translation project with the providers you are considering. This will allow you to compare costs, turnaround times, and customer service across all of your potential vendors. Most LSPs will complete small sample translations (of 500 words or less) for free, but may charge for larger tests. If your budget allows, it is best to request test translations using at least 2,500–5,000 words of source content. This will give you the best sense of whether a vendor can meet your needs.

INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY 17

Application Note Global Reach, Local Expertise BIG Language Solutions supports sponsors and CROs with fulfilling a wide range of translation requirements across diverse practice areas. Our expertise spans a wide range of disciplines in over 200 languages, and guarantees you the translation support you need to successfully operate global clinical trials.

Security First We take a 360-degree approach to the translation process, looking at the bigger picture to extend security beyond our internal platform so that all touchpoints – people, processes, and technology – are fully secure. Our entire translation approach and IT infrastructure are compliant with ISO standards 9001, 17001, and 27001 for quality, impartiality, and IT security, and we are SOC 2 Type II audited.

A Trusted Methodology We follow a three-step quality process for every translation that we deliver. Our process ensures we deliver authoritative and accurate translations that support your success and help you mitigate unnecessary risk:

Step Eight: Extend the Partnership Once you have successfully completed a test translation and selected a vendor, consider unifying the requirements of other teams in your company in order to benefit from synergies across departments. For example, BIG Language Solutions utilises various tools that help ensure consistency within documents and across multiple related projects by capturing and cataloging frequently used, specialised words and phrases that may be accessed during translation. BIG Language Solutions automates aspects of its workflow management to expedite the translation process where possible and deliver high quality translations in a timely fashion.

Why Hire a Translation Agency?

While many businesses operate globally, sometimes it can be hard to locate and enrol trial subjects across multiple sites/ countries. Composed of various regulations and cultural perspectives, international regulatory systems are made up of a patchwork of different legislations, regulations, and directives, all with diverse and often inconsistent procedures, timeframes, and costs.

For in-house clinical and regulatory affairs departments to navigate this global landscape requires project management and language talent operating locally.

Traditionally, in-house teams have had no choice but to build a network of external advisors to meet their ever-changing needs. Meanwhile, language services providers have invested heavily in processes and technology to minimise cost and timelines without negatively impacting quality.

Outsourcing life science translations to a professional translation agency with local presence thus offers a quicker, more consistent, and more cost-conscious alternative to utilising unqualified, unreliable resources.

18 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

1.

Expert Translation Done by a Qualified Professional Each translation begins with an experienced linguist with an advanced degree in the subject matter. We require all linguists to pass a robust proficiency test that is overseen by our Medical Director who is a physician and professional translator. Less than 6% of candidates pass this initial stage. Those who do must complete evaluation to allow us to further assess their background, translation proficiency and industry expertise.

2.

Independent Reviews Unless otherwise agreed, every medical translation is revised by a second specialist translator.

3.

Final Quality Assurance Review & Project Requirements Evaluation Finally, QC checks are performed against your project brief and then a dedicated project manager packages and delivers the translation in accordance with your specific instructions.

DWL DWL, A BIG Language Solutions Company is a global leader in medical translation services, providing specialised services across more than 300 languages. Drawing on 50+ years of experience, our united team of medical translation specialists provides prompt, secure, and cost-effective solutions to global pharmaceutical companies, CROs, universities, medical device companies and regulatory consultancies. Whether we're supporting global clinical trials, marketing authorisation applications or device registrations, our stringent quality assurance protocols ensure commercially sensitive data and documents are safeguarded and translated to the very highest standard.

Contact us to discuss your medical translation needs.

Summer 2022 Volume 5 Issue 2

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© 2022 FUJIFILM Wako Chemicals USA INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY 19

Research / Innovation / Development

PEER REVIEWED

Accessing Greater Dimensions of Biological Understanding Through LC-MS Proteomics Proteomics has the potential to answer vital biological questions, optimise drug development and improve clinical care. Seeing these benefits, more researchers are embracing proteomic profiling, driving demand for ever-larger proteomics studies and the high-throughput techniques needed to deliver them. But, while available affinity-based methods can provide high-throughput proteomic analysis, their specificity may be low. Luckily, liquid chromatographymass spectrometry (LC-MS) can effectively address the shortcomings of affinity-based approaches, offering both depth and throughput of data. This article discusses the evolution of high-throughput proteomics, the opportunities presented by LC-MS, and how companies are helping researchers to use this technology to drive the advancement of clinical research and care.

The rich information contained in biopsy samples can offer crucial insights into many different diseases. To access this information through biopsy sample profiling, next-generation sequencing (NGS) has traditionally been the method of choice, as it can pick up somatic mutations, helping to identify cancerrelated genomic alterations. However, much of the data gathered from mutations is inconclusive, meaning it is not always possible to link and correlate genomic data to direct the best cancer treatment. Now, biopsy profiling can be performed using deep proteomics capable of near-proteome-wide coverage, providing a whole new dimension of understanding regarding the impact of genomic changes. This is because, while genomics can identify genomic variants, proteomic profiling elucidates phenotypic information, revealing more detail about biologically meaningful changes that result from these genomic variants. With the ability to characterise drug action and diseases in a way that can be used to better direct treatment options, deep profiling using a proteomic approach represents a powerful tool to improve healthcare.

The Benefits of Proteomic Profiling Within the past decade, proteomic profiling has rapidly expanded due to methodological advances and application to exciting new research areas. But what exactly is proteomic profiling?

Proteomics refers to the in-depth study of the protein complement of a genome. Typically, proteomic profiling takes one of two forms – unbiased or targeted – with each providing different insights invaluable for drug discovery and clinical care.

Unbiased proteomics – also known as discovery proteomics – explores all proteins detectable in a sample, without predefining specific proteins of interest. This makes unbiased proteome profiling exceptionally useful for supporting drug discovery through identification of new drug targets, exploring modes of action (MOA) and unveiling novel biomarkers. Targeted proteomic profiling, on the other hand, identifies and quantifies ions of specific mass at a specific time, and effectively filters 20 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

out background noise. This makes the method highly useful for measuring predefined proteins and proteoforms, even in complex samples. Importantly, the ability of targeted proteomics to quantify a predefined panel of proteins makes the method useful in clinical care. Targeted proteomic profiling is already being used in clinical trials for pharmacodynamic biomarkers to inform dosing decisions.1 With such benefits, it is clear that proteomic assays will be increasingly used to support and enhance future clinical trials to provide a deeper understanding of how the full proteome changes in disease. Demand for proteomic profiling is therefore increasing, with a major focus on larger studies that can tackle the dynamic nature of the proteome. This means new advances and technologies – particularly high-throughput methods – will be required.

Challenges in Proteomic Profiling: Depth, Throughput and Dynamic Range Should you choose depth or sample throughput? This was traditionally one of the biggest challenges researchers faced when taking a proteomic approach, because conventional approaches are generally able to provide only one or the other.

However, both factors are vital to truly understand biology. As an additional challenge, the dynamic range problem in proteomics needs to be addressed – a single cell can have six orders of magnitude of dynamic range from the lowest to the highest copy number protein (Figure 1), yet current techniques are not sensitive enough to accurately quantify miniscule amounts of protein. In other omics-based approaches, such as genomics, this problem can be overcome by using an amplification technique, but equivalent solutions are lacking in proteomics.

Solutions for High-throughput Proteomic Profiling Several companies have addressed the high-throughput problem by using affinity-based panels. These panels use aptamers or highly optimised antibodies to bind epitopes in the target tissue. In more standardised approaches, these assays can be combined with a readout using NGS devices. In some cases, such methods offer high throughput that enables studies of over 10,000 samples. Despite this, affinity-based methods encounter a wealth of significant drawbacks. First, because they don’t provide peptide-level readouts, but only measure the presence of a short epitope on a protein, they can suffer from low specificity. In the event these short target epitopes become inaccessible due to conformational changes or other molecular interactions, further specificity and reproducibility issues emerge. Second, because these methods depend on antibodies or aptamers binding to known protein domains for detection and quantification, they can only offer a targeted, panel-based approach – unbiased exploration is simply not possible. And, without the ability to uncover unknown or less well-studied proteins, their value in discovery applications is severely restricted. Such assays are also confined by the breadth and specificity of the panels and reagents that are available.

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Figure 1: Graph highlighting two critical analytical challenges in proteomics – the broad molecular diversity and large dynamic range of protein molecules and proteoforms at the single cell, cellular tissue and human proteome levels.

Additionally, affinity-based approaches are only applicable to blood-based samples, and no multiplexes or affinity-based methods of a reasonable size for solid tissues are readily available for these yet. This is because non-blood tissue samples are normally preserved as formalin-fixed, paraffinembedded FFPE tissues, which are notoriously difficult to analyse since formalin can induce protein structural changes and cross-link modifications.2 Companies have tried to develop protein sequencing technologies to realise high-throughput proteomics. For a tissue of interest, the proteins or peptides are initially immobilised on a surface, and a degradation approach is then taken to enable the read-off of a sequence of this immobilised target. While this technique shows some promise, the technology is still in its infancy – only fundamental proof-ofprincipal data is available to-date. It is, therefore, difficult to assess the impact of this approach, and the method is far from ready to be applied to complex proteomes.

LC-MS: Delivering Deep Profiling and High Throughput A technique that is showing great promise for high-throughput proteomic profiling is liquid chromatography-mass spectrometry (LC-MS). Today, LC-MS is routinely applied to highthroughput analysis of small molecules and is now increasingly being deployed for deep proteomics. With more recent advances in LC-MS instrumentation, the throughput and scale are changing.

LC-MS methods can address and explore almost all the important dimensions of a protein – from functional aspects, such as post-translational modification (PTM), to structural elements, such as cross-linking, and this can be done at the peptide level across the entire proteome. Since LC-MS www.international-biopharma.com

is tissue-agnostic, any type of tissue or body fluid from any species can be investigated. And, vitally for proteomics, LC-MS is sensitive enough to detect both lower-abundance and higher-abundance proteins, solving the dynamic range challenges that other techniques face.

In stark contrast to affinity-based methods, LC-MS proteomics lends itself well to both unbiased discovery research and pre-defined targeted protein panels. The clinical transferability of the technology ensures that the insights generated in early-stage, unbiased discovery research can be applied in the development of targeted panels for absolute protein quantification in clinical settings.

Despite the benefits, there are key challenges to accessing high-throughput deep proteomics with LC-MS – most notably, the need for a wide skill set that encompasses sample preparation, chromatography, instrument handling and maintenance. On top of this, LC-MS provides multi-dimensional (and often convoluted) data that can be tricky to understand, so extracting useful information from LC-MS requires expert analysis.

It is also challenging to accurately design LC-MS-based studies to obtain the relevant outcome, as proteomics results in finding unexpected and dynamic changes – not just in detecting the presence or absence of a protein. For many laboratories a related hurdle is applying the correct experimental method to the sample, although standardisation of methods can address this shortcoming.

Several other complicating factors are often faced, particularly when scaling high-throughput LC-MS workflows from hundreds to thousands of samples. For example, one INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY 21

Research / Innovation / Development of the main bottlenecks is implementing a reproducible, high-performing and robust method for separations.

Additionally, as a single instrument does not have the capability to run the many thousands of samples needed, multiple instruments must be carefully maintained and controlled to ensure the results are comparable.

Simplifying LC-MS-based Proteomics to Broaden Accessibility In the face of these challenges, several companies are working hard to support researchers to adopt high-throughput LC-MS proteomics. For example, some companies are strongly focusing on automating sample preparation – something which is common for small molecule analyses, but has rarely been used in proteomics until now. Additionally, scalable software has been developed to handle large datasets, and experiments that include randomisation and quality control are being carefully designed – something that has been a roadblock for many non-specialist companies trying to scale their deep proteomics workflows.

Biognosys: Attaining meaningful biological insights through LC-MS proteomics One company that has made significant steps towards LC-MS-based high-throughput proteomics is Biognosys, a global organisation specialising in large-scale proteomics solutions. In a recent pan-cancer clinical study performed on plasma samples from patients affected by lung, prostate, breast, colorectal and pancreatic cancer, the team at Biognosys reported the highest performance to date for single injection methods across hundreds of samples.3 Here, novel biomarker candidates in colorectal and pancreatic cancer were identified, known biomarkers were identified and validated, and new models were developed to classify the disease state.

In a separate study, Biognosys showed MS-based proteomics to be excellent at analysing complex samples preserved using FFPE – the study used more than 1,000 FFPE tissue samples and demonstrated performance rivalling fresh frozen tissue analysis.4 Furthermore, in a joint study with Indivumed,5 Biognosys used an optimised, semi-automated workflow to deeply characterise the proteome and the phosphoproteome of matching normal and tumor samples, obtaining a great depth of analysis. This was the largest protein expression and phosphorylation study ever performed, using thousands of clinical samples. Application of deep tissue-based proteomics in clinical samples was demonstrated in one of the company’s pilot studies, where an unprecedented depth of 13,000 quantified proteins was reached in lung tissue.6 Building on this is Biognosys’ pioneering work in the newly emerging field of immunopeptidomics. To date, the team has analysed lung cancer needle size biopsies, recovering thousands of immunopeptides of excellent quality and reproducibility,7 and through collaboration with Johns Hopkins University School of Medicine, opened a window into the aging brain, showing the potential of MS-based proteomics in analysis of cerebrospinal fluid.8

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Specialist companies such as Biognosys are showing the unmatched precision and depth of LC-MS-based methods in deep proteomic profiling and highlighting its potential to revolutionise the development of personalised clinical diagnostics. Many of the biomarkers identified from studies such as those above came from low abundance regions, and so would have been missed by shallow profiling. Furthermore, such studies have rendered scaled-up deep plasma studies that include a protein depletion step accessible, where they had previously been limited to low throughput.

Maximising Proteomic Impact LC-MS proteomics closes the chasm between depth and throughput, with the capability to analyse more than 10,000 proteins deeply in a single run. However, this doesn’t mean affinity-based methods should be ruled out. For example, affinity methods can be more sensitive in materials such as plasma, and can measure some cytokines that aren’t currently within reach of LC-MS. Because both methods have their own strengths and can offer insight into different types of protein, they can be thought of as complementary: initial screens can provide first-level insight, and LC-MS can play an important role in answering more targeted questions.

At its core, proteomics is the study of proteomes. Often, it is approached purely from the perspective of quantifying proteins, but in reality, it can provide so much more. Proteomics, when its full potential is unlocked, provides rich insights into proteins across multiple dimensions – from levels of expression to functional and structural diversity in different biological contexts. In light of this, and to accommodate its true scope, proteomics should be redefined as the multi-dimensional, at-large characterisation of proteomes. Ultimately, it is the understanding of how proteomes function that is essential to understanding biology – not just their presence and abundance.

LC-MS in Proteomics: A Bright Future The proteomics journey is just beginning. Proteomics data obtained through LC-MS gives phenotypic functional insights far beyond the depth of information that genomics can offer – and the throughput of samples may outpace what’s possible with genomics sequencing runs in the future. We anticipate the volume of proteomics data will continue to grow tremendously, opening many exciting opportunities to accelerate drug development and better enable precision medicine.

Nevertheless, it is vital that the data obtained is made useful. As methods to access high-throughput information are developed, new ways to understand and analyse the data from LC-MS at scale will be needed. Whichever way this is achieved, addressing biological questions from a proteomic perspective will give deep and meaningful answers to solve biology’s most challenging problems.

REFERENCES 1.

2.

Biognosys Partners with Kymera Therapeutics in Precision Proteomics Biomarkers, viewed 4 May 2022, <https://biognosys. com/news/biognosys-partners-with-kymera-therapeutics-inprecision-proteomics-biomarkers/> Gustafsson O. J. R., Arentz G., Hoffmann P., Proteomic developments in the analysis of formalin-fixed tissue, Biochimica et Biophysica Acta 1854 (2015) 559–580.

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3.

4.

5.

6.

7.

8.

Tognetti M., Sklodowski K., Müller S., Kamber D., Muntel J., Bruderer R., Reiter L. Biomarker Candidates for Tumors Identified from Deep-Profiled Plasma Stem Predominantly from the Low Abundant Area. bioRxiv 2021.10.05.463153 [Preprint]. 2021 [cited 2022].

Available from: <https://doi.org/10.1101/2021.10.05.463153> Biognosys Supports Cancer Scout, a Large-Scale Multi-Omics Research Project to Accelerate Personalized Cancer Medicine, viewed 13 Apr 2022, <https://www.businesswire.com/news/ home/20211011005036/en/Biognosys-Supports-Cancer-Scouta-Large-Scale-Multi-Omics- Research-Project-to-AcceleratePersonalized-Cancer-Medicine,> Indivumed Announces Strategic Partnership with Biognosys, viewed 13 Apr 2022, <https://www.prnewswire.com/news-releases/ indivumed-announces-strategic-partnership-with-biognosys300967338.html> Biognosys Reaches New Milestone in Tissue Proteomics, viewed 4 May 2022, <https://biognosys.com/news/biognosys-reaches-newmilestone-in-tissue-proteomics/> Tognetti M., et al. 2022. Discovery of MHC Class I and Class II Neoantigens in Lung Cancer in Needle Biopsy Tissue Samples Using an Optimized High-throughput Workflow. [E-Poster, AACR 2022].

Available from: https://biognosys.com/resources/discovery-of-mhcclass-i-and-class-ii-neoantigens-in-lung-cancer-in-needle-biopsytissue-samples-using-an-optimized-high-throughput-workflow/ Feng Y., et al. 2022. Quantitative Dissection Of Healthy Aging And Cognitive Decline Using Proteoform Signatures From Paired CSF And Plasma. [Poster, ADPD 2022]. Available from: https://adpd.

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kenes.com/wp-content/uploads/sites/148/2022/02/ADPD22-FullAbstracts-Feb-14-2.pdf

Dr. Andreas F.R. Hühmer Dr. Andreas F.R. Hühmer is currently the Senior Marketing Director of Omics at Thermo Fisher Scientific in San Jose, CA. In his current role, he directs the day-to-day marketing business and leads strategic initiatives in emerging areas of OMICS.

Oliver Rinner Oliver Rinner is co-founder and CEO of Biognosys. He led the company from a spin-off from ETH Zurich in 2008 to a marketleading inventor and provider of proteomics technology and solutions today. Rinner joined the group of proteomics pioneer Ruedi Aebersold at ETH in 2005, where he worked on the development of technologies for targeted and structural proteomics, contributing to the seminal papers and patents that laid the foundation of next-generation proteomics.

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Corporate Profile

Byondis: A Passion for Patients and Precision Medicines The name says it all. “Byondis, pronounced ‘beyond this,’ is about going beyond the standard of care to provide novel treatments with high efficacy and low systemic toxicity for patients with unmet medical needs,” says CEO Marco Timmers, Ph.D. Based in Nijmegen, the Netherlands, Byondis started in 2012 as a subsidiary of Dutch-based generics pharmaceutical company Synthon. After Synthon became a recognised global entity, its co-founder Jacques Lemmens, Ph.D., redirected his focus -- from producing affordable versions of off-patent medicines, to creating next generation precision medicines to outsmart cancers and autoimmune diseases.

That was always Lemmens’ plan. The inventive entrepreneur and scientist, now Byondis Founder and Chairman, dreamed of creating “new molecules that matter, leading to medical breakthroughs.” Ten years later, the company, which separated from Synthon and rebranded as Byondis in 2020, has a broad development pipeline built on proprietary technologies, and comprising preclinical as well as early- and late-stage clinical development programs. This includes lead program [vic-]trastuzumab duocarmazine (SYD985), an antibody-drug conjugate (ADC) currently under U.S. regulatory review.

“Byondis employs the latest insights in tumour biology and immunology to search for new molecular targets and develop new mechanisms for ADCs, monoclonal antibodies (mAbs) and small molecule programs,” Timmers explains.

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The company’s next generation ADCs employ its proprietary duocarmazine linker-drug technology, ByonZine®. “ByonZine is responsible for our ADCs’ high stability in circulation and ability to efficiently release the cytotoxin in the tumour,” says Chief Scientific Officer Wim Dokter, Ph.D. In addition, Byondis’ site-specific antibody conjugation technology, ByonShieLD®, uses a controlled method of connecting the linker-drug to the antibody. “This enhances the ADCs’ antitumour activity, while helping to streamline the manufacturing process,” Dokter says.

With a dedicated team of about 400, including highly educated scientists and skilled technicians working in state-ofthe-art R&D and Good Manufacturing Practice production facilities, Byondis creates both targeted and immuno-oncology [IO] therapies.

Byondis four-phased value creation strategy: 1.

2.

Following positive results of the pivotal Phase III TULIP® study investigating SYD985 in HER2-positive metastatic breast cancer, Byondis submitted the Biologics License Application to the U.S. Food & Drug Administration. The company has also entered into a License and Collaboration Agreement and a Supply Agreement with Germany-based medac to commercialize SYD985 in Europe and the UK, pending regulatory approvals.

The potential of SYD985 in other clinical indications is being explored. A Phase II trial is evaluating the safety and efficacy of SYD985 as a standalone therapy in HER2-expressing metastatic endometrial cancers.

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Corporate Profile

3.

4.

Three new programs are planned to enter clinical development, with preclinical data suggesting a promising therapeutic window in patients:

• •

•

•

BYON4228, a mAb, is the lead cancer immunotherapy from Byondis’ next generation IO program. The mAb targets SIRPα, which increases the tumour-killing capacity of the immune system.

• BYON3521 is an ADC that targets c-Met, which is widely overexpressed in various solid tumours.

• BYON4413 is an ADC directed against the molecular target CD123, which is expressed in many hematooncological malignancies.

The company continues to identify research programs ensuring a sustainable R&D pipeline in the coming decade.

In its early discovery pipeline, three new platforms were identified, including:

A novel linker-drug technology to generate IO ADCs A linker-drug technology to generate ADCs with potential in both oncologic and other indications, such as autoimmune diseases A platform to increase the tumour-specificity of mAbs and ADCs

Byondis regularly collaborates with leading global biotechnology and pharmaceutical companies, as well as many academic research institutions. While uniquely positioned to take its innovative portfolio beyond the laboratory, up to and including pivotal clinical studies, the company welcomes partners and collaborators to help speed its medicines to those who need them.

They call this “making hope real.”

For more information, visit www.byondis.com.

Corina Ramers-Verhoeven Corina Ramers-Verhoeven, Byondis Vice President, Corporate Communications, is a healthcare corporate affairs, government affairs and communications professional with more than 25 years’ experience working for global pharmaceutical corporations and governments, national health agencies and media outlets. Prior to joining Byondis in 2020, Corina worked in leadership positions at Johnson & Johnson’s Janssen Vaccines & Prevention, Eli Lilly and Company, Schering-Plough and Organon BioSciences.

Email: communications@byondis.com Web: www.byondis.com

www.international-biopharma.com

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Research / Innovation / Development

PEER REVIEWED

Working in Tandem: Formulation Science and Drug Delivery Device Design The need to continue to innovate with drug delivery devices has been a focus for medical device companies over the past couple of decades. With self-administration of injectables increasingly prevalent, manufacturers must balance the use of new technologies with the need to make products as simple and user-friendly as possible. At Owen Mumford Pharmaceutical Services we acknowledge the importance of understanding the key trends in formulation science and how this may impact the development of new medical devices for subcutaneous administration. We recently conducted in-depth interviews with experts in pharmaceutical formulation science and device development from the US, UK, Ireland, Germany and India to understand where innovations will be directed in the coming years. This article will examine in more detail how these twin areas must work in tandem to create optimal solutions and deliver drug device combination products that can accommodate a wide range of patient needs.

Usability vs Innovation Usability factors and advances in drug formulation or technology can sometimes be at odds with one another. While medical device manufacturers may want to take advantage of new technologies and create more sophisticated devices, increased adoption of drugs for self-administration mean drug delivery devices must continue to be user friendly for a wide range of patient demographics. More complex electromechanical devices are being developed to include additional features – such as injection speed and depth settings as well as electronic patient notifications. However, devices with increased complexity may be confusing for some patients to understand and use correctly.

Simpler, intuitive devices that minimise user steps are more likely to encourage patient adherence to their treatment and minimise the risk of user error. Streamlined products focusing on key features – such as clear end-of-dose indicators – may be more successful than complex, less intuitive devices. However, connectivity and the range of additional benefits it offers not just patients but other stakeholders is still likely to play a key role in the future of medical device development. Pharmaceutical companies will seek to adopt drug delivery devices which incorporate essential elements of connectivity but ensure they remain intuitive and simple for all patients to use.

Injection Frequency vs Injection Experience Another element in improving the patient experience and potentially therapy compliance is reducing injection frequency.

Recent innovations have seen dosage administration reduced to only once a quarter. Efforts to reduce the number of injections required include the development of long-acting and extended-release formulations. Injection frequency can also be reduced by increasing drug volume and/or in case of biologics, viscosity. However, this can make administration more challenging for patients. Changes in needle length and gauge 26 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

size can impact the user experience as well as the device hold time, all important variables to be considered. Currently, the FDA guidance is to keep injection times to within 10 seconds – companies will need to find ways to deliver large volumes and higher viscosities without exceeding this duration. For larger volumes, formulation scientists will also need to address drug diffusion challenges and the possibility of reverse ‘wet injections’. Alternative delivery devices such as transdermal and wearable products can accommodate much larger volumes without presenting the same concerns, and product development is ongoing in this field.

To accommodate higher volume formulations, drug delivery device manufacturers are adapting their device designs.

With the increase in biologics there has already been a move from 1mL to 2mL devices with exploration of 3mL-plus volumes well underway. Devices which accommodate 2.25mL pre-filled syringes therefore have a distinct advantage in this market segment. Additionally, two-phase autoinjectors with independent needle insertion and dose delivery provide a more consistent patient experience during administration, even with volumes up to 2mL. Recent pain tolerance studies have shown that increasing fill volumes does not necessarily create a more uncomfortable experience. Introducing novel excipients which numb the injection site and dilate the injection area could reduce discomfort caused by larger volumes.

Both device and pharmaceutical manufacturers realise the necessity of focusing on patient experience at the earliest stages of combination device development. Designing through a patient-centric lens with a thorough human factors process helps to create devices that accommodate the various challenges that patients may face and to adapt devices accordingly. Through this structured approach, manufacturers can refine comfort, convenience and usability of delivery devices for their intended patient population taking into account age and gender as well as any physical or cognitive impairment. Extended-release formulations and novel delivery systems – such as wearable devices – will continue to interest medical device manufacturers moving forward due to their potential to innovatively solve drug delivery challenges for self-administration. However, they can also present additional challenges which need to be overcome such as compatibility with existing primary containers or the need to create novel ones.

Biologic Stability: A Multifaceted Issue There are a number of elements that affect biologic stability.

Manufacturers must bear in mind how a medication will interact with excipients, primary containers, oxygen and light and high extrusion forces. New excipients, such as artificial sugars, can help with biologic stability. For instance, cyclodextrins can prevent protein aggregation, while also reducing the viscosity of biological formulations, and improving injectability.1 However, novel excipients are being developed with caution as companies seek to avoid exceeding IID (Inactive Ingredients Database) limits, Summer 2022 Volume 5 Issue 2

Research / Innovation / Development

which would lead to potentially costly and time-consuming efficacy and safety studies. Innovations in primary containers have focused on creating glass coatings to enhance stability or attempting to reduce the risk of protein aggregation caused by silicon through the use of containers made with novel new plastics which do not require a lubricant.

Stability studies conducted after launch can provide a commercial advantage to manufacturers. Successful studies can extend the shelf life of a product beyond the typical 2–3 year mark. One key strategy to increase stability is through lyophilization (freeze drying) but with self-administration becoming increasingly desirable this can create challenges for device design and, hence trends have moved towards liquid biologic formulations for prefilled syringes and auto-injectors.

Although storage below room temperature can help to extend the shelf life, it relies on the patient remembering to keep the drug refrigerated and to remove before use. In the case of biologics, this is especially important as low temperature increases viscosity – making user experience more uncomfortable.

Steps Towards Sustainability Focus on sustainability has increased significantly over the last few years with a variety of groups lobbying for a greener industry. Efforts are being made to develop new reusable devices such as reusable autoinjectors, as an alternative to disposable designs, to reduce the level of wastage especially associated with frequent administration. In addition, there is focus on increasing the use of alternative materials such as upcycled engineering plastics. However, the practicality of these efforts is still to be proven in terms of real-world sustainability and cost across the life of the product from manufacture to disposal.

For this reason, environmental initiatives are mainly focused on the manufacturing process and reducing waste as well as 27 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

formulations allowing for less frequent injection. Reusable drug delivery devices with connectively features are likely to become increasingly common in the drive to produce less waste, however these present challenges for safe disposable or recycling of their electronic components.

This summary of the current developments in drug formulation and device design highlights how intertwined these two areas are, and how important collaboration will be to develop combination products that are cost effective and continually improve the patient experience regardless of the drug formulation. Critically, any innovations should not significantly reduce user comfort, convenience, or ease of use otherwise they may impact therapy adherence and influence the success of a product.

REFERENCE 1.

Cyclolab, Cyclodextrin enabled biologics, https://cyclolab.hu/ userfiles/Cyclodextrin%20enabled%20biologics_website.pdf

Julie Cotterell Julie Cotterell has over 20 years of sales and marketing experience, including regional, national and global roles. She has a wealth of knowledge on different aspects of drug delivery and the associated devices, and is particularly interested in bringing to market products that can allow patients to be treated as simply and effectively as possible.

Before joining Owen Mumford Pharmaceutical Services in 2018, Julie worked for both pharmaceutical and medical device companies, including Baxter, BD and Smith & Nephew.

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Application Note

Developing Stable Lentiviral Cell Lines Introduction Lentiviral vectors (LVV) are commonly used as gene delivery tools for cell and gene therapies, notably chimeric antigen receptor (CAR) T cell therapies. Like other retroviruses, lentiviruses can convert their single-stranded RNA genome into double-stranded DNA when integrating into the genome of a cell. Unlike other retroviruses, lentiviruses can transduce non-dividing and quiescent cells, which makes them highly suitable for use in cell therapy.

The positive effects of novel cell therapies on malignancies, followed by the approvals granted by regulatory bodies such as the FDA and EMA, led to an increased interest in cell therapies. This in turn has led to an increased number of clinical trials and a growing demand for lentiviral manufacture. Process scalability and robustness are therefore essential to ensure consistent and reproducible production, maximise yields and lower costs.

Lentiviral vectors are often produced in HEK293 cells transiently transfected with four (or more) plasmids that contain all the genetic material required for vector production (GagPol, VSV-G, Rev and Lentiviral genome gene of interest (LV_Genome_GOI)). However, while transient systems are useful in some contexts, transient systems can often be subject to more variability, a higher cost and larger amounts of complexity than stable systems.

The development of stable packaging and producer cell lines, which integrate some or all of the lentivirus elements into the host cell genome, could provide a simpler, more scalable alternative to transient systems, reducing the variability associated with transient transfection and generating more consistent titres across manufacturing runs.

OXGENE, a WuXi Advanced Therapies Company, is a biotechnology company based in Oxford, UK. OXGENE provides end-to-end contract services to cell and gene therapy companies seeking to discover, develop, manufacture and test innovative drug candidates at scale for global commercialization. Building

on years of experience with the transient system, OXGENE’s LentiVEX™ packaging and producer cell lines contain the same proven genetic sequence as their LentiVEX™ transient system and start from the same HEK293 clonal suspension cell lines. This facilitates a smooth transition to this more scalable technology while retaining the benefits optimised within the transient system.

LentiVEX™ packaging cell lines contain all the packaging elements integrated in the genome, with VSV-G and GagPol under the control of a tetracycline-regulated promoter (TetR) and Rev under a constitutive or inducible promoter. These cell lines require transfection of only one plasmid carrying the lentivirus genome with the therapeutic gene of interest (LV_ Genome_GOI) and doxycycline induction to produce lentiviral vectors. This platform also forms a basis for the development of lentiviral producer cell lines. LentiVEX™ producer cell lines stably integrate the LV_Genome_GOI and only require induction to produce lentiviral vectors, allowing a transfection-free manufacturing process.

Integration of lentiviral elements into the genome of a host cell line has historically been very challenging, with lower yields often reported compared to the transient system. Now more than ever, we need stable cell lines which can match the viral yield of a transient production method, but with the scalability and robustness of a stable system. This is what we have been working toward at OXGENE and WuXi Advanced Therapies.

Development of a stable lentiviral packaging cell line Engineering and development of OXGENE’s lentiviral packaging HEK293 cell line required two consecutive rounds of integration.

The first involved integration of a TetRepressor and VSV-G and GagPol genes with a doxycycline-inducible promoter by random integration of linear DNA. The second involved integration of a Rev gene, either with a constitutive or doxycycline-inducible promoter, by random integration of linear DNA. The resulting stable pools were then submitted to a single cell cloning and screening campaign to allow identification of the best performing clonal cell lines.

Figure 1: OXGENE's approach to generation of stable lentiviral packaging and producer cell lines.

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Summer 2022 Volume 5 Issue 2

Application Note Using transient transfection of a single LV_Genome plasmid carrying green fluorescent protein (GFP) as a gene of interest, LentiVEX™ packaging cell line version 1.0 was able to achieve lentiviral titres of up to 6.0E+07 TU/mL, with the highest productivity attained by maintaining cells in antibiotic throughout the subculture period. The high titres were also consistent across later generations (up to passage 21).

a lentiviral genome into HEK293 cells: this approach has been prototyped using GFP as a gene of interest.

The scientists used a transposon-based integration method, (Wild-type PiggyBac), to develop producer cell lines.

Transposons, known as ‘jumping genes’, encode a transposase enzyme, which copies and pastes the transposon gene from one genetic location to another. They can be modified to allow any gene to be integrated into a genome, and OXGENE used transposons to integrate the lentiviral genome and gene of interest into a packaging cell line, resulting in a stable LentiVEX™ producer cell line.

Transposon-based integration offers a number of benefits over random integration. Copy number is usually higher and integration is preferentially targeted to transcriptionally active sites: this approach is useful to ensure more copies of the LV_Genome_GOI are integrated in the host genome, which should therefore result in higher lentiviral vector production.

Figure 2: LV production with packaging cell line platform V1.0 cultured with and without antibiotics at passage 21 according to standard protocol and titrated by transduction of HEK293T and analysis by flow cytometry. LV genome transfected is GFP.

Despite the high titre achieved with such a platform, batch-tobatch variability was still observed. OXGENE’s acquisition by WuXi AppTec to become part of WuXi Advanced Therapies has given the team access to a new HEK293 suspension cell line platform which shows increased robustness and high viral production titres. The engineering work is enabling development of packaging cell line platform version 2.0. Upon successful retention of packaging elements and long-term functionality, the new platform will be eligible to support manufacturing processes whereby only a single plasmid transfection is required.

The resulting lentiviral producer cell line, with GFP encoded as the gene of interest, achieves lentiviral titres of up to 1–2E+08 TU/mL. This titre range is comparable with the titres achieved using four-plasmid transient transfection approaches, indicating that OXGENE’s LentiVEX™ technology can provide a solution for a stable system with high viral titres.

Long-term stability tests are ongoing to monitor the titre and the GFP copy number.

Development of a Stable Lentiviral Producer Cell Line with GFP as Gene of Interest Considering the high yields reached by packaging cell line platform version 1.0, OXGENE employed it for development of LentiVEX™ producer cell lines. This required integration of Figure 4: LV production before and after clonal isolation: LV infectious titre generated by transduction of HEK293T and flow cytometry analysis. Gene of interest = GFP. N = two production replicates at passage numbers 10 and 15; two flask replicates at each production. Error bars indicate 4 SD.

Development of a Stable Lentiviral Producer Cell Line with a Therapeutically Relevant Gene of Interest Next, the OXGENE scientists aimed to demonstrate that their lentiviral producer cell lines could produce high titres with a therapeutically relevant gene of interest, and would thereby offer a robust solution for manufacture of LVV-based cell and gene therapies.

Using the same transposon-based method, the team is developing a lentiviral producer cell line with CAR-CD19 as the gene of interest.

Figure 3: OXGENE’s use of transposons for producer cell line development. (A) Packaging cell lines, which encode VSV-G, gag-pol and rev, require plasmid transfection and induction for lentiviral vector production. Transposon integration of the lentiviral genome yields producer cell lines, (B), which only require induction for lentiviral vector production. ITR = transposon inverted terminal repeats. www.international-biopharma.com

The resulting stable pools yielded titres of approximately 3–5E+07 TU/mL (comparable to titres achieved with the GFP pool in development, explained in section 3, Figure 4). The development of a clonal cell line is ongoing.

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Application Note OXGENE has developed a stable lentiviral packaging cell line, useful for screening multiple targets at early clinical stages, but which can also be adopted for later stages of cell therapy manufacture. This LentiVEX™ packaging cell line forms the basis of OXGENE’s LentiVEX™ producer cell lines.

These producer cell lines have been created using GFP and a therapeutically-relevant transgene as genes of interest, and can produce lentiviral yields comparable with transient systems.

Figure 5: LV production. LV infectious titration by transduction of HEK293T and integrated vector copy number analysis (IVCN by qPCR). Gene of interest = CAR-CD19.

Conclusion The speed of production of lentiviral vectors needs to keep pace with the accelerating demands for cell therapies.

A substantial challenge is to develop manufacturing technologies that can produce safe lentiviral vectors at a consistently high titre and with reduced manufacturing costs.

OXGENE works with customers to understand their gene of interest and the expression system of their novel cell therapy, so they can optimise integration of this custom transgene into a high-yielding, stable lentiviral producer cell line, with the option for seamless internal technology transfer to WuXi Advanced Therapies for further process development, scale up and GMP manufacture and testing. Together, WuXi Advanced Therapies and OXGENE offer end-to-end support, from pre-clinical discovery to commercialisation, for innovators developing novel cell therapies.

In conclusion, OXGENE has developed a LentiVEX™ platform system to address the challenge of lentiviral manufacture from transient to fully-stable lentiviral production systems.

Their technology can maintain consistently high yields across different platforms and offers a cost-effective solution for large-scale manufacture of lentivirus-based therapies. This, in turn, will help meet the increasing demands for lentiviral vectors for novel cell therapies.

Corinne Branciaroli Corinne joined OXGENE in 2017, and, after a brief period working within the Molecular Biology team, moved onto Cell Line Engineering, developing cell line platforms with enhanced characteristics for viral vector manufacture (rAAV, LVV, AdV). As a Group Leader of Viral Cell Line Development, Corinne continues to optimise solutions for both commercial and internal R&D projects, the main focus being development of lentivirus packaging and producer cell lines. Prior to OXGENE, Corinne gained extensive experience in molecular biology, protein purification and immunoassays working in both academia and industry settings. Corinne holds a Bachelor Degree from Universita’ degli studi dell’Aquila and a Master Degree from Universita’ Politecnica delle Marche (Italy).

Dr. Katie Roberts Dr. Katie Roberts is Content Manager at OXGENE, a WuXi Advanced Therapies company.

She has been writing about science and communicating science, first as a Medical Writer and then within biotech marketing, for most of the last five years. Before this, she completed her PhD in cellular signalling at the University of Manchester, helping to decode oscillatory cell signalling patterns using molecular biology, live-cell confocal microscopy, and mathematical modelling.

30 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

Summer 2022 Volume 5 Issue 2

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INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY 31 Copyright © 2022 WuXi Advanced Therapies (WuXi ATU). All rights reserved.

Application Note

Manufacturing of Biological Tissues: Standardisation and Automation The manufacturing of biological tissues responds to major societal challenges, but it also faces major issues, especially those related to the standardisation of manufacturing processes and scale-up. Bearing these challenges in mind, the French start-up Poietis has developed the Next Generation Bioprinting (NGB) platform, equipped with a Stäubli TX2-40 robotic arm to perform 4D bioprinting of biological tissues in a faster, more affordable and more functional way. The world's first clinical trial of a bioprinted skin graft will start in 2022 at the University Hospital of Marseille.

Issue In the past decade, a first generation of tissue-engineered products has been brought to market, mainly for cartilage, skin or corneal indications. These products have shown good clinical results and opened the regulatory pathway, but they have also highlighted a number of issues related to the standardisation of manufacturing processes, product repeatability and scale-up, i.e. the ability to produce them in a massive and cost-effective way.

According to Fabien Guillemot, CEO & Scientific Director of Poietis, "this is due to the traditional manufacturing method used for this first generation of products. These are cell cultures that depend on operators and require an extremely large number of technicians and engineers. To overcome these problems, there was a real need for automation but also for the replacement of operators by robotics.”

Solution In this context and based on its expertise in high-resolution laser-assisted bioprinting, Poietis has developed the NGB modular platform which is designed to give tissue engineers and researchers greater freedom in the selection of biomaterials and hydrogels as well as greater versatility in their research and development.

Poietis launches two bioprinters based on the NGB platform: the NGB-R, marketed for research applications, and the NGB-C, a GMP-compliant clinical quality system for medical applications. Fabien Guillemot specifies that the purpose of this platform is not only to get more affordable treatments (today a bioprinted cornea is marketed at a price of around 100,000 euros for a patient) but also to increase the functionality of the implanted tissues by controlling their composition and their architecture. Highly inspired by the principles of the 4.0 Industry, this new platform integrates automation and robotics technologies, coupled with numerous online sensors and Artificial Intelligence processing. It also includes all bioprinting techniques (laser-assisted bioprinting, bioextrusion, micro-valve bioprinting) and is based on four single-cell resolution technologies: computer-assisted design, automated 32 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

and robotic bioprinting, in-line control and tissue formation modelling.

Customer Use The platform includes a TX2-40 6-axis robot since the end of 2017, when Poietis launched its printers automation programme. The Stericlean version of the TX2-40 is fully cleanable and sterilisable and is designed for medical and pharmaceutical applications.

What is the function of the TX2-40? The tissues are constructed on a cell culture plate within the platform isolator.

The latter is composed of different print heads, one of which can print cells and the others can print materials that are also part of the tissue. The Stäubli robot is in charge of moving the tissue being constructed from one print head to another. The robot works with the different bioprinting modes embedded in the system (laser and extrusion) and its software can be easily implemented for an industrial solution.

The platform equipped with the Stäubli robot allows to produce a substitute composed of both dermis and epidermis, and not only of epidermis (the most superficial layer of the skin) as it was the case until now with cell culture manufacturing techniques. The printing itself now takes only three to four hours for a 40cm2 square of skin, compared to eight to nine hours previously with traditional manufacturing methods.

Benefits Stäubli identified Poietis' needs in terms of biomanufacturing right from the start. “The main reason we chose Stäubli for the automation of our printers is that they are able to supply robots in both configurations, one for R&D and one for clinical applications. Besides, their robots are GMP-compatible and are already used in pharmaceutical production, which was an extremely important and differentiating factor for us," explains Fabien Guillemot from Poietis.

The robot's accuracy and speed were also convincing factors. "The TX2-40 robot from Stäubli allows us to reach the different print heads with a very high degree of precision, while at the same time meeting our needs in terms of speed and repeatability. Moreover, and this is very important for therapeutic applications, its action generates infinitely few particles likely to contaminate the tissue," continues Fabien Guillemot. Tissue contamination is a key issue as the isolator in which the printer is placed must be a Class A aseptic environment.

"The robot, just like the rest of the isolator, must be cleanable with detergents and sterilisable. The Stericlean robot meets these requirements, as well as having the right dimensions since our printers should not be too large in order to be deployed in hospital cell therapy centres," concludes Fabien Guillemot.

Summer 2022 Volume 5 Issue 2

Application Note

The Next Generation Bioprinting (NGB) platform, equipped with a Stäubli TX2-40 robotic arm to perform 4D bioprinting of biological tissue..

Future Developments The platform automation was completed in 2019 and the NGB platform went to market in 2020. The platform was installed at the University Hospital of Marseille at the end of 2021 with the intention of starting the world's first clinical trial of a bioprinted skin graft this year, with different indications regarding healing, small burns and traumatic wounds.

Poietis also works on other applications, showing the versatility of its platform. “We have more upstream projects on the bioprinting of cartilage, pancreas or neurons," explains Bruno Brisson, co-founder and Director Business Develoment.

“Some applications will require an adaptation of the platform's modules but its components will remain the same: a laser head to print cells, extrusion to print biomaterials and Stäubli robotic arm to move samples from one print head to another”.

Stäubli Stäubli is a mechatronics solutions provider with three dedicated activities: Connectors, Robotics and Textile.

With a global workforce of over 5,500, the company generates annual turnover surpassing 1.3 billion Swiss francs. Originally founded in 1892 as a small workshop in Horgen/Zurich, today Stäubli is an international group headquartered in Pfäffikon, Switzerland. Worldwide, Stäubli operates fourteen industrial production sites and 29 subsidiaries, expanded with a network of agents in 50 countries, delivering innovative solutions to all industrial sectors. www.staubli.com/en/profile

Stäubli Robotics Stäubli Robotics is a leading global player in robotics, consistently delivering engineering as effective and reliable as our service and support. A complete solutions provider for digitally networked production, Stäubli offers a broad range of 4- and 6-axis robots including robotic arms designed specifically for sensitive environments, autonomous mobile robots, driver-less transport systems (AGVs) and cobots for human-robot collaboration. www.staubli.com/robotics STÄUBLI Robotics | LinkedIn Biological tissue sample. © Poietis www.international-biopharma.com

INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY 33

Therapeutics

PEER REVIEWED

Advancing Cardiac Drug Discovery with Human Induced Pluripotent Stem Cell Technology Despite having available treatments for most cardiac diseases there is an increasing need for more specific and effective therapies. To help drug developers advance smoothly in this process, it is important to decrease the translational gap that is leading to high attrition rates and costs. Human induced pluripotent stem cell (iPSC) technology is increasingly utilised to develop disease models that reliably mimic the diversity of patient pathogenicity and cardiac disease severity in vitro.

Phenotypic screening based on iPSC models represents a big opportunity to make cardiac drug discovery more time and cost effective by increasing the translational power of preclinical candidates. Here we review common challenges and goals for drug developers and how the latest innovations in iPSC technology are contributing to efficiently advance cardiac drug discovery.

cardiac drug discovery and development. There is a need to find better and more efficacious treatments, but to do so, it is important to make the process more affordable and de-risk potential clinical candidates at early stages to optimise the use of resources (Table 1).

The discovery of human induced pluripotent stem cells (iPSCs) by Shinya Yamanaka and Kazutoshi Takahashi in 2007, brought a new tool with a high potential to revolutionise drug discovery.5,6 iPSCs are obtained from human somatic cells, have unlimited proliferation capacity, and can differentiate into any cell type of the body, including cardiac muscle cells. Since 2010, multiple cardiac diseases have been successfully modelled using this technology7 and it has been demonstrated that human iPSC-derived cardiomyocytes are a valuable solution for cardiac drug discovery.

Background Since 1960, there has been a huge growth in treatments for cardiac diseases.1 Although they have increased the longevity of human population, cardiac pathologies remain leading causes of morbidity and mortality worldwide.1,2 For a number of reasons, the number of cardiovascular drugs entering clinical trials has been in decline since 1990.3 The poor translation of safety and efficacy from preclinical models to humans has caused several major failures in advanced stages of clinical trials in the past, resulting in a challenging regulatory environment, compared to most other therapeutic areas. Therefore, phase III clinical trials for cardiac diseases now need to be performed with relatively larger groups of patients and need to demonstrate the efficacy in longer-term follow-up than other disciplines.4 Altogether, these factors cause a huge increase in the overall costs of

Table 1. Current problems and potential solutions in cardiac drug discovery 34 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

Figure 1. Human iPSC-derived disease models better recapitulate human diseasedriving mechanisms than animal models. Schematic example showing the potential to recapitulate the underlying mechanisms of certain cardiac phenotypes and how that influences the translational power of the disease models.

Summer 2022 Volume 5 Issue 2

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INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY 35

Therapeutics Increasing the Translational Power of Disease Models Preclinical testing is currently largely based on animal models, predominantly mice. Although these models have contributed towards unravelling many disease mechanisms, they are costly and present important interspecies differences to humans that diminish their predictive power for compound safety and efficacy. Murine heart rate is eight times faster than human and there are considerable differences in the expression of important sarcomere proteins, ion channel function, metabolism, and calcium handling, among others.8 For example, many mutations in the MYH7 are associated with the development of hypertrophic cardiomyopathy (HCM).

MYH7 is the dominant isoform in human heart, but this is not the case for rodent models.9 These types of inter-species differences can lead to misinterpretations during preclinical screenings that can translate into failures during clinical trials. Human iPSC-cardiomyocytes preserve the exact same intracellular environment and genetic background of patients,10 which enables recapitulation of specific disease-linked phenotypes and underlying mechanisms (Figure 1). Human iPSC-cardiomyocytes generated from a family carrying a mutation on the gene MYH7 were shown to recapitulate the HCM phenotype in vitro, and revealed that elevation in intracellular calcium levels preceded the appearance of other phenotypic abnormalities.11 This suggested that calcium cycling alterations may be driving the disease and opened new possibilities for developing more efficacious treatments.

In vitro models based on primary human cardiac cells could be another solution, as they are physiologically relevant. However, they are restricted by the tissue inaccessibility and lack of cell survival in culture. In addition, their capacity to discriminate between causes and effects of the disease can be limited. For example, a common consequence of atrial fibrillation (AF) is tissue remodelling. Using patients’ biopsies as in vitro models, where the remodelling is usually present, does not allow to determine the etiology of AF.12 Murine models have been generated, but they are quite resistant to developing AF under physiological conditions.13 However, human iPSC-derived cardiomyocytes can help in understanding the initial causes of AF. In a study using human iPSC-cardiomyocytes derived from patients with AF, it was shown that increased pacemaker and L-type calcium currents could be triggering specific types of AF.12 Overall, developing more predictive in vitro disease models with human iPSCs can help towards understanding underlying disease mechanisms and identifying better targets. Therefore, decreasing the risk of failure in later stages.

Efficient Screening of Cardiac Drug Candidates In the past, a number of challenges have hindered the incorporation of iPSCs into drug discovery projects. Differentiation

procedures for human iPSC-cardiomyocytes used to be inefficient and difficult to scale up, which limited the number of cells available. Also, assays were not yet automated and miniaturised, which was needed to minimise variability and enable large screening campaigns. Nowadays, with the adequate capabilities and expertise, it is possible to obtain billions of functional cardiomyocytes from patient-derived iPSCs, thus overcoming the limitations of tissue inaccessibility and culture maintenance of primary cardiac cells.

High-throughput Screening The incorporation of human iPSC-based models has brought a new approach to drug discovery: high-throughput phenotypic screening. While traditional screenings are focused on a specific protein (target-based drug discovery), phenotypic screenings can be target-agnostic and focus on the modulation of a diseaselinked phenotype.14 These screenings are more physiologically relevant and offer the possibility of identifying completely new targets or unknown mechanisms of action of known targets. For instance, human iPSC-cardiomyocytes derived from patients with a mutation in LMNA were used to model dilated cardiomyopathy (DCM) in vitro.15 The model displayed aberrant calcium homeostasis and arrhythmias, as described in the patients.

Based on these DCM models, it was shown that activation of the platelet-derived growth factor (PDGF) was driving the alterations and that its inhibition led to an ameliorated phenotype in vitro.15 This described an underlying cause of the disease and identified a new potential therapeutic target for DCM. Clinically Relevant Outcomes Well-designed phenotypic assays with human iPSC-based cardiac models can evaluate clinically relevant cellular functions: electrophysiology and contractile properties, metabolism, calcium handling, viability, or biomarker expression.16 This means that early drug discovery and preclinical testing outcomes are based on the same or similar parameters that are later assessed in patients, reducing the risk of failure in clinical trials and making the process more efficient (Figure 2). Many promising lead compounds have been identified with human iPSC-based phenotypic screenings.16 To give an example, isogenic diseased and genetically engineered human iPSC-derived cardiomyocytes were used to model long-QT syndrome (LQTS) in vitro.17 In this study, the small molecule LUF7346 was demonstrated to be a new allosteric modulator of the potassium channel hERG, with the capacity to rescue LQTS-phenotype in a human in vitro model.

More recently, human iPSC-derived models of diabetic cardiomyopathy were used as screening platform for small

Figure 2. The benefits of phenotypic screening with human iPSC-derived models for cardiac drug discovery. Schematic representation of the drug discovery process using phenotypic screening and iPSC-derived models. This strategy enables testing compounds’ safety and efficacy in human biology earlier and screening with readouts similar to the ones used in clinical trials.

36 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

Summer 2022 Volume 5 Issue 2

www.international-biopharma.com

INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY 37

Therapeutics molecules with a phenotype-rescue approach.18 Diabetic cardiomyopathy has a complex multifactorial etiology difficult to model with traditional methods. Two iPSC models were generated, one chemically induced and one patient-derived, both recapitulated the structural and functional disarray observed in diabetic patients’ hearts. High-content phenotypic screening of 480 small molecules on the chemically induced model led to the identification of 47 hit compounds with phenotyperescue effects. A second screening confirmed the efficacy and dose-dependency of responses for 28 hits. In a final screening with patient-derived models, two compounds were selected as the most-effective in preventing the development of diabetic cardiomyopathy phenotypes, demonstrating the power of human iPSC technology for the development of new therapeutic modalities with higher specificity and efficacy.

Effective Screening of Cardiotoxicity In addition to the poor translation of efficacy from preclinical models to humans, cardiotoxicity is another major cause of drug attrition in clinical trials. In this field, human iPSC technology has proven to be a solution to predict drug-induced structural damage and arrhythmias with high efficiency. The comprehensive in vitro proarrhythmia assay (CiPA) represents a paradigm to improve the assessment of proarrhythmic risk based on mechanistic in vitro assays and in silico reconstructions of electrophysiological activity, with verification of predicted responses in human iPSC-derived cardiomyocytes. To illustrate the power of CiPA, a screening with 28 drugs with known clinical arrhythmic effects demonstrated 87% predictivity of proarrhythmic risk that was not detected in pre-clinical studies using traditional models.19 The Future of Human iPSC Technology 3D Models It is important to mention that human iPSC technology is a relatively young field and is therefore still under continuous development to improve its resemblance to the complexity of the human body. One developing solution is the use of 3D engineered microtissues, which are composed of multiple cell types found within the human heart.20 These 3D models facilitate the study of cell-cell interactions and represent more complex microenvironments with higher similarity to native tissue, which may increase predictions of drug safety and efficacy even further. For instance, 3D cardiac models better resemble the metabolism and proliferative capacity of adult hearts, which can facilitate the identification of pro-proliferative compounds for cardiac regeneration.21 In a screening with 105 small molecules and human iPSC-derived 3D cardiac organoids, novel pro-proliferative compounds with minimal side effects were identified.21 At this moment, the throughput of these models is somewhat limited compared to 2D monocultures. However, promising advancements are being made to solve this issue that will unlock broad implementation of human iPSC-derived 3D models in drug discovery. 22 Personalised and Precision Medicine Some other major challenges for cardiac drug discovery are the oversimplified systems for patient stratification and the differences in mutation penetrance among patients. Patient stratification is usually based on phenotypes with different underlying etiologies, which leads to a wide range of treatment responses among patients.4,23 Studies with human iPSC 38 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

technology are constantly increasing our understanding of cardiac disease etiology, setting the foundations for a mechanism-driven patient classification in the future. This will also facilitate the definition of homogenous groups of patients for clinical trials and the interpretation of clinical outcomes. On the other hand, patient-derived or genetically engineered iPSC models can help to determine the pathogenicity of specific genetic variants and predict the in vitro response to pharmacological treatments of individual patients.24,25 This is of great advantage for the growing demand for personalised and precision medicine tools.

Conclusions Cardiac drug discovery has been facing a stage of paucity, but the need for more efficacious treatments for devastating cardiac diseases is waking up the interest in this area again. The current goals in the field are challenging: finding better targets and reducing attrition rates to make the process more affordable.

Incorporating human iPSC technology in cardiac drug discovery can solve many of the current challenges in the field. This technology facilitates target identification and phenotypic screening with clinically relevant readouts. Consequently, the predictability of early and preclinical drug discovery outcomes can be increased, and therefore, the chances of success in clinical trials.

The implementation of iPSC-based models into drug discovery requires significant expertise and capabilities. To overcome these impediments and obtain high-quality results in the shortest possible timeframe, partnering with expert contract research organisations is a common option for pharmaceutical companies.

Collaboration with experts avoids common pitfalls, enables selection of risk mitigation strategies, enhances productivity and, ultimately, reduces timelines and costs.

REFERENCES 1.

Gromo G, Mann J, Fitzgerald JD. Cardiovascular Drug Discovery: A Perspective from a Research-Based Pharmaceutical Company. Cold Spring Harb Perspect Med. 2014;4(6). doi:10.1101/CSHPERSPECT. A014092 2. Fordyce CB, Roe MT, Ahmad T, et al. Cardiovascular Drug Development: Is it Dead or Just Hibernating? J Am Coll Cardiol. 2015;65(15):15671582. doi:10.1016/J.JACC.2015.03.016 3. Ohlstein EH. The grand challenges in cardiovascular drug discovery and development. Front Pharmacol. 2011;JUL:125. doi:10.3389/ FPHAR.2010.00125/BIBTEX 4. Figtree GA, Broadfoot K, Casadei B, et al. A Call to Action for New Global Approaches to Cardiovascular Disease Drug Solutions. Circulation.

2021;144:159-169. doi:10.1161/CIR.0000000000000981/FORMAT/EPUB 5. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.

Cell. 2006;126(4):663-676. doi:10.1016/J.CELL.2006.07.024 6. Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell.

2007;131(5):861-872. doi:10.1016/J.CELL.2007.11.019 7. Karakikes I, Termglinchan V, Wu JC. Human Induced Pluripotent Stem Cell Models of Inherited Cardiomyopathies. Curr Opin Cardiol.

2014;29(3):214. doi:10.1097/HCO.0000000000000049 8. Matsa E, Burridge PW, Wu JC. Human Stem Cells for Modeling Heart Disease and for Drug Discovery. Sci Transl Med. 2014;6(239):239ps6. doi:10.1126/SCITRANSLMED.3008921 9. Lam CK, Wu JC. Disease modelling and drug discovery for hypertrophic cardiomyopathy using pluripotent stem cells: how far have we come? Eur Heart J. 2018;39(43):3893-3895. doi:10.1093/ EURHEARTJ/EHY388 10. Matsa E, Burridge PW, Yu KH, et al. Transcriptome Profiling of PatientSummer 2022 Volume 5 Issue 2

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Specific Human iPSC-Cardiomyocytes Predicts Individual Drug Safety and Efficacy Responses In Vitro. Cell Stem Cell. 2016;19(3):311-325. doi:10.1016/J.STEM.2016.07.006 Lan F, Lee AS, Liang P, et al. Abnormal Calcium Handling Properties Underlie Familial Hypertrophic Cardiomyopathy Pathology in Patient-Specific Induced Pluripotent Stem Cells. Cell Stem Cell.

2013;12(1):101-113. doi:10.1016/J.STEM.2012.10.010 Benzoni P, Campostrini G, Landi S, et al. Human iPSC modelling of a familial form of atrial fibrillation reveals a gain of function of If and ICaL in patient-derived cardiomyocytes. Cardiovasc Res. 2020;116(6):1147. doi:10.1093/CVR/CVZ217 Riley G, Syeda F, Kirchhof P, Fabritz L. An Introduction to Murine Models of Atrial Fibrillation. Front Physiol. 2012;3. doi:10.3389/ FPHYS.2012.00296 Vincent F, Loria P, Pregel M, et al. Developing predictive assays: the phenotypic screening “rule of 3.” Sci Transl Med. 2015;7(293). doi:10.1126/SCITRANSLMED.AAB1201 Lee J, Termglinchan V, Diecke S, et al. Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy. Nat 2019 5727769.

2019;572(7769):335-340. doi:10.1038/s41586-019-1406-x Brandao KO, Tabel VA, Atsma DE, Mummery CL, Davis RP. Human pluripotent stem cell models of cardiac disease: from mechanisms to therapies. Dis Model Mech. 2017;10(9):1039-1059. doi:10.1242/ DMM.030320 Sala L, Yu Z, Oostwaard DW, et al. A new hERG allosteric modulator rescues genetic and drug-induced long-QT syndrome phenotypes in cardiomyocytes from isogenic pairs of patient induced pluripotent stem cells. EMBO Mol Med. 2016;8(9):1065. doi:10.15252/ EMMM.201606260 Drawnel FM, Boccardo S, Prummer M, et al. Disease Modeling and Phenotypic Drug Screening for Diabetic Cardiomyopathy using Human Induced Pluripotent Stem Cells. Cell Rep. 2014;9(3):810-820. doi:10.1016/J.CELREP.2014.09.055 Blinova K, Dang Q, Millard D, et al. International Multisite Study of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Drug Proarrhythmic Potential Assessment. Cell Rep. 2018;24(13):3582. doi:10.1016/J.CELREP.2018.08.079 Savoji H, Mohammadi MH, Rafatian N, et al. Cardiovascular disease models: A game changing paradigm in drug discovery and screening. Biomaterials. 2019;198:3-26. doi:10.1016/J. BIOMATERIALS.2018.09.036 Mills RJ, Parker BL, Quaife-Ryan GA, et al. Drug Screening in Human PSC-Cardiac Organoids Identifies Pro-proliferative Compounds Acting via the Mevalonate Pathway. Cell Stem Cell. 2019;24(6):895-907.e6. doi:10.1016/J.STEM.2019.03.009/ATTACHMENT/774AA312-FC804839-B0CE-2AD3F40B82F4/MMC4.XLSX Giacomelli E, Meraviglia V, Campostrini G, et al. Human-iPSCDerived Cardiac Stromal Cells Enhance Maturation in 3D Cardiac Microtissues and Reveal Non-cardiomyocyte Contributions to Heart

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Disease. Cell Stem Cell. 2020;26(6):862-879.e11. doi:10.1016/J. STEM.2020.05.004 23. Kathiresan S, Srivastava D. Genetics of Human Cardiovascular Disease.

Cell. 2012;148(6):1242. doi:10.1016/J.CELL.2012.03.001 24. Matsa E, Rajamohan D, Dick E, et al. Fast Track: Editor’s Choice: Drug evaluation in cardiomyocytes derived from human induced pluripotent stem cells carrying a long QT syndrome type 2 mutation.

Eur Heart J. 2011;32(8):952. doi:10.1093/EURHEARTJ/EHR073 25. Wu JC, Garg P, Yoshida Y, et al. Towards Precision Medicine with Human iPSCs for Cardiac Channelopathies. Circ Res. Published online August 30, 2020:653-658. doi:10.1161/CIRCRESAHA.119.315209

Noelia Muñoz-Martín Noelia Muñoz-Martín, PhD, Scientific Content Marketer at Ncardia, obtained her PhD in biomedical research in 2019 and has extensive experience in cardiac arrhythmias and congenital heart disease research. She has contributed to science communications of several organisations and companies from different angles, writing and editing peer-review articles and blogs, and creating website and social media content.

Email: noelia.munoz-martin@ncardia.com

Elena Matsa Elena Matsa, PhD, Vice President of Cell Technology at Ncardia, obtained her PhD in stem cell biology in 2010, and subsequently worked as a post-doctoral researcher at the University of Nottingham, and the Stanford University School of Medicine. She has extensive experience and high impact publications in modeling of human cardiac disease with iPSC-derived cardiomyocytes. For Ncardia, Elena manages key strategic technical projects, provides scientific leadership, and contributes to project proposals.

Email: elena.matsa@ncardia.com Web: www.ncardia.com

Summer 2022 Volume 5 Issue 2

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INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY 41

Therapeutics

How Scalable Manufacture will Enable Progress for Lentiviral Therapies In the twenty years since creation of the first effective CAR-T cells, lentiviral vectors have become valuable tools for the development of ex vivo gene and cell therapies.1 Two ex vivo lentiviral gene therapy products have recently reached the market, one approved for treatment of acute lymphoblastic leukaemia and the other for beta thalassemia.2 The successful development of these treatments has demonstrated the potential for lentiviral therapies to treat cancer and other diseases.

There were 1,358 active clinical trials for cell therapies in 2021, an increase of 78% compared with 2019.3 In the next few years we expect to see more clinical trials and regulatory approvals, with the FDA predicting that they will be approving between 10 and 20 cell and gene therapy products per year by 2025.4 An increased number of cell and gene therapies, especially for common diseases with large patient populations, is anticipated to drive an increased need for viral vector manufacture. Scalable manufacturing technologies, such as stable, high-yielding packaging and producer HEK293 cell lines and space-efficient suspension cell platforms will be necessary to keep pace with increased demand.5 In addition to the ability to treat new and large patient populations, changes in the ways that innovators use lentiviral vectors may also drive an increased demand for scalable production. These could include the transition from ex vivo to in vivo lentiviral gene therapies and from autologous to allogeneic cell therapies. As the potential applications for lentiviral vectors expand, it’s likely to drive a corresponding need for efficient and scalable lentiviral vector manufacture.

The Ability to Treat Larger Patient Populations Cell and gene therapies hold great promise for rare diseases with small patient populations, with over 80% of rare diseases having a monogenic cause.6 However, as cell and gene therapy research advances, it brings the potential to treat more common and complex diseases such as neurological diseases, infectious diseases and a wide range of cancer types with more prevalence.7 For example, lentiviral therapies are being investigated to treat hepatocellular carcinoma (HCC), which accounts for approximately 75% of liver cancer cases in the USA.8,9 The ability to target more common diseases with larger patient populations will drive a greater demand for manufacturing technologies that reliably produce enough viral vector to treat those populations. This is particularly true for applications where one manufacturing run could be used to transfect cells for treating several patients, such as allogeneic cell therapies.10 Treatment of more common indications will require efficient manufacturing processes, with the ability 42 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

to generate as much viral vector as possible in a space- and cost-effective way.

A Move Towards In Vivo Uses for Lentiviral Therapies Traditionally, in vivo gene therapies have used adeno-associated virus (AAV) vectors, an approach which has proved successful in multiple indications. However, the use of AAV vectors is not without challenges, such as the widespread pre-existing immunity against AAV in the population, hindering the efficacy of AAV-based treatments for some patients due to immune response. In addition, AAV vectors tend to take an episomal location in the nucleus of target cells and can be lost over time, creating potential difficulties for long-term expression.2 Lentiviral vectors, by contrast, can stably integrate their transgene into the target cell chromatin and are maintained through cell replication, creating potentially longer-term expression than AAV vectors.11 Lentiviral vectors have not typically been used for in vivo gene therapies due to their risk of insertional mutagenesis, which could occur if they integrate into a transcriptional unit used for cell division. However, this risk appears to be strongly reduced for newer generations of lentiviral vectors as supported by clinical data. Several studies are also investigating non-integrating lentiviral vectors (NILVs). Their viral genome remains in the cell as an episome and does not integrate into the genome, with potential safety benefits. However, expression may be short-lived, similar to the episomal expression of AAV vectors.11 Because of their potential for long-term expression, lentiviral vectors could hold particular promise for specific patient populations if used in vivo to target dividing cells. These populations could include paediatric haemophilia patients who require drug delivery to the liver – the substantial liver growth in children would help maintain transgene expression which could be lost if AAV was used.2 In addition to the potential benefits of lentiviral vectors compared with AAV vectors for long-term gene expression, there are benefits of in vivo platforms compared with ex vivo platforms which could apply to lentiviral vectors. In vivo applications could improve consistency between patients compared with ex vivo applications, due to the variability inherent in patient cell isolation, transduction, and transplantation.12 The time to access treatment can be reduced with in vivo therapies compared with ex vivo therapies because they eliminate the delays associated with collecting, transducing and reinfusing cells, as well as the specialised facilities needed for that process. It has been suggested that in vivo treatments could therefore enable treatment of genetic disease within the first weeks of life because they eliminate the delays associated with processing cells ex vivo. For example, an in vivo treatment for X-linked severe combined immunodeficiency (SCID-X1), Summer 2022 Volume 5 Issue 2

Therapeutics usually diagnosed in the first week after birth, would provide further hope for paediatric patients.13 These features, among others, suggest that there could be benefits of lentiviral vectors for in vivo applications if their safety can be demonstrated.2 Ex vivo applications typically require relatively low quantities of lentiviral vector because the transduced cells can be expanded in culture before transplant back into the patient, with transgene expression maintained through cell passages.

Higher yields would likely be needed for in vivo applications, which usually require larger doses to transduce sufficient patient cells. This could mean that scalability becomes particularly important for the creation of in vivo cell therapies, with the requirement for platforms to produce high viral yields from each manufacturing run.

The Transition from Autologous to Allogeneic Therapies Autologous approaches have been used successfully for CAR-T cell therapies and can convey substantial advantages; for example, the reduced risk of graft versus host disease compared with allogeneic therapies. However, the widespread option for allogeneic therapies could be hugely beneficial.

Allogeneic approaches would be much more efficient to scale up because one manufacturing run can be used for multiple patients, reducing the cost per dose. The material may also be less variable than allogeneic therapies because healthy donors confer a more uniform starting material than patients, leading to more predictable manufacturing and performance.

It would also open the door to locally-available ‘off-the-shelf’ therapies rather than requiring such complex transport logistics of patients and materials, increasing accessibility.10 An allogeneic approach could use material from a universal source such as genetically modified donor T cells or immortalized cell lines. A proof-of-concept was conducted in 2015, in which two paediatric patients at Great Ormond Street Hospital, London were treated with an allogeneic CAR-T cell therapy against B cell acute lymphoblastic leukaemia.14 This, and other similar studies, have shown promising results, and if future research can sufficiently demonstrate their safety and efficacy then allogeneic cell therapies could substantially expand the number of patients whose disease could be treated.

The potential to reach more patients would increase the requirement for high yields of lentiviral vectors, and therefore for manufacturing technologies which can scale-up effectively, creating a lot of viral vector from each manufacturing run. If more allogeneic cell therapies enter late-stage clinical trials and gain market approval, this will be likely to substantially increase the demand for lentiviral vectors, in turn driving the demand for more easily scalable manufacturing systems.

Summary There has been substantial success within the field of cell and gene therapies over the last two decades, with many treatments approved and increasing numbers in clinical trials. As the industry discovers new applications for lentiviral vectors and shifts towards investigating in vivo therapies, allogeneic cell therapies and treating larger patient populations, manufacturing technologies must keep pace and deliver high vector yields in a space- and cost-effective way. Over the next few years, as we www.international-biopharma.com

see progress within in vivo applications of lentiviral vectors and allogeneic cell therapies, among other applications, scalable manufacturing platforms, such as lentiviral producer cell lines, will become even more valuable.

REFERENCES 1.

2.

3.

4.

5.

6.

7.

8.

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12.

13.

14.

Maher J, Brentjens R, Gunset G. et al. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ / CD28 receptor. Nat Biotechnol 20, 70–75 (2002).

Cantore A and Naldini L. WFH State-of-the-art paper 2020: In vivo lentiviral vector gene therapy for haemophilia. Haemophilia 27, 122–125 (2021). https://www.cancerresearch.org/en-us/blog/june-2021/io-celltherapy-development-in-2020-pandemic Published June 4 2021. https://www.fda.gov/news-events/press-announcements/ statement-fda-commissioner-scott-gottlieb-md-and-peter-marksmd-phd-director-center-biologics Manceur AP et al. Scalable Lentiviral Vector Production Using Stable HEK293SF Producer Cell Lines. Human Gene Therapy Methods. 28, 330–339 (2017). https://ncats.nih.gov/trnd/projects/gene-therapy Abdul Wahid SF et al. Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database of Systematic Reviews 12, CD011742 (2019). https://clinicaltrials.gov/ct2/show/NCT04864054 Petrick JL et al. Future of Hepatocellular Carcinoma Incidence in the United States Forecast Through 2030. Journal of Clinical Oncology 34, 1787–1794 (2016).

Caldwell KJ et al. Allogeneic CAR Cell Therapy—More Than a Pipe Dream. Frontiers in Immunology 11: 618427 (2021).

Milone MC and O’Doherty U. Clinical use of lentiviral vectors.

Leukemia 32, 1529–1541 (2018).

Allen Kaiser R et al. Hepatotoxicity and Toxicology of In Vivo Lentiviral Vector Administration in Healthy and Liver-Injury Mouse Models. Human Gene Therapy Clinical Development. 30, 57–66 (2019).

Rajawat YS et al. In Vivo Gene Therapy for Canine SCID-X1 Using Cocal-Pseudotyped Lentiviral Vector. Human Gene Therapy 32, 113–127.

Labbé RP, Vessillier S and Rafiq QA. Lentiviral Vectors for T Cell Engineering: Clinical Applications, Bioprocessing and Future Perspectives. Viruses 13, 1528 (2021).

Katie Roberts Dr. Katie Roberts is Content Manager at OXGENE, a WuXi Advanced Therapies company. She has been writing about science and communicating science, first as a Medical Writer and then within biotech marketing, for most of the last five years. Before this, she completed her PhD in cellular signalling at the University of Manchester, helping to decode oscillatory cell signalling patterns using molecular biology, live-cell confocal microscopy, and mathematical modelling.

INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY 43

Supply Chain Management

PEER REVIEWED

Live Cell Transport – The New Way of Transportation A new generation of active temperature-controlled and CO2 conditioned transport devices are challenging the existing cell shipment methods. In routine cell culture transport protocols, it is commonplace to thaw, plate and recover cryopreserved cells. When using this method, some cells survive the transport quite well, while others either do not survive the transport at all, or they come back from a near-death experience- not quite the same afterwards. Cells that are exposed to suboptimal life-sustaining conditions encounter severe stress and have a reduced survival rate.

The ever-evolving landscape of regenerative medicine and drug discovery is driving the development of innovative and structurally complex biological research tools and living therapies. Simultaneously, the number of business relationships, networks and consortia in which scientists, industry professionals and physicians from hospitals, research institutes and biobanks are cooperating with one another, is growing globally. The demand from these professionals is ever increasing for the proper handling and transportation of sensitive material under optimal physiological conditions.

Temperature-controlled Logistics take the Stage In recent years the logistics industry has made a shift from what was known as cold-chain transport to temperaturecontrolled transport. This can be attributed to the increasing number of regenerative medicines, clinical trials, targeted therapies and cell-based products that need to be shipped over greater distances, under tightly regulated conditions. The complexity and composition of these materials demand a wider spectrum of transport temperatures and as a result specialty logistics companies now offer services that can be divided into cryogenic temperatures (-80°C and -150°C), extremely low temperatures (-20°C), cold-chain (+2 to +8°C), controlled ambient temperature (+15 to +25°C) and body temperature (+37°C).1 The transport temperatures of these kinds of shipments are not only stringently regulated, but also monitored and the data is logged in order to provide evidence that the conditions were maintained throughout the trip. This is of utmost importance when considering that in many of these instances, the transported products will be administered to patients. Where the integrity of the shipment has been compromised, it may negatively impact a patient’s health on the receiving end, or in the worst case it could even lead to a loss of life.

Shipping Cells and Tissue: The status quo Traditionally, cells and other biological material have been stored and transported at low to cryogenic temperatures. Under these conditions, cellular degradation is limited, because the biological and chemical activity in the cells are either slowed dramatically or brought to a halt by cryopreservation.2 With this in mind, the temperature needs to be selected based on the 44 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

type of material being shipped, the composition of the solution wherein the material is stored during shipping, and what type of packaging is used during the shipment.3 As low temperatures only slow the onset of cellular degradation, cryopreservation is the golden standard for the majority of cells and tissues that need to be sent on long journeys.

Cryopreservation: A Love-hate Relationship?

Cryopreservation in itself is a process that has revolutionised both the biological sciences and modern medicine, by providing a long-term storage and distribution solution for biological material. Nevertheless, it is not without its own shortcomings and constraints, since most living organisms don’t survive freezing.2 During freezing, cells are damaged by what is known as cryoinjury. The damage, at least in part, can be ascribed to two reasons. The first being the intracellular formation of ice crystals, which results in the degradation of intracellular structures and the second is the solution effect, which is caused by the osmotic stress experienced by the cells.2 To counter cryoinjury, researchers add cryoprotectants during the cryopreservation. Cryoprotectants are biologically acceptable fluids with a low toxicity that can penetrate the cells in an attempt to prevent cryoinjury from occurring.4 Following the addition of the appropriate cryoprotectant, cells are either rapidly frozen by vitrification or they are slowly frozen in a controlled manner using a freezing device. To revive the cells from the low temperature, a thawing procedure is implemented.

Thawing generally involves rapid heating of the cells to 37°C, which prevents prolonged exposure to the toxicity of the cryoprotectant.5 After the rapid heating of the cells, the cells are taken up in fresh culture media and allowed to recover in an incubator. Although remarkable progress has been made in developing strategies that are compatible with diverse cell and tissue types, the toxicity of the cryoprotectants, the costly freezing devices used, the time intensive processing and the ultimate loss of cell viability during the freeze-thaw cycles are considerable drawbacks.

Cell Losses: Expected, but a Real Headache In general, the temperature-controlled logistics solutions being used today are adequate for the transport of any relatively robust cell lines and cell cultures, however, after the shipment the loss in cell viability could be as high as two-thirds of the total population. To examine the cell damage and resulting viability, investigators studied the effect of cryopreservation on cell cultures of NIH3T3 (Mouse Embryo Fibroblasts), HEK293 (Human Embryonic Kidney Cells) and K562 (Human Leukaemia Cells). Cells which have been cryopreserved at -80°C in the presence of a cryoprotectant, DMSO, showed that the damaged cells represented 20% (NIH3T3), 66% (HEK293) and 55% (K562) of the respective totals.6 In the same study, slightly better results were observed when using DMSO in combination with liquid nitrogen (-196°C), with damaged cells amounting to 17% (NIH3T3), 61% (HEK293) and 49% (K562) of all cells.6 In the control experiment, the cells were maintained under Summer 2022 Volume 5 Issue 2

Supply Chain Management

standard incubation conditions in a CO2 incubator, as opposed to being cryopreserved and recovered. In standard cell culture applications, incubation conditions are defined as a temperature of 37°C and a gaseous environment of 5% CO2 for example. The optimal temperature of 37°C is based on the physiological body temperature of the organism involved, while the CO2 is supplied to maintain pH of the bicarbonate buffered cell culture media.

A bicarbonate buffered system is preferred for cell culture, as it is the most important natural buffer that maintains the pH of mammalian blood. Under these conditions, fresh cell cultures of NIH3T3, HEK293 and K562 only showed a proportion of 15%, 14% and 2% of the damaged cells respectively.6 The aforementioned losses, due to cryopreservation, are considered within an acceptable range, since the remainder of the surviving cells are well preserved and can be recovered and re-cultured for downstream applications.5 Considerations for Drug Discovery and Healthcare While a loss in cell viability can be seen as an acceptable compromise during shipments, there are applications where www.international-biopharma.com

cryopreservation is incompatible or where cell recovery rates are unsatisfactory. Not only does cell viability need to be considered, but inadequate cryopreservation may introduce variations between different batches or could even cause genetic and epigenetic modifications.5 These concerns are becoming more prevalent where research projects and drug discovery workflows are dependent on the delivery of highly viable fragile cells, co-culture, engineered cell/tissue constructs and 3D cultures, such as spheroids and organoids.

A very interesting example is the effect of cryopreservation and storage on peripheral blood mononuclear cells (PBMCs).

PBMCs are collected from a patient’s blood during the apheresis process and they are important components of basic research and clinical trials.7 They are also the source from which pure T-cells can be isolated for CAR-T research. The recommended handling procedure is to cryopreserve and then store these cells until they are needed. This however raised some concerns as to the effect of cryopreservation and long-term storage of these PBMCs. To address these concerns, researchers found that the viability of the cells was affected and the gene expression INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY 45

Supply Chain Management patterns were significantly altered when comparing the fresh and cryopreserved cells. More than a thousand genes were differentially expressed and a substantial amount of them mapped to pathways such as stress response, immune activation and cell death.7 These effects may be less significant when the cells undergo shorter periods of storage, but it would be reasonable to assume that cryopreservation and shipping may have an influence on the outcome of in vitro assays which are dependent on PBMCs as its starting material. When cells are destined to be used as treatments in healthcare and therapeutics, the viability, cell quality, and reproducibility are even more crucial factors. Medical products are subject to strict regulations and any potential threat to the efficacy of the final product should be addressed and verified before it is administered to a patient.5 It may also be sensible to explore the testing requirements that viable and healthy cells should conform too. Basic tests applied to cells directly after thawing may underestimate the proportion of damaged cells, since a sizable number of cells will experience a delayed-onset cell death and start to die 24 hours post-thaw. Assays that stain for membrane integrity or other simple dye-based assessments could also be misleading, as they provide very limited information regarding the molecular physiology, health and quality of the cells. Cells may appear viable, nevertheless they may have lost their ability to renew themselves or differentiate from precursor cells.5 Furthermore, selective pressure applied under low temperature conditions may favour subpopulations, which are epigenetically and genomically distinct from the original culture.5 Made to Survive Shipping cells under non-physiological conditions will influence the cell’s quality and viability. If the benchmark for cell survival in most tests is fresh/live material maintained under optimal laboratory conditions in a CO2 incubator, would it not be sensible to also ship them under these conditions? Even though this is not a completely new idea, as Styrofoam boxes with 37°C gel packs or 37°C PCM (phase change material) containers have been used before to maintain the near physiological temperatures1,3, these methods do not provide the needed stable CO2 environment for the bicarbonate buffer system. In addition, these methods cannot and are not regulated. To circumvent the need for CO2, bicarbonate buffers may be exchanged for an alternative, but this could eventually be toxic to sensitive cells and it introduces another parameter which may affect the cell’s quality. To adhere to the regulated conditions used in laboratory incubators, cells should be shipped in a portable CO2 incubator which maintains not only the ideal temperature for the cells, but also the appropriate CO2 concentration. Technological constraints have been the limiting factor for the development of such regulated shipping incubators in the past. Now, however, the first generation of portable and truly autologous CO2 incubators have been brought to the market, due to clever engineering.

Innovative manufacturers already offer both flight and ground portable incubators.8 With these two methods of transport, shipments are made possible to any destination worldwide (depending on local regulations). The cells can therefore be kept at regulated and user-defined incubation conditions for more than 24 hours in transit. When the shipment is handled by a specialty logistics provider, this transit period can even be extended up to 48 hours, thereby ensuring the optimal solution for sending cells to distant locations.

46 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

The Impact and Future Portable CO2 incubators can have a tremendous impact on the conditions of the cells which are delivered for research collaborations, drug discovery projects, clinical trials and therapies in the future. In the case where losses in cell viability and cell quality are completely unacceptable, these devices guarantee shipment under optimal laboratory conditions. Moreover, every shipment can be verified, due to comprehensive and accessible data logs that provide detailed evidence of the transport conditions. Taking all of the benefits into account, it becomes relatively simple to integrate these shipping incubators into distribution and supply chains where end-to-end monitoring is of utmost importance. The future might be here already! Portable CO2 incubators are currently changing the way in which fragile cells are being transported in the fields of neurodegenerative diseases, cardiovascular diseases, oncology and fertility. Expansion into other medical use fields are underway. For example, initiatives to provide expanded cell therapy related capabilities to transport cell-based products for clinical application, (i.e. device and software upgrades, packaging solutions designed to guarantee sterility and lack of cross-contamination, Device Master File submission with the FDA and implementation of a QMS are already in development.8 Although live cell shipments have many known benefits, they are not intended to replace cryopreservation, rather offer new possibilities.

REFERENCES 1.

2.

3.

4.

5.

6.

7.

8.

Visit: www.worldcourier.com/insights/packaging-for-the-mostchallenging-shipments Jang, Tae Hoon, et al. “Cryopreservation and its clinical applications.”

Integrative medicine research 6.1 (2017): 12-18.

Visit: www.yourway.com/articles/keys-to-successful-storagemanagement-and-transport-of-biological-materials Pegg, David E. “Principles of cryopreservation.” Methods in Molecular Biology 368 (2007) 39-57 Hunt, Charles J. “Technical considerations in the freezing, low-temperature storage and thawing of stem cells for cell therapies.”

Transfusion Medicine and Hemotherapy 46.3 (2019): 134-150 Guilluamet-Adkins, Amy, et al. “Single-cell transcriptome conservation in cryopreserved cells and tissues.” Genome biology 18.1 (2017): 45 Yang, Jun, et al. “The effects of storage temperature on PBMC gene expression.” BMC immunobiology 17.1 (2016): 6 Visit: www.cellbox-solutions.com

Dr. Corné Swart Dr. Corné Swart is the Executive Director of Business Development & Global Sales at Cellbox Solutions GmbH. Combining a deep understanding of molecular biology with more than 12 years of experience in sales and marketing roles, Corné is spearheading the movement to Rethink Cryopreservation – and challenge the norms of shipping cells & tissues. In line with Cellbox Solutions’ vision to heal patients through Regenerative Medicine technologies, he has been working with logistics partners, healthcare experts and regulatory advisors to define the supply chain procedures that are required for the therapies of tomorrow.

Email: enquiries@cellbox-solutions.com

Summer 2022 Volume 5 Issue 2

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Supply Chain Management

Preparing Biopharmaceutical Downstream Processing Supply Chains for Resiliency Post-Pandemic From monoclonal antibodies (mAbs) that treat ailments such as cancer and arthritis to messenger RNA (mRNA) vaccines to fight a pandemic, biopharma’s place in global healthcare has rarely been more prominent. By 2030 the global market for biopharmaceuticals is projected to reach $856.1 billion and expand at a compound annual growth rate (CAGR) of 12.5% from 2021 to 2030.1 In response to the increasing number of infectious diseases around the world antibody development is also fuelling tremendous growth in the biopharmaceutical manufacturing sector. According to the World Health Organization, approximately 41 million people die annually from non-communicable diseases, accounting for more than 80% of all deaths.2

However, the biggest driver recently has been the unprecedented response to the global COVID-19 pandemic. This massive effort to vaccinate the global population has sustained the spike in demand for resins to tackle a range of challenges, from creating active pharmaceutical ingredients (APIs) to purifying virus material for vaccines, to acting as excipients in drug formulations. Further, year-on-year growth in the demand for monoclonal antibodies (mAbs) to treat disease is also contributing to overall growth in the sector. Going forward, supplying this demand will become increasingly challenging and require a response from the entire supply chain, especially suppliers of critical materials and equipment.

Analysts note that among the enabling technologies the biopharmaceutical industry will need most are chromatography resins. They also note that in particular as demand for biologics continues to rise, so will the demand on the industry’s resin suppliers to reduce supply chain risk, expand capacity globally and introduce higher performing, more efficient resin products, to serve the biopharmaceutical industry’s growing need more efficiently and sustainably.3 Resin’s Crucial Role in the Biopharmaceutical Supply Chain The biopharmaceutical industry uses chromatography resins for a wide variety of downstream processes including chemical and biomolecular isolation, protein purification for drug delivery, and diagnostics. Across pharma, food processing and commercial manufacturing, biomolecules and proteins of all kinds are purified and separated using chromatography resins.

chromatography resin technologies to help process biologics and bring them to market faster and more efficiently. Growth is expected to be significant. As a result, in 2022 the global resins market grew to $2.3 billion and is expected to reach $3.3 billion at a compound annual growth rate (CAGR) of 7.3% by 2027.3 This growth in the specialty resins segment over the last 12 months has been driven by several factors and has required innovation on the part of resin suppliers to meet changing biopharmaceutical demand.

As the industry moves through 2022 and beyond, demand for resins to support global vaccine and biopharmaceutical production can be expected to remain robust. That also means resin supply will become an even more critical aspect of the therapeutic biologics supply chain, which as it expands and demand grows, becomes even more prone to risk and disruption. This will likely drive innovation in the sector, as suppliers strive to develop products to meet customers’ increasingly demanding bioprocessing needs while increasing their capacity and capabilities globally to assure quality supply at higher volumes. mAb Purification Development Trends to Stretch Suppliers 2021 saw the authorisation of two mAbs immunotherapies for emergency use by the FDA to treat COVID-19 symptoms in patients hospitalised by the disease.4 Both treatments received full approval by the UK Medicines and Healthcare products Regulatory Agency (MHRA) this year.5 In fact, as of May 2021, the industry had reached a major milestone seeing the approval of 100 mAbs therapeutics since 1986.6 Consequently, there has been an increase in demand for bioprocessing technologies to support this expanding and specialist development area. Resin manufacturing specialists have stepped up to meet the challenge by offering customerfocused innovation to meet this sector’s unique needs. This is no easy task, as increasingly, the bioprocessing industry requires novel resin solutions that can optimise performance while reducing the cost of manufacturing.

Due to chromatography’s critical role in downstream bioprocessing and separation, it is clear dramatic growth in the demand for biopharmaceuticals globally will continue to stretch and challenge the resin industry’s supply chains.

Innovative Resin Materials Helping to Future-proof Supply For chromatographic mAb purification, agarose is widely considered the industry’s gold standard. Agarose is frequently used to separate large molecules and DNA, typically through a combination of affinity and ion exchange chromatography steps. In chromatography, agarose can be formed into resin beads and used in a range of methods for protein purification. It is a useful material as it is extremely hydrophilic, is very stable under alkaline conditions, does not absorb biomolecules to any significant extent and has good flow properties. Further advantages of using agarose include:

Answering the Global Demand for Effective Biologics More drug developers need high-performance, cost-effective

• •

48 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

High tolerance to pH extremes Extremely hydrophilic – minimal unspecific binding Summer 2022 Volume 5 Issue 2

Supply Chain Management A key strategy that larger manufacturers are employing is to source a second supply of critical raw materials (such as bioprocess resins), as well as ensure those suppliers have both domestic manufacturing and international manufacturing capabilities. This helps ensure supply chain risk is mitigated as much as possible.

From a global supply chain risk perspective when a resin supplier has more than one facility located in more than one country, it can help to ensure robust global distribution and business continuity as a hedge against risk – whether from a pandemic or social/geopolitical shifts.

• •

Low matrix volume (4–8%) – possible to achieve high capacity Easy to conjugate – To address continuing demand for higher capacity Protein A and Ion Exchange resins, resin suppliers must continue to build on the gains in dynamic binding capacity the industry has achieved in the last decade.

Innovation by biopharma’s resin suppliers is going to be needed across the landscape to address a growing list of critical challenges facing the industry now and in the future.

Increasingly, biopharma needs resin solutions that offer unique performance benefits, economies, and efficiencies beyond what is available through current synthetic, natural and inorganic resin technologies.

New Manufacturing Techniques Required Upstream titres currently have a growth rate of 2.4% at manufacturing scale and 3.5% at clinical scales.7 It’s therefore vital that the chosen resin can meet these demands both now and, in the future, to account for growth and to mitigate supply-chain caused manufacturing bottlenecks in downstream purification.

The development of advanced resin manufacturing technologies is also an important hedge against future supply chain risk and technological needs. For example, recent innovations in greener, continuous manufacturing processes are producing chromatographic resin beads with uniform particle sizes for unique performance characteristics and significantly reduced environmental impact.

These innovations are providing more sustainable alternatives to traditional resin manufacturing techniques which also boost mAbs manufacturing efficiency. Like the biopharma industry, its resin suppliers must do their best to manage supply risk end-to-end. Continuous resin manufacturing methods can help to achieve this by reducing manufacturing times, meaning better capacity utilisation in the facility, more available manufacturing slots, and greatly reduced lead times.

Supply Chain Agility and Resiliency Supply chain resilience is more important than ever for biopharma manufacturing. As a result, manufacturers are continually seeking ways to protect their supply chains against ongoing uncertainties, and other geopolitical shifts. www.international-biopharma.com

Reduce supply Chain Risk Strategically When a global network of qualified resin suppliers with long-term supply agreements is connected digitally and aligned operationally, the risk of a supply disruption interrupting production and delaying supply becomes less likely.

The technologies and platforms making this possible are becoming easier to implement and more effective in engaging trading partners effectively. It is imperative that every supplier in biopharma’s critical supply chain, especially resin suppliers, take their approach to supply chain operations and business processes very seriously.

REFERENCES 1.

2.

3.

4.

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6.

7.

https://www.precedenceresearch.com/biopharmaceutical-market https://www.who.int/data/gho/data/themes/topics/topic-details/ GHO/ncd-mortality#:~:text=Noncommunicable%20diseases%20 (NCDs)%20kill%2041,71%25%20of%20all%20deaths%20 globally. https://www.marketdataforecast.com/market-reports/ chromatography-resin-market https://www.fda.gov/news-events/press-announcements/ fda-expands-authorization-two-monoclonal-antibodies-treatmentand-post-exposure-prevention-covid-19 https://www.ema.europa.eu/en/news/covid-19-ema-recommendsauthorisation-two-monoclonal-antibody-medicines https://www.nature.com/articles/d41573-021-00079-7#:~:text= Thirty%2Dfive%20years%20on%20from,new%20 drug%20approvals%20each%20year.&text=In%20the%20 mid%2D1970s%2C%20immunologist,had%20a%20lab%20 space%20problem. https://www.bioprocessonline.com/doc/s-bioprocessing-year-inreview-key-takeaways-0001

Hans J. Johansson Hans J. Johansson is Global Applications Director at Purolite Life Sciences, Llantrisant, Wales. He has spent more than 30 years in the Biotech industry. Most of the time in research and development at Pharmacia/Amersham/GE Healthcare with a special focus on design and applications of industrial chromatography resins intended for antibody purification.

He frequently publishes in scientific journals and is the holder of more than ten patents around resin design and large-scale protein purification. He is currently working with development and applications of novel, agarose-based, chromatography resins.

INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY 49

Events Preview and Review

Scientific Conferencing of the Future During the COVID global pandemic it was inevitable that face-to-face scientific conferencing, a key aspect of which is to bring people together, would be affected. ELRIG was no exception, typically holding up to 15 events per year, from small informal networking sessions with only 40 attendees to large scientific gatherings with over 1300 delegates, a mandatory global lock down, meant things couldn’t proceed as usual (see Call Out Box 1; Who ELRIG is).

One of the advantages of the ELRIG operating model (with a small staff team and a fully engaged volunteer Board) meant that ELRIG was able to apply agile thinking and pivot immediately, turning many of its smaller events into webinars by making use of commercially available video meeting platforms.

Taking learnings from these smaller events, ELRIG was keen that a more ‘life-like’ approach should be taken for its flagship event, Drug Discovery. Then more than ever, it was critical that ELRIG’s 12,000 strong community could meet, learn, collaborate, and contribute to the pandemic’s scientific response, as well as meeting the needs of patients across the therapeutic space. Thus, Drug Discovery Digital was created, where a web-based digital platform combined with a virtual Who is ELRIG? The European Laboratory Research & Innovation Group (ELRIG) is a leading European not-for-profit organisation that exists to provide outstanding scientific content to the life science community. The foundation of the organisation is based on the use and application of automation, robotics and instrumentation in life science laboratories, but over time, we have evolved to respond to the needs of biopharma by developing scientific programmes that focus

50 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

convention centre, successfully enabled our community to listen and learn from talks and digitally walk the floor of our exhibition centre and posters (see Call Out Box 2; ELRIG’s Virtual Convention Centre). The response was tremendous with over 1500 delegates, listening to the 90 talks, across 8 days, with on-line questions and live voting sessions, the engagement was high, and vendors reported plenty of contacts through their digital booths, all achieved with the delegates being based from their home offices.

Despite the success, the informality and spontaneity of informal meetings was missed, and ELRIG worked hard to make events covid safe for their community as soon as Government guidelines enabled them to take place. However, the additional opportunity digital conferencing provided for remote attendees and speakers, highlighted that there was value in combining both approaches. This sparked, ELRIG’s approach to scientific conferencing of the future.

For ELRIG’s remaining 2022 events and especially Drug Discovery 2022, taking place in London Excel on the 4th and 5th October (see Call Out Box 3; Drug Discovery 2022 Topics), ELRIG now have talk tracks that have a mix of “in-person” and “live-virtual” speakers. This enables ELRIG to engage speakers who normally would not be able to attend, either because they on cutting-edge research areas that have the potential to revolutionise drug discovery.

Comprising a global community of over 12,000 life science professionals, participating in our events, whether it be at one of our scientific conferences or one of our networking meetings, will enable any of our community to exchange information, within disciplines and across academic and biopharmaceutical organisations, on an open access basis, as all our events are free-of-charge to attend.

Summer 2022 Volume 5 Issue 2

Events Preview and Review are too busy or unable to travel. The technology enables the creation of an environment where virtual speakers feel like they are in the auditorium, as they have a view of the room, can answer questions, and engage with the in-person audience.

In addition, the delegate experience has also changed. Using the conference app means delegates can plan their meeting experience in much more detail than they have in the past.

ELRIG has already planned it’s 2022 face to face events which include plenty of time for networking and interactions that just can’t be obtained virtually (see Call Out Box 4; ELRIG’s 2022 Events). Whilst you may miss out on the informal aspects of the meetings, as most ELRIG talks are now recorded and are made available for viewing later, the events are accessible to those who cannot or choose not to attend in person. This digital component not only extends the ‘shelf- life’ of the conference beyond its planned dates it also increases the reach of ELRIG’s open-access science across the globe.

ELRIG is leading the way in creating the scientific conferences of the future, hosting hybrid meetings that contain cutting edge content delivered by its community and partners and creating the right face-to-face elements that encourage the informality needed for collaboration and innovation, as well as making content accessible to all.

ELRIG’s Virtual Convention Centre

Drug Discovery 2022 Topics DRUG DISCOVERY 2022 DRIVING THE NEXT LIFE SCIENCE REVOLUTION. 4–5 OCTOBER 2022, EXCEL, LONDON DRUG DISCOVERY 2022 ELRIG’s annual Drug Discovery meeting which remains Europe’s largest meeting for life sciences industry professionals. During this conference, ELRIG will celebrate its long history of hosting disruptive and innovative drug discovery technology developments, whilst exploring the next life science revolutions.

Since the pandemic, Drug Discovery and scientific achievements have reached into people’s lives in way not seen before. This has driven support for diverse and collaborative thinking to make unprecedented scientific progress. The ELRIG community are now facing an exciting prospect to help drive this renaissance in life sciences.

Drug Discovery 2022 promises to provide a platform for the whole drug discovery community to meet at a free to attend, in-person event. ELRIG has partnered with; BPS, SLAS, and RSC to draw together an exciting and progressive 2-day event containing; cutting-edge advancements in screening, automation and high content imaging, and innovations in disease models, advances in cell and gene therapies, revolutions through partnerships, future perspectives in medicinal and green chemistry and finally creative thinking to deliver therapies to one of the most challenging diseases facing society; COPD. ELRIG committee invites you to attend this exciting meeting, and contribute to this revolution through, submission of (poster Abstracts) and round-table discussions throughout the 2-days – We look forward to your contribution!

• • • • • • •

Overcoming Challenges and New Directions in Medicinal Chemistry High Content Imaging in Drug Discovery Cell & Gene Therapy Drug Discovery and Development in COPD (BPS) Innovation through partnership Frontiers of Chemistry applied to Drug Discovery (The RSC) Developments in Preclinical Models Advancements in Screening and Automation (SLAS)

Conference Directors: Simon Chell | Simon Ward | Katie Chapman | Jon Hutchinson

www.international-biopharma.com

INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY 51

Events Preview and Review

Anglonordic Life Science Conference 2022 Entering its eighteenth year, the Anglonordic Life Science Conference 2022 took place at County Hall in London, just a stone's throw away from the buzzing South Bank.

This was the first in-person event after two years of onlineonly events due to the pandemic. The Anglonordic Life Science Conference continues to grow by giving its delegates and partners the opportunity to meet over 250 decision makers representing leading and upcoming R&D companies, international pharmaceuticals and investment firms.

As a prelude to the conference, H.E. the Ambassador of Denmark to the UK, hosted an exclusive Anglonordic Drinks Reception at his Central London Residence for all conference attendees. The reception was organised in collaboration with Invest in Denmark, part of the Ministry of Foreign Affairs of Denmark.

trade organisation that assists international partnerships, leading Investment firm M Ventures, and Optimum Strategic Communications producing the conference programme.

With an established format of panel discussions, company presentations, parallel technology and biotech investment rooms, plus 1:1 meetings, this conference added exceptional value to the world of biotechnology, medicine and pharma.

Highlights of the programme included a panel discussion on Trends in Life Science Investments, where Europe's leading investors provided an overview of their outlook on the market, as well as current and future trends that are driving investment in the healthcare sector. This was followed by an interactive workshop hosted by McDermott Will & Emery, which gave an overview of key considerations for venture capital investment rounds for early stage life sciences companies as well as licences and collaborations.

This year's conference, held on May 5th, 2022, had an elite audience of over 250 people including decision-makers from the fields of drug discovery, medtech, pharmaceuticals and investment firms. More than 70 investors were in attendance.

Guest countries Spain and Denmark also participated with delegations of R&D companies and investment firms.

A panel discussion on 'RNA in the Spotlight' saw industry experts discuss RNA therapy's potential to treat a wide variety of diseases, including cardiovascular disease, and cancer. Another panel discussion, Anticipated Developments in Neuroinflammation Therapies, explored the anticipated developments in neuroinflammation to reverse neurodegeneration, chronic pain and many other conditions.

As in previous years, Anglonordic kept to its tradition of exclusively connecting European investors and R&D companies from the Nordics and the UK. The conference is organised by established industry names: BioPartner UK, the

After conclusions on the day's discussed themes and topics, everyone signed off with celebratory drinks and a promise to meet at the same place, with the same enthusiasm and new ideas and new developments next year.

52 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

Summer 2022 Volume 5 Issue 2

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Ad Index

Page 53

Achema 2022

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Airfreight Pharma

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BioEurope 2022

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Bio Pharma Group

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Cellbox Solutions GmbH

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FUJIFILM Wako Chemicals USA

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Page 5 SGS OBC UPC Cambridge Limited Page 40–41

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I hope this journal guides you progressively, through the maze of activities and changes taking place in the biopharmaceutical industry

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Summer 2022 Volume 5 Issue 2