IPI Summer 2021

Volume 13 Issue 2

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Medical Monitor’s Conundrum Making Sense of Site/Central Discordance in Radiology Assessment Multifactorial Disease Models Their Role in de-risking Topical Formulation Development Pharmaceutical Trends Water Activity Measurement Covid Vaccination Serialization The Journey So Far

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Contents 06 Editor’s Letter TALKING POINT 08 A World Leader in Naturally Derived Products Discusses Commercial Success and New Innovations DIRECTORS: Martin Wright Mark A. Barker INTERNATIONAL MEDIA DIRECTOR: Ty Eastman ty@pharmapubs.com BUSINESS DEVELOPMENT: George DeSouza george@pharmapubs.com EDITORIAL: Virginia Toteva virginia@pharmapubs.com DESIGN DIRECTOR: Jana Sukenikova www.fanahshapeless.com FINANCE DEPARTMENT: Martin Wright martin@pharmapubs.com RESEARCH & CIRCULATION: Jessica Dean Hill info@pharmapubs.comn COVER IMAGE: iStockphoto © PUBLISHED BY: Pharma Publications J101 Tower Bridge Business Complex London, SE16 4DG, United Kingdom Tel: +44 (0)20 4541 7569 Fax: +44 (0)01 480 247 5316 Email: info@pharmapubs.com www.ipimediaworld.com All rights reserved. No part of this publication may be reproduced, duplicated, stored in any retrieval system or transmitted in any form by any means without prior written permission of the Publishers.

The next issue of IPI will be published in Autumn 2021.

ISSN No.International Pharmaceutical Industry ISSN 1755-4578.

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

This publication is protected by copyright.

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Mr. Darren Alkins CEO at SPL – Scientific Protein Laboratories, speaks with IPI about their continued development in their science and technical expertise to meet the demanding requirements for new applications and to realise commercial success in a timely manner.

REGULATORY & MARKETPLACE 10 How Technology can Help Build a Fairer, Healthier World Over the past couple of years, how we live our lives and do business have both fundamentally and irrevocably shifted. Richard Ettl at SkyCell explains that despite the hurdles we’ve had to jump this year, technology has continued to meet and answer these challenges and will set us up for a fairer, and healthier future – if used correctly.

16 The EU Medical Devices Regulation and its Market Impact Under the Spotlight The global drug-device combination products market was estimated to be worth US$ 123.5 billion in 2020 and is forecast to grow at a CAGR of 8.2% between now and 2027. The new combination products entering the market don’t just include traditional parenterals, but autoinjectors and inhalers too, as well as other next generation devices. Nadine Kasidas-Neale at Recipharm explains the incoming changes to EU medical device regulations and their impact on pharmaceutical companies developing drug delivery devices, including autoinjectors for the EU market.

20 Digital Technology for Building Resilient Healthcare Systems in Thailand and Southeast Asia The healthcare systems in Southeast Asia are at a critical juncture today. The new wave of COVID-19 infections is straining healthcare facilities as cases continue to rise at an alarming rate, while most countries struggle to organise the required medical resources. Roshel Jayasundera at Axios International reveals that Thailand, much like the rest of the region, has been busy expanding its in-patient hospital capacity to accommodate the surge of COVID-19 patients and minimise the damage caused by the virus.

DRUG DISCOVERY, DEVELOPMENT & DELIVERY 22 Multifactorial Disease Models: Their Role in De-risking Topical Formulation Development (MedPharma) A company’s attitude towards risk fundamentally affects their product development strategy, which can vary between the development of a simple or prototype formulation or a fully market-ready, commercially viable product to be used in initial preclinical/clinical evaluation. Large pharma, with many potential drug candidates to prioritise, tends to be more risk-averse and so generally focuses on entering clinical evaluation with a market-ready formulation that has been developed with risk mitigation considered throughout the development process.

Dr. Jon Lenn and Prof. Marc Brown at MedPharm explain why, for these large companies, an early failure is much less expensive than a failure in the clinic.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 1

Contents 26 Compartmentalised Microfluidic Devices for Drug Discovery in the Neurosciences Neurological disorders are incredibly complex, and this is reflected in the lack of knowledge of the underlying pathological mechanism for many of these diseases, and in turn to the slow speed at which novel drug targets are identified. Mark Aurousseau at eNUVIO reveals that regardless, research in the field remains vibrant, and the emergence of novel research technologies and tools continues to lead to exciting discoveries that hold promise to translate into the development of novel therapeutics.

30 Time to Put the Spotlight on the Substance of your Drugs through Solid-form Development The global pharmaceutical industry generated more than $1.25tr in revenue in 2019, up from $1.2tr in 2018, and the final figures for 2020 are expected to be even more impressive. In such a fast-paced environment, pharmaceutical companies need to do all they can to ensure their products, no matter whether they are new innovations or improvements to existing active pharmaceutical ingredient (API) solids, stand out in the market. The question facing pharmaceutical companies is: how to? John Mykytiuk at Sterling Pharma Solutions explains that the answer to achieving these all-important enhancements lies in perfecting the physical characteristics of the API solid itself through solid-form development.

34 Accelerating Pharma Research with Sensitive Spatial Analysis of Challenging Molecules To reduce attrition rates in pharmaceutical research and development (R&D), powerful quantitative analytical methods are needed to monitor therapeutic compounds, their metabolites, and target engagement. The ability of matrix-assisted laser desorption/ ionisation (MALDI) imaging to perform quantitative spatial analysis of drugs and their metabolites, as well as pharmacodynamic (PD) biomarkers in tissues, is accelerating its use in pharmaceutical research. Dale Shannon Cornett at Bruker describes how advances in technology and methodology are opening MALDI imaging up to analysing a wider range of small molecules without compromising image resolution.

40 How Endotoxin Contamination Can Affect Gene and Cell Therapies Gene therapy is revolutionising the way we treat human diseases.

Any technique that modifies a person’s genes to treat or cure a disease is considered a form of gene therapy. Lisa Komski at FUJIFILM Wako Chemicals U.S.A. Corporation says that this can occur via several possible mechanisms that she discusses in this article.

44 Choosing the ‘Right’ Device to Deliver Your New Therapy: Four Simple Steps When you develop a new therapy, the device you develop or select to deliver will be a key to the overall success of your product. You may have spent considerable time and investment developing your drug. However, if your device doesn’t perform technically or the patient struggles to use it, then the chances of that drug successfully delivering the therapy to the patient are severely compromised. In this article, Charlotte Harris at Team Consulting discusses how to select the ‘right’ device to deliver your therapy.

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CLINICAL & MEDICAL RESEARCH 48 Medical Monitor’s Conundrum: Making Sense of Site/Central Discordance in Radiology Assessment Concerns over disagreements between the interpretation of medical images performed by investigators and those performed by blinded independent reviewers (BICR) accompany most trials that involve imaging biomarkers. This article by Dr. Surabhi Bajpai and Dr. Manish Sharma at Calyx is intended to be a brief introduction to this topic and provides some guidance on how to manage such disagreements.

TECHNOLOGY 52 Pharmaceutical Trends: Water Activity Measurement Water activity has been universally used in the pharmaceutical industry since the publication in 2006 of USP. It is defined as the energy status of water in a system and is rooted in the fundamental laws of thermodynamics through the Gibbs free energy equation. It represents the relative chemical potential energy of water as dictated by the surface, colligative, and capillary interactions in a matrix. In the next lines, Dr. Brady Carter at Carter Scientific Solutions discusses this topic further.

MANUFACTURING 56 Dwell Time and its Influence on Tablet Production Manufacturers of pharmaceutical tablets are continuously under pressure to make production more efficient. It needs to be quicker, more cost-effective and able to keep in line with the competition from fellow oral solid-dose producers and developing markets. Alex Bunting at I Holland discusses why quality must be a top priority, on top of all these challenges.

60 Extrusion-Moulding-Coating Process Advantages for Continuous Manufacturing of Oral Solid Dosage Forms Traditionally, the pharmaceutical industry has employed batch processes to manufacture solid oral dosage forms. In batch manufacturing, the typical lead time of a solid oral dosage form can be up to one year, which can result in drug shortages in case of a significant change in the demand. In addition to major reductions in the production time and footprint, continuous manufacturing decreases the manufacturing costs significantly, as well as the number of unit operations involved.

Federica Casati at IMA Active notes that continuous manufacturing can be coupled with in-line analytics to monitor the process material constantly and reject a much smaller quantity in case of an anomaly.

PACKAGING 66 How the Rise of Biologics is Spurring a Packaging Revolution With global sales of biopharma treatments hitting an all-time high of $300 billion in 2020, it is clear that the biologics space is playing an increasingly important role as a driver of growth in the wider pharmaceutical industry. Marcelo Cruz at Tjoapack explores the rise of biopharma treatments and explains why, to keep up, pharmaceutical packaging needs to change.

68 Serialisation: Headache or Opportunity?

The scourge of counterfeit drugs continues to threaten global health programmes. When it comes to dealing with the impact of counterfeit Summer 2021 Volume 13 Issue 2

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Contents trade, there is an increasingly heavy burden placed upon healthcare systems, healthcare professionals, national medicine regulatory authorities, law enforcement agencies and criminal justice systems.

To counter this growing threat, Gaurav Mohite at ACG Worldwide reveals that government bodies are enacting more robust and stricter regulations to control the genesis and proliferation of fake medicines.

72 Fake Medications? Suggestions and Approaches to Help Ensure that Patients and their Family Members are Not Left Worrying Until recently, only those medications purchased online were considered dangerous. 90% of all products purchased from internet pharmacies have been shown to be fake. However, the more parcel shipping is becoming an everyday part of the supply chain, the greater the vulnerability of stationary pharmacies to potential fraud.

Marietta Ulrich-Horn at Securikett discusses that with its Directive 62/2011, the EU has introduced stringent measures to ensure that prescription drugs can be traced back to their origin with a unique code for each package, allowing for tracking. Additionally, tamperproof sealing for the package is intended to guarantee this.

74 EU Falsified Medicines Directive: A Technical & Implementation Success Since early 2019, manufacturers of pharmaceutical goods have been required to add additional security labelling to certain products sold in the European Union. Under the terms of the EU Falsified Medicines Directive (EU FMD), prescription pharmaceutical products are now required to have a verifiable 2D data matrix code and tamper-evident labelling included as part of their product packaging. In addition, Bart Vansteenkiste at Domino Printing Sciences clarifies that a humanreadable unique serial number is required to meet the Directive’s requirements, as well as a product code, batch number, and expiry date for the contents.

79 Thinking Inside the Box The idea of sustainability as we know it today began to step out of the shadows around 30 years ago. Back then, healthcare executives and practitioners couldn’t know whether this would prove to be a willo’-the-wisp or a guiding light on a critical journey. Matt Tomkinson and Paddy O’Hara at Softbox discuss if new temperature control packaging initiatives meet cold chain sustainability goals without compromising performance.

LOGISTICS & SUPPLY CHAIN MANAGEMENT 82 Tackling Supplier Management Challenges to Build a More Agile and Resilient Supply Chain

and track-and-trace sector has been in overcoming the multiple logistical challenges posed by the global Covid vaccination roll-out.

86 Trust But Verify: Importance of Packaging Compendial Testing to Secure the Parenteral Drug Supply Chain We normally think of trust in the context of our personal relationships with other people, but how often do we consider trust with respect to the products we use? Most of the products used on a daily basis we implicitly trust them to work as advertised because we assume the company providing the product has done sufficient functionality, safety testing and quality control and that there exists somewhere a governmental/regulatory rule requiring testing of said product for human safety by some approved standard before the product can be sold to the consumer. Marc Mittermueller, Flor Toledo Rodriguez and Dan Haines at Schott discuss that for parenteral products, we go one step further with trust, verifying the potentially severe impact to patient safety from counterfeit, mislabelled, mispackaged, defective or non-compliant products.

92 Lessons Learned from the COVID-19 Vaccine Cold Chain Control Tower Gisli Herjolfsson at Controlant explains the tracking technology used by the company's supply chain visibility systems. Controlant is providing temperature monitoring and supply chain visibility for the Pfizer-BioNTech vaccines and is working with the U.S. federal government and Operation Warp Speed stakeholders to monitor vaccines during onsite storage.

98 The role of Hostile Vehicle Management in a Protective Security Strategy Hostile vehicle management (HVM) has a critical role to play in protecting property and, more importantly, people. In this article, Richard Winstanley at Bft Automation explores how pharmaceutical firms can incorporate HVM into their security plans.

100 Pharma Airports: A Key to Global Success?

The past year has proven that the medical world is at the forefront of human innovation. The pharmaceutical industry is our weapon of choice against the COVID-19 pandemic, whilst simultaneously tackling other diseases, treatments and cures, thus extending our life expectancy age. Samuel Speltdoorn at Brussels Airport discusses how the developments and manufacturing of recent biopharmaceuticals are groundbreaking, although the logistics behind them are often overlooked and ignored at the board level, resulting in an undervaluation of a well-organised supply chain.

The ongoing supply chain disruptions caused by COVID-19 have made one thing clear, says John Bermudez at TraceLink. Pharmaceutical companies need a new and innovative way to work with suppliers and supply chain networks, so they can more quickly adjust to changing conditions, avoid or mitigate disruptions, and ensure that the right medicines are delivered to patients on time, in full (OTIF).

84 Covid Vaccination Serialisation – The Journey So Far The global Covid pandemic has been one of the worst disasters we have collectively faced for generations, resulting in hundreds of thousands of deaths, disabilities, and losses of livelihoods. Alf Goebel at advanco examines how successful the pharmaceutical serialisation 4 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Editor's Letter So, 2020 has been a bit like living inside a sci-fi movie, strange and fantastical, in all the wrong ways. However, if a year ago you had told me about the pandemic and told me that we had already had six vaccines developed and being rolled out, less than a year since we made ‘first contact’ with the virus, then I really would have thought you had taken leave of your senses and entered a parallel universe. The global response, particularly from the pharmaceutical industry, has been nothing short of phenomenal. The previous record for developing a vaccine against a new pathogen was held by the Ebola virus vaccine, which took five years to develop. A decade is more commonplace. But instead of 10 years, we did this in 10 months. As a result, we can see a light at the end of the tunnel. The US government even borrowed a Star Trek term to help us to get here, calling its COVID-19 vaccine acceleration programme ‘Operation Warp Speed’.

One effect of this most science fiction-like of years has been to put the pharmaceutical industry centre stage like it never has been before. Who would have thought a year ago that we had all become such experts on vaccine types, cytokine storms and R numbers? While the likes of Pfizer and AstraZeneca were probably household names beforehand, few outside of our industry would have heard of BioNTech and Moderna a year ago. The pharma industry, which, by and large, did not have the greatest of public images, is now riding to all our rescues. Whereas previously, many viewed big pharma as a nefarious shadowy enterprise, now it is coming together to save the world. It is to be hoped that it can continue to build on its enhanced reputation in the months ahead as the vaccine challenge moves to be one which is more logistical than scientific. But we should not underestimate the enormity of that challenge, for both pharma and governments. It is a sobering thought that tuberculosis, a disease for which there have been not only vaccines but drug treatments for decades, still manages to kill.

So, on this quest for a greater and good pharma industry, IPI has bought you a vivid array of articles, which will help our executives to boldly venture into uncharted territories.

Our Regulatory section begins with Richard Ettl at SkyCell describing how technology can help build a fairer, healthier world, and Nadine Kasidas-Neale at Recipharm explaining the incoming changes to EU medical device regulations and their impact on pharmaceutical companies developing drug delivery devices, including autoinjectors for the EU market.

explain why, for these large companies, an early failure is much less expensive than a failure in the clinic.

The Asian market has seen a rapid onslaught by this COVID 19 predicament. Roshel Jayasundera at Axios International reveals that Thailand, much like the rest of the region, has been busy expanding its in-patient hospital capacity to accommodate the surge of COVID-19 patients and minimise the damage caused by the virus.

Marietta Ulrich-Horn at Securikett discusses that with its Directive 62/2011, the EU has introduced stringent measures to ensure that prescription drugs can be traced back to their origin with a unique code for each package, allowing for tracking, and tamper-proof sealing for the package is intended to guarantee this.

The Drug Discovery and Development Section starts looking at the role of multifactorial disease models in de-risking topical formulation development.

Dr. Jon Lenn and Prof Marc Brown at MedPharm Our world was disrupted during 2020. Are you ready to gain a deeper understanding of the year that changed our perceptions of possibility?

Much like the real universe then, it seems that the pharma R&D universe continues to swell inexorably and that not even evil alien invaders from the planet Corona can halt the expansion of its empire.

In an atmosphere of mounting pricing pressure and changing regulatory requirements, global pharmaceutical and life sciences companies face increasing challenges to achieve and maintain profitable growth. Global pharmaceutical outsourcing offers companies an opportunity to face these challenges. By forming strategic relationships with outsourcing partners, companies can focus on core competencies, access specialised expertise, achieve cost-saving benefits and reduce burn rates that lead directly to greater shareholder value.

Over the past two decades, the outsourcing of R&D and manufacturing processes has become increasingly prevalent and is now a major trend

Another topic of enormous importance in today’s online market environment is fake medications. What is being done to help ensure that patients and their family members are not left worrying?

I hope this issue of IPI keeps you entertained this glorious summer. Get your vaccines and look forward to meeting you all in person soon.

Lucy Robertshaw, CEO LucyJRobertshaw in the pharmaceutical industry. Pharmaceutical companies have moved up the value chain for outsourcing from non-core functions, such as IT and human resources, to secondary core functions, such as R&D and manufacturing.

Even a small reduction in drug development time can yield substantial cost savings and significant benefits. Contract research or contract manufacturing (CRO/CMO) partners help eliminate bottlenecks, provide immediate access to advanced technologies and, ultimately, help reduce development cycles and time-to-market.

How can pharmaceutical and life sciences companies strategically engage global outsourcing?

I am delighted to bring you a wide array of articles in this issue of IPI, which will help you understand all the recent developments in the industry.

I look forward to meeting you with the next issue in October and hopefully see all of you in person at CPHI/ICSE, Pharmapack and others. Till then, stay safe.

Virginia Toteva, Editorial Manager – IPI

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

Georg Mathis Founder and Managing Director, Appletree AG

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

Catherine Lund, Vice Chairman, OnQ Consulting

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

Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

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

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

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

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

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

Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group

Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

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

Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

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

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

Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting Stefan Astrom, Founder and CEO of Astrom Research International HB T S Jaishankar, Managing Director, QUEST Life Sciences Summer 2021 Volume 13 Issue 2

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 7

Talking Point

A World Leader in Naturally Derived Products Discusses Commercial Success and New Innovations Mr. Darren Alkins, CEO at SPL – Scientific Protein Laboratories, speaks with IPI about their continued development in their science and technical expertise to meet the demanding requirements for new applications and to realise commercial success in a timely manner.

Q: SPL – Scientific Protein Laboratories LLC (SPL) is a World Leader in Heparin and Pancreatic Enzymes. Can you tell our readers the brief history of your company, how the company got started and your growth so far?

A: SPL was started in 1976 as a branch of Oscar Mayer, a large meat producer located in Madison, the capitol of Wisconsin. Oscar Mayer launched SPL to take advantage of unused animal tissues containing pharmaceutical substances (Heparin & Pancreatin). SPL’s mission has always been to be the world’s leading manufacturer of high-quality Active Pharmaceutical Ingredients (APIs) derived from biological sources supplying the healthcare industries.

Our growth has been driven by the increased demand for heparin and pancreatic enzyme products. As the uses for these invaluable, essential medicines has expanded, SPL has grown to keep pace with these innovations.

SPL’s original focus was on Heparin, Pancreatin, and Blood Protein products.

Now, 45 years later SPL’s portfolio includes Heparin and heparin derivatives, Pancreatic enzymes, Blood products, Thyroid, peptide hormones, collagen and related derivatives, molecular scaffolds, and other biologically derived products. SPL has expertise in extracting specific molecules/substances of interest from all types of biological tissues.

SPL’s products can meet the rigorous requirements for both pharmaceutical dosage forms, medical devices, and complex combination products.

Q: How do you fit into the landscape of drug development?

A: SPL, Scientific Protein Laboratories, is a world leader for manufacturer of highquality Active Pharmaceutical Ingredients derived from natural sources supplying the healthcare industries. Our expertise supports development, purification, and supply of active ingredient from a diverse 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

range of biological sources. Because of our long history in handling, defining, and controlling these complex materials, we can produce high quality products that few others can manage. In some cases, we are the sole source. In all cases, our experience and skills managing the safety and compliance risks related to biological sources is unique and one of the best in the industry.

Q: You have placed great emphasis on expansion and diversification of your product pipeline, and corporate development programmes. Can you tell our audience how you have achieved this and what is your vision for the future?

A: SPL has expanded its product portfolio in two primary ways. First, we have built the infrastructure and capabilities to meet and exceed our customers’ expectations. Second, we have formed strategic partnerships to bring new products to market. In both cases, the result is world-class technology and quality.

SPL has the scientific and engineering expertise to make any product derived from biological substances. Throughout the entire process, SPL applies the highest regulatory and quality standards to all

aspects of the process. SPL is regularly audited by regional authorities and customers. We maintain a strong reputation for high technology, reliability and quality.

Q: You offer more than 30 years’ experience in manufacturing APIs from biologically-derived sources. What are your product pipelines, and how have you made a difference in the industry through your portfolio?

A: SPL’s customer base includes some of the highest performing companies in the pharmaceutical industry. For decades, SPL has been supporting new indications, regulations, patient safety concerns, and global supply chain changes. SPL has developed global experience with a wide variety of complex products and their related supply chains.

The primary difference between SPL and our competitors is our science, quality, discipline, knowledge, and experience from the point of harvest, through purification of the product, up to and sometimes including the finished product.

We offer high-quality products, with excellent traceability and risk management controls. Our scientific, regulatory, and quality departments are best in class.

Summer 2021 Volume 13 Issue 2

Talking Point

Q: Can you explain your regulatory and analytical support services? What are you offering, and how do you make a difference in the industry?

A: SPL has a world class fully operational QC, Micro, and qPCR laboratory. We specialize in bio-sourced materials but can work with a broad array of substances. Additionally, we have the capability to develop test methods for products, for new or existing method improvement. SPL’s analytical team is key to our success with manipulating biologically derived substances from a complex supply chain. We have special expertise with the complex matrices presented by bio-sourced products.

Our regulatory group effectively supports drug filings across the globe. We also have significant experience in devices and other technologies that require biologically derived drug substances. We are best in class at bridging the gap between common pharmaceutical standards and non-drug industries.

Q: SPL offers a broad spectrum of technology capabilities in support of development and manufacturing services for the extraction, isolation and purification of naturally-derived materials and fermentation, isolation, and recovery of therapeutic proteins.

Can you give us a detailed market demand, and tell us your growth potential?

A: SPL’s capacity is often sold out well into the future. With each expansion and capacity increase, we establish close, long term customer relationships. We carefully select our partners to ensure we can support their needs and exceed expectations over the long term.

We judiciously manage the full supply chain, ensuring that everyone benefits and hold the finished product to the highest standards. As an example, the markets for porcine derived products (heparin and pancreatin in particular) are under pressure (globally) from the African Swine Fever (ASF) outbreak in 2019. In both cases demand for the products is at or above 2019 demand, but global raw material supply remains less than before. Our supplies and quality remain some of the highest in the world.

Many of the new products we are working on are new markets or have limited competitors. In both cases, SPL is competitive and experienced great success.

Q: What major events have occurred in the industry and what has been its effects.

A: As the population in the developed nations has aged and as more people have access to modern medical care, the demand for SPL products has been growing robustly.

We expect that these demographic trends will continue and will require SPL to continue innovating to meet this need. In addition, medical science continues to find new applications for bio-sourced ingredients.

SPL has continued to develop its science and technical expertise to meet the demanding requirements for these new applications.

Q: What role do SPL and your services play on their client’s journey to commercial success?

A: SPL’s quality, experience and expertise enable our clients to realise commercial success in a timely manner. We apply our experience to new products and processes, but always adapt to the specific requirements of the new innovations.

Dareen Alkins Darren is the CEO of SPL and has 32 years experience in the pharmaceutical business. He started his career at Bristol – Myers Squib in sales, marketing and business development. He has been the president of three pharmaceutical companies. Darren is the former head of Teva US business development.

Most recently, Darren was the General Manager of generics and dermatology at Sandoz US.

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 9

Regulatory & Marketplace

How Technology Can Help Build a Fairer, Healthier World Everyone can agree that the world has changed irreversibly – so much so that the term ‘new normal’ has been dropped, as it has become the normal that we now live by. Over the past couple of years, how we live our lives and do business has both fundamentally and irrevocably shifted. With a ‘glass half full’ mindset, I believe that despite the hurdles we’ve had to jump this year, technology has continued to meet and answer these challenges and will set us up for a fairer, and healthier future – if used correctly.

The pandemic has meant that technology has become deeply ingrained throughout society and has put the limitations of equal access into stark perspective. In order to create a fairer, and healthier, world, we need to ensure that access to life-saving medicines and the technologies that deliver them are felt in every corner of the world – not just the countries who can afford them.

Though not a new issue, with sensitive medicines such as the current batch of COVID-19 vaccines – from Pfizer to AstraZeneca – temperature control and safe transport are more crucial than ever. With limited ability to manufacture vaccines at the scale the world needs, making every drop count is of the utmost importance.

With accidental temperature excursions, lack of storage facilities and potentially long waiting times in-transit, it is imperative that technology answers this problem to help ensure that within the supply chain, margin for error is removed and where possible, vaccines are not spoiled and will indeed reach their end destination – saving millions of lives.

A truly global problem, with every country in the world affected, the COVID-19 pandemic has shown us that we need to make access to life-saving pharmaceuticals ubiquitous across the globe. Shining a light on resources available to first world vs third world countries, with rich nations vaccinating one person every second vs poorer nations who are yet to give a single dose, there is a clear divide between the two and their respective access to these medicines. This is a present and growing threat, as for these countries without access to vaccines, the risk of outbreak and further spreading of the virus is rising. It must be a massive global effort, by rich and poor countries alike, to work together to stop the spread and eliminate COVID-19 altogether.

In fact, People’s Alliance, which includes Oxfam and Amnesty International, have stated that at least 90 per cent of people in 67 low income countries stand almost no chance of getting vaccinated this year because wealthier nations have reserved more than they need. In the UK, 400 experts have called on the Prime Minister to waive vaccine patents. However, if we suspend patents entirely, it will kill off innovation if the vaccine needs to be updated, or in the next pandemic. We should instead ensure that countries can obtain a licence and be able to manufacture the vaccine

properly. This divide, with wealthy countries vaccinating their populations and poorer nations unable to get enough doses, has essentially created a ‘vaccine apartheid’.

With changes to the aforementioned intellectual property laws, efforts of the global vaccine project will be increased tenfold, and would address the disparity between wealthy and poor, ensuring equal access to vaccines. This would also reduce the politicisation of vaccines and transform vaccines from a benefit afforded to some to a guaranteed right. Funding is also an issue, with poorer nations having difficulty affording doses. Though the hope is that the expected 90 million Covax doses will help even out distribution, with rising cases in both India and Europe that is looking ever more unlikely, as countries continue to prioritise their immediate needs and not long-term global requirements.

COVID-19 is extremely infectious – it may seem logical to prioritise vaccinating a single national population, but in a globalised world, this health crisis only truly ends with a concerted international effort. A harrowing parallel to draw is the patent laws and distribution of HIV/AIDS drugs, also resulting in deaths – still to this day, there are countries where this is seen as merely a chronic condition, but there are others

Luckily, innovations driving new technology meeting these challenges have emerged to meet this increased demand – necessity is the mother of invention, after all. As such, technology can be an equaliser in this space, with new innovations that look to ensure lack of access to basic technology does not stop anyone, anywhere, from receiving the medications they need.

10 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2021 Volume 13 Issue 2

Regulatory & Marketplace where an HIV/AIDS diagnosis is in effect a death sentence. In this current crisis, we must learn from the mistakes of our past.

For most countries, vaccine rollout will continue to gain momentum over the coming months, and the pharmaceutical supply chain will need to continue to both adapt and be flexible in this unprecedented environment for the foreseeable future, and possibly forever. This pressure applies to all vendors within the supply chain, from manufacturers producing the vaccines, to the distributors managing logistics, to the carriers transporting these vaccines to their end destination.

Prior to COVID-19, the supply chain within the pharmaceutical industry was not a point of discussion. Before the pandemic, vaccines made up just 1.5% of global pharmaceutical sales and so their distribution has always been a niche aspect of the supply chain. Now, with the healthcare industry across the globe aiming to vaccinate around seven billion people, most requiring a double-dose, 14 billion doses will need to be manufactured and distributed with minimal spoilage, which

TOPRA Symposium now online!

would counteract these efforts. Strain is to be expected, and distribution will take time, but it can be said that the ‘teething stage’ within the entire supply chain might just be behind us, or might nearly be behind us if the right moves are made and laws are revised appropriately.

There are many challenges facing the safe delivery of vaccines to poorer nations, due to remote locations and lack of infrastructure, as well as the political roadblocks that inevitably exacerbate these issues. Often, climate is a factor, leading to even more problems when timing is everything and infrastructure is lacking.

This presents a considerable challenge, with every solution unique to each country by necessity.

At the beginning of the pandemic, UNICEF pre-emptively reserved a stockpile of a half a billion syringes outside the countries producing them. However, countries put export controls on both vaccines and syringes and as prices rose, supplies were of course limited. Other countries followed suit, leading to a sort of ‘vaccine nationalism’, effectively putting a massive

chink in the global vaccine supply chain and disrupting fair and consistent rollout.

Though the rollout of Covax vaccine is looking promising in achieving more widespread distribution, only the countries that are part of Covax have the infrastructure needed to get the vaccine pallets off planes and into refrigerated storage warehouses.

Ghana is one of these lucky countries to successfully distribute Covax doses, though countries in West Africa, for example, do not have that luxury. It is critical that the means of distribution are adaptable to different environments. This can be on a large scale, such as adapting to temperature fluctuations within a given country, with things as simple as making sure vaccine containers can withstand both metaphorical and literal bumps in the road.

As I mentioned above, funding remains one of the quintessential roadblocks to fair distribution. With remote areas lacking infrastructure to house vaccine shipments, funding is needed to support the construction of warehouses. Though there have been many contributions from countries, from the EU to the UK and the US,

“The platform has worked very well and given the challenges of speakers and delegates all being remote, I think that the speaker discussions and responding to delegate questions has been done well.”

— 2020 TOPRA Symposium attendee

22–24 September 2021 | Online event

Revolution in Regulatory Affairs: How the pandemic is shaping regulatory science Register now www.topra.org/ipi-sym21 What is TOPRA? TOPRA is the professional membership organisation for individuals working in healthcare regulatory affairs across all sectors – from medicines and combination products to medical devices and IVDs. We work with our members internationally to enable and promote excellence across the healthcare regulatory profession.

www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 11

Regulatory & Marketplace we are still nowhere close to closing this funding disparity. UNICEF estimates that an additional 2 billion dollars is needed to help the 92 poorest countries who are in need of fridges, expenses for vaccinators, health worker training, fuel for trucks and more.

Finally, the last challenge is resistance – both from wealthier countries not willing to share their doses, and ‘vaccine hesitancy’ with people cautious to receive the vaccine.

Individual countries are doing one-to-one deals with pharmaceutical companies, further putting strain on the supply chain. Alongside this, richer countries find themselves with an over-supply of available doses, which could be shared with countries in need – and worse, some of these vaccines are even being wasted.

This ‘vaccine hesitancy’ is something that must also be addressed, as though evidence supports vaccines saving lives, fear outweighs the life-saving potential. This is partly driven due to misinformation, so much so that the UN launched the ‘Verified’ campaign – aiming to educate and fight distorted information and messages – to become a source of trusted truth. This is the ultimate hurdle; it's one thing to ensure a country has enough supply of vaccines; it's another question convincing a population to take it. In the US, this is presenting a major problem, where vaccine uptake has become divided along political lines. We need to make sure that we have an exclusively medical public discourse and we continue to promote the critical importance of vaccines long after the pandemic has subsided.

Infrastructure problems, coupled with export controls, patent issues, intellectual property laws, and vaccine hesitancy present multiple challenges in getting the vaccines to those in need.

Over the past year, there have been a number of innovations in the pharmaceutical industry, especially when it comes to the supply chain. For example, there are now innovative containers that can maintain a stable internal temperature in extreme conditions from as low as -30°C to as high as 70°C. This year even saw the launch of deep-frozen containers that are able to cool to -80°C while maximising aircraft capacity utilisation, mitigating the traditional capacity limitations caused by the use of dry ice by making energy transfer more efficient.

Combating spoilage rates is important, not only in the current pandemic, but generally across the pharmaceutical industry. The industry accepts up to 12%, meaning a standard shipment of vaccines, similar to that which any COVID-19 vaccine would travel in, would be around 100,000 vials. The standard spoilage would mean that 12,000 vials would not be viable upon arrival. Innovations in the industry have brought this double-digit number down to almost zero.

This is a revolutionary improvement, as each of these vials will save lives and help stop the continued impact of the pandemic. Being able to deliver the vaccines to countries around the world in the first instance, be they rich or poor, with spoilage rates approaching zero per cent, will be the key to containing the spread and preventing further infections and deaths until we can eliminate the virus once and for all.

However, it’s not only innovation in the industry that is important. It is the partnerships across the industries that are pivotal in not only improving the supply chain, but helping to ensure medicines make it to where they need to go. Partnerships with airlines and shipping companies are paramount here. The likes of Qatar, Saudia Cargo, KLM Airfrance Martinair Cargo, Korean Air, LOT, and Virgin Atlantic cover almost all corners of the world, and make shipping these life-saving medicines a smoother process.

Furthermore, collaboration within the entire pharma supply chain is needed to maximise these airline and shipping company partnerships, allowing for fast and efficient distribution of vaccines. An

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Summer 2021 Volume 13 Issue 2

Regulatory & Marketplace

example is the Hope Consortium – a UAEbased public-private partnership offering a unique end-to-end supply chain solution capable of delivering large quantities of COVID-19 vaccines – from production to patients in emerging markets.

As I’ve mentioned, necessity is the mother of invention and we have been down this road before. The Spanish Flu brought about the early stages of DNA understanding, the plague during 1665 resulted in Newton’s theories on the concepts of gravity, and the Second World War prompted the invention of the first computer. I would like to hope that COVID-19 will be looked upon as a revolutionary time for the pharmaceutical industry, with innovations across the full expanse of the supply chain – though we still have a way to go. The pandemic has taught us that in a globalised world, diseases can spread faster than ever before. This also means that future pandemics will never be isolated to single countries – if there’s a lesson to be learned in the international community, it's that isolationist policies will not work. We need the international cooperation we have seen in the last year and a half to remain, in order to protect everyone from whatever www.ipimediaworld.com

comes next. Time will tell, but in any event lessons will be learned from this pandemic and past mistakes and ultimately impact our response to future pandemics – hopefully for the better.

In summary, technology has gone a long way towards contributing towards a healthier planet – but we are neither out of the woods nor all the way there just yet. We have seen rapid innovation arise to help fight against the pandemic, from vaccines to deep-frozen storage containers to an overhaul of the healthcare industry around the world. We are just witnessing the tip of the iceberg, so to speak, with more to follow as we continue to live in this ‘current normal’. Using these innovations and adaptations, we must now ensure that anyone, anywhere receives access to these vaccines. Not only do we have infrastructure hurdles to jump, but also financial, political and resourcing obstacles to overcome first.

It is great to witness that progress is moving in the right direction, and as necessity and global need increase as we hopefully edge nearer and nearer to the end of the pandemic – with new technology constantly being developed to meet our new way of living and working, we are on track to

becoming not just a healthier planet but a fairer, more just one.

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

INTERNATIONAL PHARMACEUTICAL INDUSTRY 13

Corporate Profile

Foodmek Celebrates 50 Years with Growth Plan Success Scottish bespoke engineering company Foodmek is celebrating both its 50th birthday and the continued success of its ambitious Scottish Enterprisebacked growth plan, which includes entry into the pharmaceuticals manufacturing engineering markets.

Thanks to the quality of the products and service delivered by its highly-skilled, dedicated workforce, the company, based in Tayport – just across the River Tay from Dundee – which designs, makes and installs engineering solutions for the pharmaceuticals, food, drink and cosmetic industries is enjoying a renaissance since its growth plan received the first tranche of £500,000 Scottish Loan Scheme funding from Scottish Enterprise in November 2019.

It enabled Foodmek to invest in new equipment, innovation and extra highlytrained engineers in its design office and factory. This has allowed a dedicated focus on research & development.

Apprentices The funding also allowed it to recruit and train more staff through Graduate, Modern and Foundation Apprenticeships in collaboration with the University of Dundee – a core part of its strategy to prepare for the retirement of its most experienced staff, many of whom have long service of many decades. In fact, its longest-served staff member, Jim Carson, is 78, and still working after clocking up 42 years to date!

Foodmek now employs six design staff and is hiring two more Modern Apprentices to add to the pair recruited last year. Overall, eight people joined Foodmek last year, with five more planned this year.

That investment in people has helped Foodmek bounce back strongly from a decrease in orders caused by the COVID-19 lockdowns around the world.

Pharmaceuticals Market The global pandemic, however, helped Foodmek gain momentum in the international pharmaceutical market – part of its growth plan.

Between May last year and January this year it delivered 25 high-specification 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Foodmek MD Scot Kelly (centre), apprentices (left) Cameron Bell and (right) Lewis Ritchie with a stainless steel ‘50’ join staff members in marking 50 years in business.

200-litre stainless steel vessels over four orders to a global manufacturer of COVID-19 PCR test kits – for the production of the fluids required.

The client was so impressed with the high quality of the vessels it is currently in discussions about its next order. Foodmek is also working on a vessel for a veterinary medicine manufacturer and several large tanks for a bioengineering company.

Turnover Up 13% Despite Lockdowns That market entry success helped Foodmek grow in its 2020–21 financial year, despite the effects of the global pandemic on economies around the world.

“During the end of our fiscal year ending May 2020, we saw an impact of the global pandemic,” revealed Managing Director, Scot Kelly. “However, in the fiscal year ending May 2021 we’ve seen a 13% increase in our turnover and are projecting a further 33% increase during our next fiscal year. This has also seen our headcount increase from 32 to 43 over the last two years.

“Thanks to our success in the financial year to May 2021, we met all the requirements from Scottish Enterprise to draw down the second tranche of our Scottish Loan Scheme loan.

Investment “This has enabled us to invest in a new ERP system, which will transform our enterprise planning capability. A six-figure capital investment has also been made in upgrading our manufacturing equipment.”

Funding from the Energy Saving Trust has also enabled Foodmek to buy a Kia e-Niro electric pool car for customer visits – part of Foodmek’s net zero sustainability strategy.

‘Healthy’ Order Book Orders from existing and new customers have also driven Foodmek’s progress.

Further orders are expected soon, adding to its “healthy” order book.

In line with its ethos, Foodmek plans to keep using its success to invest in the local community – through employability talks to local schools, engaging with community groups and a publicly-accessible defibrillator.

Foodmek believes that continuing to invest in people, machinery and new technologies is the blueprint for another successful 50 years. That’s begun already – it’s a Finalist for Engineering Company of the Year in the Scottish Business Insider Made in Scotland Awards.

For more information about Foodmek, go to http://bit.ly/Foodmek50Years About Foodmek Foodmek Ltd provides design, manufacturing and installation engineering solutions to the pharmaceuticals, food, drink and cosmetic industries.

It supplies some of the largest food processing plants in the UK, as well as pharmaceuticals manufacturers and major cosmetics brands, and has exported to more than 20 countries since its foundation in 1971.

Summer 2021 Volume 13 Issue 2

Corporate Profile Foodmek is a member of Scotland Food & Drink, Fife Chamber of Commerce and Dundee & Angus Chamber of Commerce.

For more about Foodmek’s work with the biotechnology sector, go to http://bit.ly/ FoodmekBiotech For enquiries, call Business Development Manager, Ross Waite on 07943 024881.

Some of the COVID-19 test kit vessels made by Foodmek.

Foodmek manufactures processing machinery for liquids – from conveyors, filling machines and cooking / mixing vessels to access platforms, pasteurising and cleaning equipment.

Biotechnology As well as the food industry, it also works with the biotechnology, cosmetics and other industries which benefit from using bespoke high-specification machinery.

Foodmek has been working closely with some of the UK’s leaders in biotechnology – providing them with cooking and mixing vessels tailored to comply with the increasing demands of the pharmaceutical industry’s regulations and requirements.

Modern pharmaceutical processes require incredibly sophisticated techniques and precise control to ensure the end product is as accurate as possible, something few equipment manufacturers can guarantee.

Consistent Foodmek’s 200- and 400-litre steamjacketed tanks are popular among its clients for their consistent, hygienic, robust and precise mixing and cooking. These are designed to the client’s individual needs to ensure end-product consistency.

It can make these larger if required – with a vast range of mixing options. It works with each client to make sure it gets the perfect vessel for its requirements.

LinkedIn – linkedin.com/company/ foodmek-limited/ Twitter – twitter.com/FoodmekLtd Facebook – facebook.com/ Foodmek-157904604603674/ Instagram – instagram.com/foodmek_ltd YouTube – youtube.com/channel/ UCdN7FlFYoK2nZwNmVHKyFFw

Foodmek designs can be tailored to meet specific requirements of production output as well as overcome space constraints.

Highly Durable The company, based at Tayport, Fife, manufactures highly-durable products which adhere to established quality assurance standards.

During installation, Foodmek engineers work to provide its customers with optimal productivity while keeping production downtime to a minimum.

Foodmek offers a wide range of services, including full refurbishment of its equipment and stainless steel fabrication.

Foodmek is Safe Contractor-certified, and ISO9001 and EN1090 certified.

Scottish Business Pledge In 2019, Foodmek committed to its staff with the Scottish Business Pledge, which includes: 1. Paying the real Living Wage 2. No inappropriate use of zero hours contracts 3. Action to address the gender pay gap 4. Environmental impact 5. Investing in a skilled and diverse workforce 6. Workforce engagement 7. Innovation 8. Internationalisation 9. Support our community 10. Prompt payment

Scot Kelly This month marks four years since Scot Kelly arrived at Foodmek to take up the position of Managing Director.

He brought with him almost two decades of experience in precision manufacturing with global players to the firm with a long history of high-quality engineering and big brand clients. With a BSc in mechanical engineering from the University of Strathclyde and a DMS in management studies from Edinburgh Napier University, Scot became Global Commodity Director for NCR, based in Dundee, in August 2000.

In 2002, he became its Director of Manufacturing – responsible for manufacturing assembly of ATMs, particularly low-volume, high-feature machines and new product introduction.

In July 2008, Scot moved on to GE. There he spent just over two years as Fulfilment & Productivity Manager with GE Drilling & Production Systems, before moving to GE Oil & Gas to take up the role of D&P Engineering Planning Leader.

In January 2012, Scot became the Subsea Engineering Operations Manager, based in Aberdeen. Scot’s final role at GE Oil & Gas was as Subsea Services Site Leader, based in Montrose, starting in July 2013.

Before taking on the leadership of Foodmek, Scot was the Interim Project Manager at ATMRC Ltd.

Some of the COVID-19 test kit vessels made by Foodmek, including Stevie Clark (left) and Aaron Clark (right). www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 15

Regulatory & Marketplace

The EU Medical Devices Regulation and its Market Impact Under the Spotlight We spoke to Nadine Kasidas-Neale [Head of Regulatory and Compliance] at Bespak by Recipharm to explore the incoming changes to EU medical device regulations. She explains their impact on pharmaceutical companies developing drug delivery devices including autoinjectors for the EU market, with reference to relevant regulatory pathways.

The global drug-device combination products market was estimated to be worth US$ 123.5 billion in 2020 and is forecast to grow at a CAGR of 8.2% between now and 20271. The new combination products entering the market don’t just include traditional parenterals, but autoinjectors and inhalers too, as well as other nextgeneration devices.

The rise of such combination products means that the integration of pharmaceutical and device regulatory requirements at the development stage is more important than ever before.

Combination products – meaning medicinal products / drugs that are fully integrated with a drug delivery device, such as autoinjectors or pressurised metered dose inhalers (pMDIs) – are governed by strict regulations in the European Union (EU) and other advanced markets. Pharmaceutical developers must demonstrate compliance with these requirements to deliver a safe and effective product to patients and trade within those territories.

Previously, in the EU, companies have had to demonstrate conformity to the essential requirements (a list of requirements outlined in the EU Medical Device Directive), by preparing drug dossiers. The intent of this directive was for individual country regulatory authorities to assess this information in the marketing authorisation applications (MAAs) that they review.

As of 26 May 2021, companies must comply with updated requirements in the new Medical Devices Regulation (MDR).

The MDR is a specific regulation that all 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

EU Member States must comply with and changes the measures companies must take to demonstrate the safety, effectiveness, and performance of their product.

Why the Change in Regulations?

Medical devices have been regulated throughout the EU since the 1990s. Three distinct directives were initially published to regulate medical devices, covering a range of different device types. These were the Medical Device Directive (MDD), the Active Implantable Device Directive (AIMDD), and the In Vitro Diagnostic Device Directive (IVDD).

These existing directives require updating for several reasons. Key among these is the need to incorporate rapid product innovation, and to address recent safety issues in the market by reviewing any concerns over the assessment of product safety and performance.

In addition, it is increasingly necessary to place stricter requirements on clinical evaluation and post-market clinical followup, as well as improve the traceability of devices. The ageing European population is revealing new risk and health factors that must be considered to ensure devices remain suitable for the patients using them.

The new MDR is designed to strengthen the requirements included in the previous legislation and implement a life-cycle approach to product development to provide effective products that enhance the patient experience.

Until now, combination products have been regulated as medicinal products under the Medicinal Product Directive (Directive 2001/83/EC) without specific examination of the device itself by another competent authority or notified body.

This gap has existed in European regulations for many years. Companies have dealt with this by effectively providing a technical file in their marketing application that addresses the essential requirements of the directives as part of their MAAs. The MDR specifically addresses this issue through article 117 that covers drug delivery devices and effectively amends the Medicinal Product Directive.

As a result, integral drug-device combination products, such as an autoinjector or pMDIs, must show conformity to the general safety and performance requirements (GSPRs), or Annex I of the MDR. Additionally, developers must now also find Summer 2021 Volume 13 Issue 2

Regulatory & Marketplace •

•

Updates to requirements for clinical evidence, evaluation, and data as the MDR moves away from equivalence between devices. The publication of more safety and performance data is required post-market clinical followup as well as a Summary of Safety and Clinical Performance (SSCP).

•

New transparency, traceability, and supply chain requirements: •

• a notified body to review the information and issue an opinion that their product is in conformance with the requirements.

Experienced combination drug developers should already be familiar with this new approach, as this has been the direction of many recent regulatory changes worldwide, such as the update to ISO 14971 in 2019.

How Has the Safety Approach Changed?

The MDR largely shares the same basic regulatory requirements as the directives it replaces; new standards build on this foundation.

Crucially, the MDR promotes a life-cycle approach to safety, backed by clinical data.

This encourages policies and procedures elevating the responsibilities of companies for their products.

What are the Key Changes Affecting Device Development?

Under the new MDR, there are several key changes that companies need to consider for their device. These include: •

Reclassification of devices according to risk, contact duration and invasiveness.

•

New requirements at the pre-marketing stage: •

There are now common specifications that some medical devices must meet in order to comply with enhanced scrutiny for high-risk devices.

A Person Responsible for Regulatory Compliance (PRRC) is now required for manufacturers of medical devices.

•

•

Under the MDR, new medical devices and the companies responsible for them must be registered centrally.

Unique device identification (UDI) must be included on packaging and devices to aid traceability.

Increased responsibilities for authorised representatives, importers and exporters within the supply chain.

Post-marketing surveillance: •

The MDR requires the manufacturers of medical devices to proactively collect and review, in cooperation with other economic operators, the experience of the device they place on the market.

This is intended to make it easier to identify the need for corrective or preventive actions.

The intent is to improve the safety of products by strengthening the rules on placing new devices on the market, and by tightening surveillance once they are available to patients. These stricter requirements regarding the quality, safety, and performance of devices, together with steps to improve traceability of devices, are designed to provide greater transparency for both patients and authorities.

Greater emphasis is also placed on enhanced governance of notified bodies, whilst also providing them with the right to perform unannounced audits on manufacturers. www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 17

Regulatory & Marketplace •

Device manufacturers are also required to report safety and clinical performance annually.

•

"Grandfathering" provisions have been removed. Some exemptions may be implemented.

The most significant change for devices such as autoinjectors is that now the device is no longer considered as just secondary packaging under medicinal regulations.

For integral drug-device combination products, article 117 within the MDR requires that developers must demonstrate conformity to the GSPRs, or Annex I of the MDR. A notified body opinion is required to confirm conformance to these requirements.

This should not be a significant change for experienced developers, who would already be generating appropriate technical data to support their products under the existing MDD essential requirements. Such information includes documentation on technical and functional requirements, a detailed technical description of the device, design verification reports, and a risk management file. In addition, it should incorporate design validation through

18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

useability and human factors and potentially a clinical evaluation report.

body opinion will also have to be provided as part of any change application.

Failure to ensure products meet these updated requirements could mean that pharmaceutical companies are unable to market their products in the EU. Not only would this impact on their revenue, but it would also have a negative effect on the patients that rely on their treatments.

Obtaining a notified body opinion may take time that will need to be factored into any development project to ensure deadlines are met. The need to work with one of the few notified bodies already certified for the MDR may cause further delays, as many companies will be seeking their services at the same time.

Do Changes Need to be Made to Existing Products?

Depending on the classification of the product, different approaches to compliance are needed. For medical devices, when new or CE recertification is required, compliance to the MDR is mandatory.

For combination products, Article 117 of the MDR is not intended to be applied retrospectively to products already authorised, or to those that have been submitted prior to the date the new regulation was originally due to come into force.

However, in the case of significant changes to the drug or device, or if a new EU certificate of conformity is required, then companies will have to ensure that the product complies with the MDR. A notified

How to Address Regulatory Changes in the Development Process?

Regardless of the nature or classification of the product, it is crucial to set a clear regulatory strategy at the outset of a project. This is essential to guide the development process and generate the required documentation to meet new MDR requirements; this is an approach that experienced developers should already be taking.

An effective strategy will consider the resource required to collate clinical and technical evidence to support MDR compliance. It will also involve in-depth analysis at the beginning of the project to understand where additional work is needed to generate the required information.

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Regulatory & Marketplace

The responsibility for collating the required data for combination devices on the market lies with the pharmaceutical company, and not with third parties, such as device partners. However, when selecting the best partner, the ability to work collaboratively and support the integration of the drug and device into the overall system application is critical.

The MDR also defines specific postlaunch requirements for products. To comply, pharmaceutical companies must take a proactive approach in the management and in the regular assessment of their products.

How to Work with Development Partners to Ensure MDR Compliance There is a considerable amount of information that needs to be generated and collated, not just from within the pharmaceutical company, but from suppliers as well. It is crucial that development of the regulatory strategy includes close collaboration between the pharmaceutical company and their device development partner.

Not all third-party providers will be able to meet the required level of collaboration, so it is important to choose the right device partner. Experienced device development partners will not only be able to support www.ipimediaworld.com

in the design and commercialisation of the device, but they will also be able to enhance useability for patients which can optimise the regime compliance.

The right partner will be able to support drug developers in establishing and realising their regulatory strategy and advise on what information needs to be collated to comply with the MDR requirements and support its generation.

Most importantly, an expert development partner can provide support beyond the MDR compliance, encompassing global regulations for key markets. Pharmaceutical companies should talk to their device partners now, to understand fully the assistance they can offer to ensure regulatory compliance.

Time to Act The upcoming changes to the regulatory environment for medical devices have been in development for some time, and companies across the industry should already have taken steps to ensure their current and future projects meet the new requirements under the MDR. As global regulatory frameworks develop and evolve, we can expect more enhancements over the coming years. By working closely with expert device partners,

pharmaceutical companies can be confident they have the support they need to meet the stringent requirements of new regulations, not just in the EU, but in all key markets across the globe.

Nadine Kasidas-Neale Nadine is the Head of Regulatory Compliance at Bespak by Recipharm.

In her role, Nadine combines her experience as a research and development scientist and global regulatory professional, leading the Bespak

by Recipharm teams to deliver new products and ensure full lifecycle regulatory and scientific product development strategies. She has also led the implementation of new strategies to meet global regulatory landscape changes across multiple product portfolios and business units, including compliance with the new European Medical Device Regulation.

With over 17 years of experience in the diagnostic, medical device and combination product industry, Nadine brings a wealth of experience to the Bespak by Recipharm team.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 19

Regulatory & Marketplace

Digital Technology for Building Resilient Healthcare Systems in Thailand and Southeast Asia The healthcare systems in Southeast Asia are at a critical juncture today.

The new wave of COVID-19 infections is straining healthcare facilities as cases continue to rise at an alarming rate, while most countries struggle to organise the required medical resources. Thailand, much like the rest of the region, has been busy expanding its in-patient hospital capacity to accommodate the surge of COVID-19 patients and minimise the damage caused by the virus. While the challenges created by the pandemic are recent, Thailand has anyhow been grappling with overwhelming healthcare demands caused by an ageing demographic and a rapid growth in non-communicable diseases (NCDs) within the country’s population.

These challenges have overburdened Thailand’s healthcare system – its physical infrastructure has been constrained by capacity and the network is yet not fully developed to effectively reach patients outside healthcare settings. This has been particularly unfavourable for patients suffering from NCDs, whose chronic conditions typically require extended treatment plans and consistent engagement with healthcare providers. In the absence of regular follow-ups and limited visits to hospitals or clinics, patients are known to fall off their treatment schedules, resulting in suboptimal health outcomes.

Thailand has undertaken several initiatives to arrest this problem, including the deployment of pharmacies as an important touchpoint to retail prescription drugs in an effort to reduce congestion at hospitals, while seeking to build medical adherence. Physician-led efforts have also ensured some effectiveness, but given the inadequate doctor-to-patient ratio and their uneven distribution across the country, the results have been far from ideal. For healthcare systems to be responsive and resilient against pandemics like COVID-19, a much more deep-rooted healthcare transformation is required – a system that places patients at the heart of the matter, 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and effectively deploys all possible means to serve them, irrespective of where they are.

Over the last decade, healthcare digitalisation has been rapidly adopted across Southeast Asia, which has led to disruptive changes and an improvement in overall healthcare outcomes. Under the Thailand 4.0 policy, the government has launched various digital healthcare initiatives including a personal health profile tool, a patient administration cloud service and a telehealth and telemedicine app. While these introductions will definitely aid the process of medical care and help reach patients beyond healthcare settings, it is vital to treat these tools as enablers and not the solution itself.

Digital Tools and Building Access During Public Health Emergencies In the wake of the ongoing pandemic, countries across the world are strengthening their healthcare infrastructure to undertake the mammoth task of inoculating large populations, necessary to build herd immunity, and restrict further spread of the virus. Thailand has been no exception and the government has been working relentlessly to vaccinate its people, starting with more vulnerable sections of the society.

But what is important to note here is the difference between vaccine availability and accessibility. Many nations today have the wherewithal to purchase / receive vaccines in the required quantity, but not all have the efficient infrastructure and technologies to immunise people using them. Hence, vaccine availability is of no consequence till it is converted into vaccine accessibility.

There’s a need for nations to invest and plan in building this accessibility – after all, a stockpile of vaccines is not what builds immunity for nations; it is the ability to deliver shots into arms that does!

Unfortunately, health systems in developing countries are largely centred around hospitals and clinics and solely depending on these facilities will not allow nations to reach the massive population numbers required for effective inoculation.

As experts in healthcare access for over 25 years, we’ve often dealt with the issue of

availability vs. accessibility and understand the need to connect with patients beyond the physical settings of health facilities.

Dealing in chronic illnesses, we’ve utilised different channels to build a sustained engagement with our patients, which has been crucial in achieving treatment adherence and optimum health outcomes.

Drawing from this experience, we recognise that it is imperative for countries to look beyond hospitals and tap into complementary, proactive mechanisms to reach patients wherever they are. In fact, a combination of these channels will be required as nations attempt to vaccinate populations in the most efficient and nimble manner possible.

Digital solutions can play an important role here, as they can be used for personalised communication between patients and healthcare providers. If properly deployed, they can help structure immunisation plans better and administer shots in the most informed manner.

In my organisation, we’ve developed a range of innovative digital tools that help us communicate with patients after they leave health facilities to ensure that they keep up with their care plan and steadily improve in their health conditions. They also enable physicians to refer a patient to an access programme and to follow up on their patients’ progress remotely, and pharmacists to track medical supply efficiently. Based on a patient-centric design, these tools complement our offline channels aptly, and help serve our patients in an all-inclusive manner.

Thailand is a strong player in the digital healthcare space and has been diligently investing into new and modern digital technologies. During the COVID-19 lockdown, the MOPH and Department of Medical services launched an initiative with 27 hospitals where patients were allowed to virtually visit doctors and medicines were delivered at home. This project was crucial as it allowed patients to continue accessing healthcare services, despite restrictions on people movement and hospitals being out of reach. The government has also been Summer 2021 Volume 13 Issue 2

Regulatory & Marketplace healthcare needs of people to strengthening it for improved, tailored responses – it’s the human behind the gadget that makes it all possible and allows for a better patient management system.

In Conclusion Digital healthcare technology is a positive force; it has the capability to forge a strong connection between patients and healthcare stakeholders which can be instrumental in driving better treatment adherence and positive health outcomes.

These tools, though, need to be harnessed effectively – they should always be focused on assisting patient journeys and improving quality of life rather than being medicationoriented. using artificial intelligence (AI) and 5G technology to address the challenges posed by the ongoing pandemic, and deliver timely healthcare solutions to people. Leveraging these digital tools, doctors have been able to quickly and accurately distinguish early, advanced, and severe stages of COVID-19, leading to better diagnoses.

Complementing the efforts of the Thai government, the private sector has also stepped up its efforts, and contributed to bolstering the overall effectiveness of the healthcare system. For example, one of the leading hospitals in Thailand expanded its telemedicine consultations as the pandemic intensified over a period of time, making sure that patients had access to highquality medical care at the convenience of their fingertips. Similarly, a local medtech startup in the country grew exponentially in its subscriber base as it offered a one-stop medical ecosystem to patients, taking care of all their needs in the most convenient manner. While the adoption of digital healthcare technologies has been steadily increasing over the years in Southeast Asia and the rest of the world, the pandemic has accelerated the trend significantly.

Digital Tools and the Future of Healthcare Digitalisation will be an important element in the future of healthcare as it helps facilitate connected care. In other words, it helps build a strong connect between healthcare providers and receivers across the entire treatment journey, ensuring efficient management of current illnesses while effectively preventing future ones. In fact, WHO makes a similar argument when it criticises fragmented health systems – it highlights how these systems can create a mismatch between actual performance and www.ipimediaworld.com

rising expectations of the society, leading to frustration and suboptimal health outcomes.

Healthcare systems working in isolation will never be as effective; synergies need to be built between healthcare providers and receivers while using technology as an efficient conduit between the two. This approach was confirmed in our recent survey conducted in Thailand which revealed that a majority of our physicians (75%) found the company’s digital app useful to get updates on their patients, while 88% of the patients shared how the tool helped them manage their chronic conditions effectively.

In addition, digitalisation can also help streamline operations, leading to faster decision-making and decreased risk of human error. It can complement physical systems’ suitably and ensure enhanced productivity for all stakeholders in the ecosystem, resulting in better patient outcomes. Digital technology can also help build personalised solutions for patients as it continuously assesses patients on a per-patient per-cycle basis, offering more holistic insights about their treatment outcomes. Finally, digital technology can be instrumental in designing new innovative access solutions as a rigorous system of capturing and analysing data helps understand the efficacy of ongoing access solutions, and the re-configurations required to make them more impactful.

Though the benefits of digital technology make it indispensable in the current healthcare framework, one must understand the crucial role that the human factor plays in ensuring its effectiveness.

Right from the user-friendly design of the interface, its alignment with the evolving

Thailand has constantly innovated and improved its healthcare systems to offer advanced medical solutions, aligned with the evolving healthcare needs of its people.

But the ongoing pandemic has compelled us to reassess healthcare systems and make important integral changes. Going forward, Thailand should further embrace digital technologies, build a system of connected care where both healthcare providers and receivers are equally involved and empowered to drive better healthcare outcomes. This will help strengthen Thailand’s healthcare system and build its resilience to withstand the pressures of any public health emergency, making sustainable healthcare access a reality for its people.

Roshel Jayasundera Roshel Jayasundera is Senior Director of Global Consulting at Axios International, a global healthcare access company specialized in developing sustainable solutions to patient access challenges in emerging markets. Roshel oversees consulting and operations across multiple therapeutic areas for all Axios’ healthcare access programs.

Specialized in pharmaceutical and medical capacity building, technical process design, and regulatory affairs, Roshel has developed business improvement solutions for governments, international private and public companies and start-ups across Europe, the Middle East and Asia. She is also a certified ISO 9001:2015 Lead Auditor.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 21

Drug Discovery, Development & Delivery

Multifactorial Disease Models: Their Role in De-risking Topical Formulation Development The global topical pharmaceutical market is valued at around $95 billion USD and is forecast to grow by $70 billion USD over the next 4–5 years1.

Currently, there are approximately 900 new products in development for dermatology, split between small molecules (65%) and biologics (35%)2 with a considerable focus on topicals for the treatment of conditions such as psoriasis, atopic dermatitis, and acne vulgaris.

A company’s attitude towards risk fundamentally affects their product development strategy, which can vary between the development of a simple or prototype formulation (higher risk) or a fully market-ready, commercially viable product (lower risk) to be used in initial preclinical/ clinical evaluation. Large pharma, with many potential drug candidates to prioritise, tends to be more risk-averse and so generally focuses on entering clinical evaluation with a market-ready formulation that has been developed with risk mitigation considered throughout the development process. For these large companies, an early failure is much less expensive than a failure in the clinic.

Conversely, small biotech companies that may only have a single drug candidate and are typically funded by external investment often favour the development of a prototype formulation. These small companies tend to be more risk-tolerant and prefer to address problems as they arise, so they can evaluate the drug candidate in a clinical proof of concept (PoC) study as quickly as possible.

The challenge with this prototype formulation approach is that if the PoC study achieves a positive outcome then further reformulation work would be required to achieve a more patient-friendly and usable product leading to extensive bridging safety studies. In the worstcase scenario, the formulation development may have to restart to proceed to final marketing authorisation application (MAA) or new drug application (NDA). Therefore, the time and money initially saved in the early stages is often lost and/or exceeded later in the project.

22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Perhaps the optimal route to success sits somewhere between these two approaches where experienced formulators can leverage their extensive technical and regulatory expertise, and utilise innovative models, to mitigate the risks described above as much as possible.

Different Types of Performance Testing Performance testing is an integral part of any formulation development programme and can be used strategically throughout the development process to mitigate development risks and failures. The method that has historically been used for assessing a drug’s thermodynamic activity is in vitro drug release testing (IVRT), where a nonrate limiting synthetic membrane is used to support the semi-solid topical formulation and the drug’s release rate is measured in a receptor solution beneath the membrane.

Regulatory bodies are increasingly requiring IVRT use as a quality tool in release and stability specifications and for demonstrating generic bioequivalence.

Nevertheless, IVRT methodologies can only be used to assess and compare the diffusion and release of a drug from a formulation. They provide no insight on the ability of a drug to partition in and permeate across the Stratum corneum and subsequent skin layers or any mechanistic understanding of how a formulation will affect the barrier properties of the skin.

Given the difficulties, costs and time associated with in vivo experimentation, most topical formulators will attempt to use ex vivo/in vitro methodology to optimise and compare their formulations in this regard. In vitro permeation testing (IVPT) is an established methodology recognised by regulators to assess the skin permeation (and commonly penetration) of a drug from topical formulation. It is used to understand the influence of formulation on drug absorption across and into the skin whilst also being used to optimise and compare different formulations during the early stages of development and through product development to post-marketing studies and competitor analysis.

The major limitation of any permeation and penetration model is that it shows how

the drug is moving into the biological tissue but does not give any indication of how the formulation affects the skin and whether the drug is bioavailable, engages the target and can act on the desired pathway(s).

Traditionally IVPT models have utilised human cadaver skin or ex vivo surgically excised healthy skin, but for many topical products these skin samples do not reflect the condition of the skin to which they will ultimately be applied.

Human and Animal Studies Clearly topical and transdermal formulations are for the treatment of patients in situ, therefore the “gold standard” in the experimental design for formulation development would be to employ human volunteers and monitor drug delivery in vivo. Practically, this is extremely difficult for most drugs (e.g., NCEs/NMEs) and would be unethical and cost-prohibitive for formulation development. Performing pharmacokinetic (PK) studies in humans for transdermal formulations, where the intent is to deliver the drug systemically with drugs of known safety, is well established. Additionally, for topical steroid formulations in vivo studies have been performed, typically using vasoactive agents with measurements of pharmacological activity, such as blanching, used to assess drug delivery. Such vasoconstrictor studies have been useful for researching dose dependencies, or the influence of thermodynamic activity on drug delivery, but are necessarily limited and do not transpose to allow predictions for delivery of other therapeutic agents.

Other in vivo techniques include skin stripping using adhesive tapes or cyanoacrylate glue, punch biopsies, suction blister techniques, various forms of microdialysis and non-invasive determinations such as confocal laser scanning microscopy, confocal Raman spectroscopy or ART-FTIR. Animals are obviously a potential alternative to human testing. The testing of cosmetic and pharmaceutical excipients and active ingredients for possible irritation effects has remained relatively unchanged since its inception in the early 1900s. In 1944, the first U.S. Food and Drug AdministrationSummer 2021 Volume 13 Issue 2

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 23 To learn more or inquire about pricing, please contact us through our website www.wakopyrostar.com or via the email address wkuspyrostarinfo@fujifilm.com

Drug Discovery, Development & Delivery recognised animal testing was implemented, known as the “Draize test”. It utilised rabbits for ocular and skin irritation of cosmetics and personal care items. While these advances allowed a decrease from six test subjects to one to three rabbits per test, little else has changed.

Although the 7th amendment to the European Union Cosmetics Directive now forbids animal testing of cosmetics in Europe, irritation testing in up to two animal species (rodent and mini-pig) is still required by regulatory authorities for various toxicological studies before a new topical medicine approval (e.g., new drug application).

Furthermore, due to the time and cost associated with product failure in the clinic, a range of in vivo animal models using fish, rodents, mini-pigs, and nonhuman primates have been developed to mimic human skin diseases such as skin cancers (e.g, basal cell carcinoma), atopic dermatitis, psoriasis, skin infections (e.g., acne, MRSA, viral infections) and wounds.

Many models exploit genetic engineering as many involve gene mutations. However, increasing regulatory restrictions and ethical concerns around the use of these animals in product development (mirroring existing sentiment with cosmetics), combined with the dissimilarities between animals and humans (skin thickness, density, and immune system irregularities), has led to many proponents arguing for their discontinuation over recent years.

In Vitro Alternatives Reconstituted Human Epithelium Models In the 1980s, researchers began to develop reconstituted human epithelium (RHE) skin models which have now evolved to include collagen, fibroblasts, and melanocytes.

Commercially available examples include EPISKIN (L’Oreal) EpiDerm (MatTek Corporation), and ZenSkin (ZenBio). These models have quickly gained acceptability in topical product testing for various aspects of pharmacotoxicological and dermal irritation evaluation and contributed to the refinement, reduction and replacement of whole animal testing. The primary advantage of this model above ex vivo human skin is its high reproducibility, which allows for comparison of developed formulations with control formulations of known irritancy.

Most RHE models attempt to replicate “healthy” human skin, but adaptation to replicate skin disease in a controlled, 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

reproducible, and qualifiable manner has become an increasing requirement in topical product development. Such models are generally developed in-house to screen drug candidates and/or formulations, but commercially available RHE models are becoming available. For example, RHE models for inflammatory and autoimmune diseases have been developed, including for psoriasis and atopic dermatitis where the specific pathway leading to expression of the disease state is induced by a cytokine stimulation/ inflammatory cocktail or by downregulation of filaggrin. Alternatively, a commercially available psoriasis RHE is available (e.g. MatTek), produced from normal human epidermal keratinocytes and psoriatic fibroblasts harvested from psoriatic lesions to form a multi-layered, differentiated tissue. The psoriasis tissues maintain a psoriatic phenotype, as evidenced by increased basal cell proliferation, expression of psoriasis-specific markers, and elevated release of psoriasis-specific cytokines. Morphologically, the tissue model closely parallels lesional psoriatic human tissues but lacks the inflammatory cellular components. Skin cancer models have been constructed by incorporating various tumour entities within the three-dimensional RHE matrix. The melanoma model (again from MatTek) consists of human malignant melanoma cells (A375), normal, humanderived epidermal keratinocytes (NHEK) and normal, human-derived dermal fibroblasts (NHDF) which have been cultured to form a multi-layered, differentiated epidermis with melanoma cells at various stages of CM malignancy. Structurally, the melanoma model closely mimics the progression of melanoma in vivo.

The biggest limitation of commercially available RHE models is they do not harbour the true epithelial barrier properties of human skin, potentially resulting in false positives in toxicity studies. These models also lack appendages (sweat glands, sebaceous glands, hair follicles, etc.) which may further deviate from the true performance of the formulations when applied to human skin.

Diseased Skin Models Some of the biggest recent advances in dermatology have been with the introduction of biologics for severe skin diseases. These biologics have revolutionised the management of skin disease and have also been instrumental in expanding the basic understanding of inflammatory dermatosis and new target

discovery. This growing interest and understanding in the basic biology of inflammatory dermatosis has led to the development of novel pharmacological (PD) disease models using fresh human skin.

Relatively simplistic diseased skin models such as the TurChub® system have existed for some time and have been utilised to enhance early-stage topical formulation development. The modified zone of inhibition (ZOI) assay includes all the barrier functions associated with the human skin, but with the skin mounted to prevent lateral diffusion of the active formulation around the edges and with the organism growing under the skin layer. This mediumthroughput screen measures inhibition of organism growth (area of no growth) on the underlying agar. As the organism itself is used as the biomarker for permeation and antimicrobial activity, the test avoids the need for analytical methods (HPLC, UPLC, etc.) and multiple formulations containing different drugs can be screened at once.

An advance on the relatively simple modified ZOI assays is infected skin models.

These rely on the ability to grow and culture the organisms on the skin, and accurately recover and quantify the viable organisms after treatment. Typical organisms used are yeasts such as C. albicans or P. ovale, dermatophytes such as T. rubrum or T. mentagrophytes, or bacteria such as P. acne, S. aureus (including MRSA), P. aeruginosa and S. epidermis. In these models, an organism most relevant and causative of the infection is artificially introduced under controlled conditions and growth is controlled. The location of the infection within the skin is also controlled, for example, superficial or on the underside of the appropriate dermal layer, such that the position of the organism closely resembles that of the clinical presentation. Additionally, where appropriate, the barrier properties of the diseased skin can be replicated. The ability of the drug or formulation to exert its antimicrobial effect is then assessed using the measurement of a biological marker in the form of ATP, a direct indicator of cell viability, PCR, or direct viable counts. This model also allows the use of living ex vivo skin to explore the effects of an infection and consequent inflammatory responses for multimodal mechanistic studies.

Both the infected skin models and the modified ZOI assays are currently limited to monocultures, meaning only one organism is included per replicate. However, advances Summer 2021 Volume 13 Issue 2

Drug Discovery, Development & Delivery in analytical techniques (e.g., differential PCR techniques), are leading to more complex biofilms (comprising multiple organism types in an infection) within the tissue to be explored.

Skin research’s huge advantage is its direct access to large sections of surgical tissue. The latest advances in tissue culture have allowed scientists to keep this surgical skin alive in culture for over a month; thereby creating a living tissue explant. Recently, this has led to the development of the combination of the models described above for those diseases that comprise a multimodal mechanistic nature (e.g., rosacea, infected eczema, seborrheic dermatitis and infected wounds). This is where infected skin elicits an immune response and the therapeutic effects from a topical treatment can be assessed as a reduction in the organisms and key inflammatory cytokines, antimicrobial peptides and wound remodelling biomarkers. For example, application of live S. aureus or Ps. aeruginosa bacterial culture to wounded live human ex vivo skin tissue results in an infection causing increases in inflammatory gene expression such as the cytokines IL1α, IL1ß, TNFα and IL8; as well as antimicrobial genes DefB4, and S100A7. Such responses to viable bacterial infection can be used to monitor both anti-inflammatory activity of therapeutics based on biological activity and antimicrobial therapy as described above. Wounding of the tissue can be used to evaluate re-epithelisation capabilities of therapeutic formulations in the form of keratinocyte and fibroblast proliferation and differentiation markers (FGF, PDGF, involucrin and KRT16), as well as collagen production and extracellular matrix remodelling (Col1A2 and MMP9) along with histology to visualise re-epithelisation of the wound.

The use of human ex vivo skin culture has the advantage of the inherent physical condition of the tissue. Although as with other models, ex vivo human skin will lack cell migration from the circulatory

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and lymphatic system into the dermis, unlike RHE it will contain resident immune cells (lymphocytes, dendritic cells and Langerhans cells). Of these, the resident memory T cells (TRM) are known to be potent mediators against infection and autoimmune disease and in ex vivo human skin it has been shown that they secrete inflammatory cytokines.

As well as the resident immune cells, the existing cell population(s) in these explants can be stimulated with specific mixtures to elicit biological responses. This allows the exploration of different disease states, for example, the release of chemokines, antimicrobial peptides and keratinocyte differentiation biomarkers associated with clinical psoriasis can be analysed by quantitative reverse transcription polymerase chain reaction (qRTPCR).

Research has shown similar success with other inflammatory skin diseases e.g., acute (Th2 mediated) and chronic atopic dermatitis (Th1 mediated, vitiligo, and alopecia), along with wound healing, skin ageing, damage, and environmental stress, various skin infections (bacterial and fungal) and complex multi-mechanistic skin diseases, such as acne and infected dermatitis.

Final Thought While pain and itch are elusive targets to investigate by ex vivo explant culture, recent developments suggest that co-culturing neurons with ex vivo skin explants may extend the life of the skin culture for longterm assay and in order to even better understand the neuronal cross-talk in pain, itch and wound healing.

By combining an increased understanding of immunology, tissue culture, and pathway biology, these ex vivo skin PD models have allowed us to explore the possibilities of a multifactorial skin model that more closely represents the human state for the purpose of more translatable therapeutic testing, as

well as de-risking the development process for topical products.

REFERENCES 1.

2.

https://www.businesswire.com/news/ home/20190816005358/en/Global-TopicalDrug-Delivery-Market-Report-2019-2024 BioPharm Insight, 2020

Dr. Jon Lenn Jon Lenn has direct responsibility for MedPharm’s operations in the United States based out of Durham, North Carolina. Since joining in 2015 he has led MedPharm’s development of cutting edge performance models for assessing penetration and activity of clients’ products targeted towards key biochemical pathways. He has over 15 years’ experience in developing dermatological projects with Connetics, Stiefel and GSK and has been directly involved with the development and approval of 8 products. He received his PhD on the topical delivery of macromolecules from the University of Reading.

Marc Brown Marc Brown co-founded MedPharm in August 1999. He has been the guiding force behind all of MedPharm’s scientific developments and intellectual property. He has been Professor of Pharmaceutics in the School of Pharmacy, University of Hertfordshire since 2006 and has visiting/honorary professorships at the Universities of Reading and King's College London. He has over 200 publications and 26 patents describing his work. His research interests lie mainly in drug delivery to the skin, nail and airways. To date, he has been involved in the pharmaceutical development of over 38 products that are now on the market in Europe, America and Japan. Prior to MedPharm he was an academic in the Pharmacy Department at KCL.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 25

Drug Discovery, Development & Delivery

Compartmentalised Microfluidic Devices for Drug Discovery in the Neurosciences With an aging global population, neurological disorders are the leading cause in disability-adjusted life-years (the sum of years lived with disability and years of life lost) and the second leading cause of death1. Despite the increasing need for new therapeutics in this area, the drug discovery process faces several unique challenges when it comes to addressing the nervous system. Neurological disorders are incredibly complex, and this is reflected in the lack of knowledge of the underlying pathological mechanism for many of these diseases, and in turn to the slow speed at which novel drug targets are identified. Regardless, research in the field remains vibrant, and the emergence of novel research technologies and tools continues to lead to exciting discoveries that hold promise to translate into the development of novel therapeutics.

The emergence and adoption of stem cell reprogramming technology has been an absolute game-changer for neuroscientific research. The ability to differentiate human neurons from healthy or patient sources provides the necessary basis for beginning to develop relevant in vitro disease models of neurological disease.

However, and as will be discussed further, the ability to generate neuronal populations alone does not faithfully reproduce some critical characteristics of in vivo neuronal physiology, especially as it applies to the context of modelling neurological disease. To address some of these shortcomings, several groups have turned to utilising advanced microfabrication techniques to produce a series of innovative compartmentalised microfluidic devices to complement neuronal cultures. The combination of these approaches has led to the emergence of next-generation in vitro disease models in neuroscience that are not only valuable in fundamental research settings but are also scalable for high-throughput drug screening.

Physiological Relevance in Neurological Disease Modelling Physiological relevance is one of the key 26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

characteristics to developing a useful cell-based disease model. The chances of successfully identifying a new drug candidate that exhibits efficacy for any given disease is linked to the strength of the assay being used in the drug screening process.

In other words, by building physiological relevance early in the discovery process, the goal is to reduce the likelihood that a drug will fail in later (and much more costly) clinical stages of the development process. In the case of neurological diseases, physiological relevance entails generating a model which mimics as many aspects of neuronal physiology as possible such that non-target based phenotypic screens can be performed. Until the advent of iPSC technology to produce human neurons in vitro, many cell-based assays used in the early phases of drug discovery were based on immortalised cell lines overexpressing a target of interest. These target-based approaches are problematic for neurological disorders as targets are generally not known. Additionally, such simplified models do not exhibit the most important aspects of neuronal physiology such as cell morphology and excitability which form the basis of neuronal function in both health and disease. Consequently, there is demand for the development of complex, physiologically relevant in vitro assays to pursue phenotypic-based drug screening in the context of neurological disorders.

Neuronal Systems are Highly Organised Generally, induced pluripotent stem cell (iPSC)-derived neuronal cell cultures recapitulate many important characteristics of neurons at the levels of expression profile, cellular morphology, and functionality.

However, it is important to recognise that neurons are highly polarised cells, and this polarity is the basis for the formation of highly organised structures in vivo that are critical for proper physiological function.

Neurons have three distinct cellular compartments: dendrites, somas, and axons. Dendrites and axons serve as the respective functional inputs and outputs of the neuron, while the soma (or neuronal cell body) is mainly responsible to maintain the health of the neuron such that it can perform its transmission function. Given

the defined input/output function of the neuron, it is evident that the orientation and physical location of each of these specialised compartments within their environment is critical to establish the directional flow of information throughout the nervous system.

For example, in the human neuromuscular system, the lower motor neurons are responsible for relaying motor information from the central nervous system to skeletal muscle effectors. The lower motor neuron somas are located in the ventral horn of the spinal cord where they project axons that form synapses on skeletal muscle located some distance away (in some cases this distance can be as much as one metre).

In vivo, it is the axonal outputs of the motor neurons that innervate their muscle target, while their dendrites and soma do not come into physical contact with the muscle tissue. During development, this neuronal orientation and positioning are established by a complex guidance system that is generally based on the release of chemical cues in a spatially and temporally defined manner. In this way, neuronal inputs and outputs are correctly guided to their specific target and location.

In the absence of environmental cues, as is the case when neurons are seeded in standard laboratory culture vessels, neurons will project dendrites and axons in random directions. Axonal projections will readily form connections or synapses with neighbouring neurons in a random fashion and may even synapse onto themselves (autapses). This neuronal “rat’s nest” is simply not representative of the organisation and polarity of neurons in vivo, greatly reducing the value of such systems as physiological models of the nervous system. To address this, neuroscientists have turned to utilising microfabricated and microfluidic devices in conjunction with neuronal cultures. In their most basic forms, such devices contain a series of microchannels (or micro-tunnels) that act as structural guides for projecting axons, leading them away from their somas into an adjacent compartment. In this way, compartmentalised microfluidic devices can successfully mimic the polarisation and Summer 2021 Volume 13 Issue 2

Drug Discovery, Development & Delivery organisation of neurons observed in vivo.

As discussed further below, these simple, passive tools open a wealth of possibility when it comes to developing complex, physiologically relevant models of the nervous system.

How Compartmentalisation is Achieved Using Microfluidics In basic neuronal applications, microfluidic devices contain two adjacent chambers that are separated by a series of microchannels.

These microchannels are sufficiently small such that fluid flowing through them is strictly laminar, where the direction of flow depends on forces provided by the fluid level in each of the adjacent chambers.

Fluidic isolation of one chamber from the other becomes possible by simply adjusting the relative fluid levels in each of these chambers. Despite their small size, the microchannels are still large enough to permit axons to pass through them, and neurons seeded in one chamber will project their axons through the microchannels into the adjacent chamber (Figure 1). This effectively segregates axonal and somatic components of the neuron, and these can be subsequently accessed, treated, and analysed individually.

The ability to fluidically isolate an individual chamber allows molecules to be applied to one component of the neurons, without exposing the components in the adjacent chamber (Figure 2). This unique feature of compartmentalised microfluidic devices is particularly advantageous in the development of powerful disease models of neurodegeneration. For example, a neuronal compartmentalisation model is well suited for studying neuronal uptake, intraneuronal transport, and propagation of toxic or misfolded proteins such as tau, α-synuclein pre-formed fibrils (PFF), amyloid-ß or prion PrP (Figure 3) where compartmentalisation greatly simplifies the interpretation of data. Fluidic isolation is also useful in co-culture applications where adjacent chambers contain distinct cell types. For example, motor neurons located in one chamber will project axons into an adjacent chamber containing skeletal muscle. In this case, skeletal muscle media is not ideal for the neurons to differentiate, so fluidic isolation of the neuronal chamber from the adjacent muscle chamber prevents mixing of the media.

Advanced Neurological Disease Models Made Possible Most microfabricated and microfluidic www.ipimediaworld.com

Figure 1

Figure 2

devices are made from polydimethylsiloxane (PDMS), a flexible, non-toxic polymer with excellent optical properties. These microfabricated PDMS structures are typically bonded to a glass bottom that serves to form the surface for seeding and culturing cells. There is a wealth of information available that includes a huge variety of diverse microfabrication techniques and methodology based on using PDMS. Combined with its low cost, availability, and well-described biocompatibility, it is no wonder that PDMS has become the material of choice when it comes to fabricating microfluidic devices for cell culture purposes. With few limitations, PDMS-based microfluidic devices are available in a plethora of designs and configurations to accommodate a defined experimental purpose.

The versatility of employing PDMS-based compartmentalised microfluidic devices

opens the possibility for the development of even more complex models with the goal of increasing physiological relevance (Figure 4).

For example, the newest microfluidic devices have designs to house self-assembled 3D tissues (such as spheroids and organoids) or tissue explants that can be configured to interface through microchannels with more classical monolayer (2D) cultures. In other applications, additional chambers and microfluidic interfaces can be added or reconfigured to create multicompartment models. The addition of a third compartment can add an extra layer of complexity (and interpretational confidence) to neuronal propagation assays.

Since these devices can incorporate cultures from both neuronal and non-neuronal sources, compartmentalised devices are ideal platforms to model sensory and motor systems. Examples include the co-culture of motor neurons with skeletal muscle to model neuromuscular degeneration (e.g., INTERNATIONAL PHARMACEUTICAL INDUSTRY 27

Drug Discovery, Development & Delivery

Figure 4

glass and sterilisation) prior to their use in culture, again making these completely impractical for implementation in a highthroughput setting.

Figure 3

ALS or SBMA) or sensory neurons with skin fibroblasts to model pain. For even more complex multi-co-culture models, a triple compartment device can house motor neurons, Schwann cells and skeletal muscle in adjacent chambers.

Adapting Devices for Drug Screening One of the earliest phases of the drug discovery process is the use of cell-based in vitro assays in high-throughput drug screens to identify promising drug candidates from large chemical libraries. The large number of molecules to be screened necessitates the use of automated machinery and robotics for cell culture seeding, maintenance and processing. For many phenotypic screens, imaging data is commonly collected using high content imaging platforms, and subsequently analysed using well-defined parameters. Importantly, these systems are nearly all designed around a standardised consumables format, the familiar 96-well microplate format.

Although neuronal microfluidic and compartmentalisation devices have existed for quite some time, their use in highthroughput drug screening has been limited.

This is largely due to an inherent design flaw in most compartmentalised devices 28 INTERNATIONAL PHARMACEUTICAL INDUSTRY

that stems directly from limitations in the way they are traditionally microfabricated.

While these conventional devices are still extremely useful in an academic or fundamental research setting where individual scientists experiment with them in an artisanal manner, they are incompatible with automated or robotic systems used to carry out large-scale drug screening. Additionally, many conventional microfluidic devices require users to go through a series of time-consuming preassembly steps (e.g., plasma bonding to

Recently, advances in microfabrication methods have overcome these design limitations and have led to the development of a series of compartmentalised microfluidic devices that are fully high-throughput screening-compatible (Figure 5). These newgeneration devices are catered specifically to the requirements and needs of the pharmaceutical and safety pharmacology industries, and are designed in industrystandard ANSI/SLAS microplate formats for seamless compatibility with existing infrastructure. Furthermore, these new devices are available pre-bonded to a glass, pre-coated and sterile, further streamlining

Figure 5 Summer 2021 Volume 13 Issue 2

Drug Discovery, Development & Delivery their implementation in large drug screening programmes.

Moving Forward Microfluidic technologies are simple tools that provide necessary sophistication to enhance the physiological relevance of neurological disease models. Microfluidic systems were largely incompatible with high-throughput drug screening, precluding their implementation in the pharmaceutical industry. With recent advances in microfabrication methods, the combination of microfluidics and stem cellderived neuronal culture technologies form a solid basis for generating powerful in vitro models of neurological disease.

Innovative solutions to scientific problems are often developed in response to the evolving needs of researchers looking to push the boundaries of science. By continuing to communicate new ideas and current limitations openly, academic, and industrial labs can work efficiently to create better tools and methods to move forward.

In line with this, the continuous effort to improve upon current model systems for drug screening and safety testing by utilising appropriate new technologies, such as microfabricated cell culture devices for neuronal applications, have the potential to dramatically accelerate and facilitate the discovery of promising new therapeutics for neurological disease.

REFERENCE 1.

GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016.

Lancet Neurol. 18(5): 459–480. (2019)

Mark Aurousseau Mark is a co-founder and chief scientific officer of eNUVIO. After obtaining his PhD in pharmacology at McGill University, he continued his training at the Montreal Neurological Institute, where he worked to develop new stem cell-derived models of neurodegenerative disease suitable for drug screening purposes. At eNUVIO, he works closely with R&D to design, develop and commercialise novel microfabricated and microfluidic devices to address the specific needs of life science researchers.

Email: mark.aurousseau@enuvio.com

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 29

Drug Discovery, Development & Delivery

Time to Put the Spotlight on the Substance of your Drugs through Solid-form Development The global pharmaceutical industry generated more than $1.25tr in revenue in 2019, up from $1.2tr in 20181, and the final figures for 2020 are expected to be even more impressive.

With this expansion, it is no surprise that the space is growing ever more competitive.

In such a fast-paced environment, pharmaceutical companies need to do all they can to ensure their products – no matter whether they are new innovations or improvements to existing active pharmaceutical ingredient (API) solids – stand out in the market. Even marginal gains in therapeutic effect or the cost of manufacturing can make all the difference to whether a product succeeds or fails to make an impact.

The question facing pharmaceutical companies is: how to achieve these all-important enhancements? As John Mykytiuk at Sterling Pharma Solutions explains, the answer to this question lies in perfecting the physical characteristics of the API solid itself through solid-form development.

Even with the turmoil of the ongoing COVID-19 pandemic, the pharmaceutical industry has continued its impressive legacy of innovation. Over the last year, it has produced not only new coronavirus therapies and vaccines at an unprecedented pace, but has delivered exciting new treatments for a variety of other serious medical conditions as well.

The European Medicines Agency (EMA) recommended 97 new medicines for authorisation by European Union (EU) Member States in 2020, and 39 new active substances2.

This is up from 66 new medicines and 30 new active substances the year before. The story is the same in the US, where the Food and Drug Administration (FDA) approved 53 novel therapies last year3, up from 48 in 20194.

In this fast-paced environment, pharmaceutical companies are under more pressure 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

than ever before to produce therapies – new or improved – that can outpace those of competitors, by being more efficacious or more cost-effective. Even the smallest enhancements can make a big difference in terms of success.

With this in mind, it is crucial that pharmaceutical companies make every effort when developing new drugs, or enhancing existing treatments, to optimise their effectiveness and simplify the required manufacturing process.

However, the process of optimising a drug is more than simply looking at its chemical make-up, or the delivery method.

It’s vital to also consider the physical characteristics, from the packing of the API’s molecules, to the shape and size of its individual particles – a process known as “solid-form development”.

The Impact of a Drug’s Solid Form The physical make-up of an API plays a key role in the optimisation process for any API, whether a new substance or an existing one, due to its effect on the behaviour of the drug in the manufacturing process and subsequently in the human body.

It is possible for an individual API to have multiple possible crystal lattice packing arrangements – a phenomenon known as “polymorphism”. On top of polymorphism, the range of possible shapes and sizes of API particles results in very different consequences in terms of the drug’s behaviour.

For example, all these factors can impact on an API’s solubility in water or in other solvents, with repercussions for therapeutic effect.

A poorly water-soluble API might have reduced bioavailability – meaning less of it can enter the bloodstream when introduced to the body to have an active effect. This undermines its efficacy as a treatment, requiring more frequent dosing to maintain therapeutic blood levels, with consequences for patient convenience and adherence.

The molecular structure of an API polymorph also has ramifications for formulation

manufacturing efficiency. It can affect the melting point of the substance, meaning that energy used during drug product manufacture may change the form. More complex salt, cocrystal, hydrate and solvate formation processes may be required to produce the target version or polymorph.

In addition, particle size reduction such as milling operations may be needed to achieve the required particle shape and size. All of these will impact on an API solid’s commercial feasibility.

Given the impact of these physical characteristics, it is clearly vital that drug companies take steps to identify the most appropriate polymorph and other features if they want to produce commercially successful drugs.

Moreover, the physical properties of an API – including the polymorphs, salts, cocrystals, hydrates, particle shape and size – form a key part of product patents. Taking this into account, investing in appropriate solid-form development can identify the preferred physical properties. In doing so, it can not only help ensure the success of a drug product, but can help safeguard a company’s intellectual property (IP), protecting it from the competition.

The Search for the Right Physical Profile Identifying the right physical characteristics for an API requires drug companies to consider many factors.

The thermodynamic behaviour of an API polymorph –the structural stability of the solid and how it changes over time – including its mechanical properties, such as brittleness, compressibility or ductility, are crucial to determine, due to their impact on manufacturing.

Likewise, the surface texture of an API particle can impact its solubility and therefore bioavailability. It can also affect how API particles interact with each other, with irregular surfaces potentially leading to the particles clumping together, with consequences for dosing.

In addition, the surface properties can affect how it responds to its surroundings Summer 2021 Volume 13 Issue 2

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 31

Drug Discovery, Development & Delivery

or its ability to absorb water or dissolve, its responses to light via photodegradation, and how the API is handled and drug product packaged.

The kinetic properties of an API, meaning how particles dissolve in a medium, such as PBS or biorelevant media, is another important characteristic to consider, as it can impact on bioavailability and, therefore, efficacy.

Finally, and as important to consider, is the chemical purity of the API. Drug developers must identify any impurities in the API in order to be able to develop a manufacturing process capable of controlling them effectively to ensure optimum health and safety.

32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Considering the Formulation In addition to optimising the efficacy of the API, it is necessary to consider how the physical characteristics of an API will impact on other factors in the development process.

In particular, the API’s physical properties must be appropriate for the formulation of the finished drug product to ensure optimum performance in the final delivery method – whether oral, parenteral or inhalation.

The interaction of a formulation’s components with the API has a vital part to play in the therapeutic effect of the drug, as well as the shelf-life of the product.

All of this highlights the vital role played by the solid form of an API on therapeutic

effect. Perfecting the physical characteristics of a substance is vital to achieve the most effective product.

Optimising the Process, Enhancing Efficiency Once the appropriate properties have been determined, drug companies must then carefully consider how they can reproduce them consistently during the manufacturing process in an efficient manner.

It is crucial to achieve this goal, as the cost of producing the API will impact profitability for the finished product. With this in mind, to ensure the product succeeds on the market, any manufacturing process must be able to minimise production costs to maximise profit margins.

Summer 2021 Volume 13 Issue 2

Drug Discovery, Development & Delivery The time it takes to manufacture and refine an API directly impacts the cost of production. Solid-form development can identify ways to simplify the manufacturing process for the API, helping to streamline the scaling and commercialisation process, so companies can benefit from a return on their investment (ROI) more quickly.

Enhancing synthesis processes to produce the API is an important first step in reducing production time. Even more important, though, is the filtration and drying of the produced API, be it a new chemical entity, NEC, or existing material. The right methods can wash and isolate the desired drug substance, eliminating impurities and achieving consistent chemical purity and solid-form characteristics from batch to batch of API. Finding an effective method for both filtration and drying is key to ensuring any API’s commercial viability and can be addressed through crystallisation development.

However, filtration and drying on their own may not always be enough to ensure consistency across a batch of API, as the dried particles may still be irregular in size and shape. Therefore, it may be necessary to incorporate milling or micronisation into the manufacturing process to reduce the API particle size and achieve an optimum profile.

This step can add time to the production process, so it is important to find solutions at earlier stages in the development cycle to eliminate the need for particle size reduction. Better filtration procedures can reduce waste, while improvements to drying can reduce the amount of additional processing, such as milling, further downstream. This can ultimately reduce the cost of manufacturing, increasing eventual ROI for the drug compound.

Seeking Expert Solid-form Development Help It is clear that solid-form development has a vital role to play not just in delivering more effective drugs for patients, but also in minimising manufacturing costs and optimising productivity for drug companies.

Despite the importance of this stage in the drug innovation journey, pharma companies, regardless of their size, often do not have the expertise or infrastructure to carry out the investigative processes needed to identify the ideal physical properties www.ipimediaworld.com

of an API, and optimise manufacturing processes.

However, it is possible to outsource the solid-form development process to expert partners. A growing number of contract development and manufacturing organisations (CDMOs) are offering specialised material sciences services, including expert teams and dedicated infrastructure and capacity, in order to help drug companies to develop their API solid.

When engaging a CDMO for solid-form development services, though, there are some investigative processes that are essential for effective and comprehensive solid-form development. If they want the best possible support, drug companies should ensure that their CDMO partner offers the following investigations: 1.

Polymorphism investigation – to identify the polymorph that not only offers the greatest therapeutic effect, but also has the thermodynamic qualities and chemical stability required to ensure commercial viability.

2.

Salt/cocrystal investigation – to improve the solubility of the API and identify ways to improve it for optimum bioavailability and manufacturing feasibility.

3.

Pre-formulation evaluation investigation – to optimise the API’s solubility as well as chemical and mechanical stability for the needs of the formulation.

4.

Flow characteristic determination – to understand how the formulation will flow through processing equipment and delivery device to customise both for optimum performance.

5.

Crystallisation development – to devise the most effective and efficient process to reproduce the target API characteristics consistently.

6.

Bulk particle manipulation – to determine whether particle size reduction such as milling is needed following isolation of the drug substance, to achieve an appropriate particle shape and size.

In addition to offering these, it is important that drug companies work with

CDMO partners that offer the flexibility and capacity to meet their solid-form development needs.

More and more CDMOs are investing in dedicated material science facilities and teams to deliver specialist support in this area – working with these, drug companies can ensure the highest possible standard of solid-form development.

Work with Experts to Shape the Perfect API Particle Solid-form development lays the groundwork not just for therapeutic effectiveness, but also for commercial viability, so it is vital that sufficient time and attention is dedicated to this part of the drug development process. Failure to do so can result in drugs that are unnecessarily expensive to make, without adding value to healthcare professionals and patients, ultimately undermining their market value.

By engaging with CDMOs that specialise in solid-form development, however, companies can minimise the risk of this occurring. The right partner can give them the guidance and support they need to live up to the pharmaceutical industry’s reputation for innovation, delivering better, more cost-effective therapies that transform patients’ lives.

John Mykytiuk John Mykytiuk obtained his degree in chemistry and PhD in polymerisation reaction kinetics from the University of Bradford. Following two post-doctoral positions at Sussex University, he joined Cyanamid GB as part of a drug development group. John then moved to a CRO, Evotec/Aptuit, were he was involved in chemical process research and development including solid state investigations. John then moved to Onyx Scientific to take up a role to develop solid state services where he was involved with numerous and diverse solid state investigations. John now leads the solid state activities at Sterling Pharma Solutions encompassing physico-chemical characterisation, salt and polymorphism investigations, crystallisation development and particle characteristics.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 33

Drug Discovery, Development & Delivery

Accelerating Pharma Research with Sensitive Spatial Analysis of Challenging Molecules Abstract To reduce attrition rates in pharmaceutical research and development (R&D), powerful quantitative analytical methods are needed to monitor therapeutic compounds, their metabolites, and target engagement.

The ability of matrix-assisted laser desorption/ionisation (MALDI) imaging to perform quantitative spatial analysis of drugs and their metabolites, as well as pharmacodynamic (PD) biomarkers in tissues, is accelerating its use in pharmaceutical research. Advances in technology and methodology are opening MALDI imaging up to analysing a wider range of small molecules without compromising image resolution.

The discovery and development of safe and efficacious pharmaceutical products is a lengthy and expensive process that, today, still suffers from frequent failure to progress a drug through to clinical trial. Overall failure rate in drug development has been reported at over 96%, including a 90% failure rate during clinical development1.

Attrition rates are particularly high for drugs targeting previously ‘undrugged’ proteins and for diseases with poorly understood pathogenesis. Researchers must establish early in the development pipeline the exact distribution of the drug in the appropriate tissues, understand and quantify in situ drug metabolism, and establish any off-target activity and toxicity that could pose a safety risk.

Drugs that fail late in the development or clinical phase not only incur huge costs for pharma companies, but inflate the price of drugs that do succeed through research and development (R&D). There is also a risk that high attrition rates could deter companies from pursuing drugs with innovative mechanisms of action.

One challenge that both academic and industrial researchers face is the translatability of preclinical research into clinical applications. This reinforces the need for a better understanding of the 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

molecular defects leading to complex diseases, which can provide new insights into fundamental biology and translational opportunities2. Powerful quantitative analytical methods are needed to monitor therapeutic compounds, their metabolites, and target engagement, but traditional analytical techniques such as liquid chromatography mass spectrometry (LCMS), although widely used, face limitations such as a lack of spatial information which is required for establishing efficacy and toxicity within different tissues. The emergence of advanced mass spectrometry (MS) techniques, such as matrix-assisted laser desorption/ionisation (MALDI) imaging, has enabled the non-radioactive, label-free, and non-destructive localisation of targeted therapeutics as well as endogenous biomolecules – from metabolites to proteins – in an untargeted manner3.

Adding a Spatial Dimension to Molecular Analyses MALDI imaging is a label-free omics technique that enables spatially resolved molecular analysis of single cells with highthroughput and high spatial resolution, enabling the monitoring of both drug metabolism and pharmacokinetics (DMPK), with absolute quantification. Relatively new techniques such as trapped ion mobility spectrometry (TIMS) are now being utilised in MALDI imaging workflows to separate structural isomers.

TIMS is a gas-phase MS technique that enables ions to be separated according to their collisional cross-section (CCS) – a measure of how likely they are to be deflected by a collision with other gas molecules as they drift through an ion tube. This provides another way of separating ions and adds an additional dimension to the analysis.

For pharma R&D, this allows researchers to image a wider range of small molecules and their metabolites in tissues and establish spatially resolved evidence of target engagement, PK/PD, and druginduced toxicity. The greater depth of molecular information in a spatial context available during R&D improves the chance of a drug candidate’s success in clinical trials.

However, research centred around small molecules typically tests the limits of MALDI sensitivity and molecular coverage.

Ion suppression and quantification limit molecular characterisation. The recent introduction of a novel laser-induced postionisation (PI) method has addressed the trade-off between sensitivity and resolution and, together with TIMS, increases the sensitivity of MALDI imaging by up to two or three orders of magnitude depending on sample, matrix, and analyte, compared with traditional MALDI methods4. Importantly, this opens the technology to a wider range of small molecules, including classes of phospho- and glycolipids, liposoluble vitamins, glycans, and steroids, without compromising image resolution.

Laser-induced PI and TIMS are an essential combination that add significant value to MALDI imaging, enabling stronger signals, fast data acquisition speeds, high molecular separation, and CCS alignment to further improve the number of possible molecular identifications5.

Boosting Sensitivity in Targeted Drug Imaging Drug compound imaging experiments have demonstrated the significant sensitivity enhancement of MALDI imaging when target compounds and metabolites are imaged with laser-induced PI methods. In one study, a dilution series of standard compounds was used to define the ionisation efficiency of the drug of interest, called BI-YYY6. Solutions of caffeine, chloroquine, rosuvastatin, reserpine and BI-YYY were spotted onto control liver tissue and analysed under traditional MALDI and laser-induced PI conditions.

Sensitivity for all five test compounds was significantly increased by laser-induced PI. In particular, the peak intensity of BI-YYY was enhanced by a factor of 300 using the laser-induced PI method.

After determining the laser-induced PI enhancement of BI-YYY signal under controlled conditions, rats (n=2) were dosed with BI-YYY or chloroquine and analysed by MALDI imaging to determine whether the sensitivity advantage translates to better Summer 2021 Volume 13 Issue 2

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Drug Discovery, Development & Delivery samples, resulting in the destruction of important histological information8. But untargeted MALDI imaging methods make it possible to identify target molecules that may be locally concentrated, providing spatial information about potential new biomarkers.

Figure 1: Rat control and dosed organs were compared between MALDI and laser-induced post-ionisation (MALDI-2, timsTOF fleX, Bruker Daltonics). BI-YYY intensity is shown in SCiLS Lab software where yellow colours indicate higher intensities than blue colours as shown in the intensity gradient. Kidney (top) and liver (bottom) from control and BI-YYY dosed rats were used to compare the ionisation efficacy in MALDI and laser-induced post-ionisation (MALDI-2). The intensity difference between the two treated samples is shown in the extracted mean spectra.

drug localisation information. Images from BI-YYY dosing exhibited 8.5-fold higher peak intensity with laser-induced PI in kidney and a six-fold higher intensity in liver, based on mean peak intensity (Figure 1).

Additionally, metabolites of chloroquine were investigated to explore the detection limit of laser-induced PI in comparison to MALDI. As with findings from BI-YYY dosed tissue, images reveal that the signal intensity for chloroquine in kidney was six-fold greater using laser-induced PI (Figure 2).

For chloroquine in liver, results were similar where mean peak intensity reveal a five-fold higher intensity boost from laser-induced PI.

Laser-induced PI methods substantially enhanced the sensitivity for many compounds, delivering new distribution information from previously undetected metabolites as well as providing lower limits of detection for target compounds, both vitally important to DMPK studies.

Elevating Biomarker Discovery The direct analysis of tissue sections by MALDI imaging has facilitated significant advances in biomarker discovery7. Traditional biomarker studies using genomics, tran-scriptomics, metabolomics, and proteomics techniques often require extraction of potential biomarkers from

Glycoprotein biomarkers are a group of glycoproteins involved in pathological processes, which can be used as indicators of certain diseases in the clinic. Given that most of the US Food and Drug Administration (FDA)-approved biomarkers for different types of cancer are glycoproteins9, these proteins are often targeted for biomarker discovery. N-glycans are important players in a variety of disease pathways, including different types of cancer, (auto)immune diseases, and viral infections, and MALDI imaging is an important tool for obtaining spatial information on glycans in tissue.

A recent study has demonstrated the ability of laser-induced PI MALDI imaging (negative ion mode) to increase ion yields and enable the acquisition of high-quality MS/MS spectra and structural analysis of N-glycans from minute sample amounts10. To evaluate whether ion species generated from the same N-glycans in both positive ion mode MALDI and negative ion mode laserinduced PI would show the same profiles and spatial distributions in tissue, a comparison experiment was performed on human cerebellum tissues. Figure 3A shows the representative average tissue spectra obtained from the two analyses, and the recorded distributions showed the same glycans to be present in similar morphological areas upon measurement with the two ion polarities (Figure 3B-I).

By coupling laser-induced PI to a TIMS quadrupole time-of-flight (QTOF) mass spectrometer, researchers could increase detection sensitivity of molecular [M – H]species of N-glycans from tissue sections of human cerebellum by approximately three orders of magnitude. Compared with traditional MALDI imaging techniques, laser-induced PI mode analysis of [M + Na]+ adducts achieved a 10-fold sensitivity increase.

Figure 2: Rat control and dosed organs were compared between MALDI and laser-induced post-ionisation (MALDI-2, timsTOF flex, Bruker Daltonics). Chloroquine intensity is shown in SCiLS Lab software where yellow colours indicate higher intensities than blue colours as shown in the intensity gradient. Kidney (top) and liver (bottom) from control and chloroquine dosed rats were used to compare the ionisation efficiency between MALDI and laser-induced post-ionisation (MALDI-2). The intensity difference between the two treated samples is shown in the extracted mean spectra.

36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

An additional benefit of the analysis of glycans with laser-induced PI is the absence of peak-splitting that occurs with traditional MALDI imaging through the presence of multiple alkali-metal adducts for the same glycan (e.g., sodium and potassium adducts; Summer 2021 Volume 13 Issue 2

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Drug Discovery, Development & Delivery Figure 3A). Further research is needed to assess potential differences in (post) ionisation efficiencies of various glycan classes (e.g., high-mannose vs complextype, sialylated and/or fucosylated species), but these results show that laser-induced PI can be a useful tool for the visualisation of N-glycans in tissue.

Studies such as these not only facilitate developments in glycobiology research, but shed light on how evaluating N-linked glycosylation and other glycan classes with MALDI imaging could help provide new therapeutic and diagnostic assay leads, for example in cancer. One of the longstanding challenges of glycan imaging is the number of structural isomers. In glycobiology, how sugars are arranged on proteins dictates the impact on cancer growth and which cancer pathway has been activated. Because ion mobility separation is an MS technique that separates molecules based on their conformation, TIMS can therefore be used to detect isomers and glycoforms, and lead to more accurate cancer biomarker development.

Figure 3: Spectra and images of positive ion mode MALDI imaging and negative ion-mode laser-induced post-ionisation (MALDI-2) imaging (timsTOF fleX, Bruker Daltonics). (A) Average spectra for negative ion-mode MALDI-2 imaging (red) and positive ion-mode MALDI imaging (blue) with assigned N-glycan species. Coloured N-glycan compositions represent a > ± 10% variation of intensity between positive and negative ion-mode analyses. Peaks with an asterisk (*) in the positive ion mode spectrum are potassium adducts. (B,F) H&E stained consecutive section displaying cerebellar brain morphology.

(C,G) Example images for N-glycan H5N2 in human cerebellum. (D,H) Zoom in on histology with different morphological structures annotated (P, Purkinje cell, G, granular layer, M, molecular layer, W, white matter). (E,I) Zoom in on example H5N2 images. In red, negative ion-mode laser-induced post-ionisation (MALDI-2) images, and in blue, positive ion-mode MALDI imaging images. Reproduced from reference10 in accordance with Creative Commons Attribution License.

38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Future Adoption in Pharma R&D The pharmaceutical industry is in need of fast and sensitive analytical tools to visualise the spatial distribution of drug, metabolite and endogenous biomarkers directly in tissue sections. The ability of MALDI imaging to co-localise drug/ metabolite distribution with histological information in a label-free manner is highly

Summer 2021 Volume 13 Issue 2

Drug Discovery, Development & Delivery advantageous for pharma R&D. For example, the typically heterogeneous compound distribution in tumours can be matched with tumour biomarkers in oncology drug development11.

Recent advances in instrumentation, such as the incorporation of TIMS to QTOF MS, have led to more widespread adoption of MALDI imaging in pharma research and the development of drug discovery beyond drug disposition analysis, particularly in PD biomarker research and toxicology3. Laserinduced PI methods, together with TIMS, can provide enhanced measurement speeds and increased sensitivity without compromising spatial resolution, and deep molecular content when combined with QTOF MS. The combination of these technologies shows great potential as a MALDI imaging tool to support distribution, metabolism, efficacy and toxicity testing of a wide range of drug compounds in pharma research, all in the same dataset.

REFERENCES 1.

Hingorani AD, Kuan V, Finan C et al. Improving the odds of drug development success

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through human genomics: modelling study, Scientific Reports, 2019; 9: 18911.

Seyhan AA. Lost in translation: the valley of death across preclinical and clinical divide – identification of problems and overcoming obstacles, Translational Medicine Communications, 2019; 4(18).

Schultz S, Becker M, Groseclose MR et al. Advanced MALDI mass spectrometry imaging in pharmaceutical research and drug development, Current Opinion in Biotechnology, 2019; 55: 51-59.

Soltwisch J, Kettling H, Vens-Cappell S et al.

Mass spectrometry imaging with laser-induced postionization, Science, 2015; 384(6231): 211215.

Soltwisch J, Heijs B, Koch A et al. MALDI-2 on a Trapped Ion Mobility Quadrupole Time-ofFlight Instrument for Rapid Mass Spectrometry Imaging and Ion Mobility Separation of Complex Lipid Profiles, Analytical Chemistry, 2020; 92(13): 8697-8703.

Henkel C, Koch A, Becker M et al. The combination of MALDI-2 and timsTOF flex brings targeted drug imaging to the next level, Application Note, Bruker Daltonics, 2020.

Reyzer ML and Caprioli RM. MALDI Mass Spectrometry for Direct Tissue Analysis: A New Tool for Biomarker Discovery, J Proteome Res, 2005; 4(4):1138-1142.

Scott AJ, Jones JW, Orschell CM et al. Mass Spectrometry Imaging Enriches Biomarker Discovery Approaches with Candidate

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Mapping, Health Physics, 2014; 106(1): 120-128.

Song E and Mechref Y. Defining glycoprotein cancer biomarkers by MS in conjunction with glycoprotein enrichment, Biomark Med, 2016; 9(9):835-844.

Heijs B, Potthoff A, Soltwisch J et al. MALDI 2 for the Enhanced Analysis of N Linked Glycans

by Mass Spectrometry Imaging, Analytical Chemistry, 2020; 92: 13904-13911.

Shannon Cornett Dale Shannon Cornett, PhD. is a MALDI Imaging Market Manager at Bruker. He has over 30 years in the field of MALDI, having held numerous roles at Bruker, including Applications Scientist and Product Manager, and as Research Assistant Professor of Biochemistry at Vanderbilt University. Over the last 20 years he has worked with many leading researchers to develop new strategies and tools for using MALDI imaging mass spectrometry in pharmaceutical and clinical research.

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Drug Discovery, Development & Delivery

How Endotoxin Contamination Can Affect Gene and Cell Therapies Gene therapy is revolutionising the way we treat human diseases. Any technique that modifies a person’s genes to treat or cure a disease is considered a form of gene therapy. This can occur via several possible mechanisms. A disease-causing version of a gene may be inactivated or replaced with a healthy version. Alternatively, a new gene may be introduced to combat a disease. Gene therapy products work by introducing genetic material into the nucleus of the cell. To introduce the genetic material, scientists need a delivery system that can transport the gene, nuclease, or short hairpin RNA (shRNA) to the nucleus of a human cell. The vehicle that carries this genetic material is known as a vector.1 A wide variety of vectors are available for gene therapy and can be categorised into viral and non-viral types. Viral vectors serve as the current delivery system used in FDA-approved gene therapies, while non-viral techniques are being studied as a safe and effective way to deliver genetic material to cells for therapeutic effect.1 In addition, viral vectors have in comparison to non-viral vectors demonstrated 10 times to 1000 times higher efficacy of gene transfer. We should note; however, that the high safety levels and low production costs for non-viral vector-based gene therapies are highly attractive features that continue to be considered in the development of future medicines.5 The two most common vectors are plasmids and viruses. A plasmid is a small, extrachromosomal DNA molecule within a cell that is physically separated from chromosomal DNA and can replicate independently. They are most often found as small circular, double-stranded DNA molecules in bacteria, but are sometimes present in archaea and eukaryotic organisms. When found in nature, plasmids often carry genes that benefit the survival of the organism and can provide distinctive advantages, such as a strong resistance to antibiotics. While chromosomes are large and contain all the essential genetic 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

information for living under “normal conditions”, plasmids are usually very small and contain only additional genes that may be useful in certain situations of stress and adversity or during states of disease. 2 On the other hand, the genes packaged by viral vectors can be integrated into the host cells’ genomes and permanently expressed. Some types of viruses insert their genome into the host's cytoplasm, but do not actually enter the cell, while others have been found to penetrate the cell membrane disguised as protein molecules by which entry into the cell is easily accomplished. There are two main types of viral infections that can occur. One is known as a lytic infection and the other a lysogenic infection. Shortly after inserting its DNA, viruses of the lytic cycle quickly produce more viruses then burst from the cell to continue infecting more and more cells. Lysogenic viruses integrate their DNA into the DNA of the host cell and may live in the body for many years before responding to a trigger. The virus reproduces as the cell does and does not inflict any harm to the harbouring host until it is triggered in some way. Once triggered, the virus releases the DNA from that of the host and employs it to create new viruses.3 The first viral vector used in gene therapy was based on adenovirus, which is a virus that causes the common cold, as well as other respiratory, intestinal, and ocular infections in humans.1 The genetic material of the adenovirus is carried in the form of double-stranded DNA. When introduced into a host cell, this genetic material remains transient in the nucleus, thus allowing it to be freely transcribed just like any other gene. Unfortunately, the adenovirus has been found to trigger strong, potentially dangerous, immune reactions in patients, so research using these types of viruses in gene therapy has been ongoing.3 Other viral vectors such as retrovirus and herpes simplex virus have also been used.

Like all human therapeutics, it is critical for gene therapy products to be free of endotoxin contamination. Endotoxin, also known as lipopolysaccharide or LPS, is a

component of the outer cell membrane of Gram-negative bacteria. It is an extremely potent pyrogen, with even miniscule exposure leading to dangerous fever or even sepsis. Furthermore, endotoxin is highly heat-resistant and thus difficult to remove through traditional means.

According to FDA guidelines, all intravenously injected pharmaceutical products must contain below 5 endotoxin units per kg of body weight. Endotoxin is highly ubiquitous, with lab environments being no exception, and so it is crucial for gene therapy products to be tested for endotoxin contamination prior to use in human subjects.

A 2019 paper published in Molecular Therapy – Methods & Clinical Development tested a new method to remove endotoxin contamination from recombinant adenoassociated virus (rAAV) stocks, a common vector for gene therapy. rAAV is prepared using plasmid DNA isolated from E. coli bacteria, which is a frequently a source of endotoxin contamination.8 The authors used the LAL assay to quantify endotoxin levels. One of the challenges with decontaminating rAAV stocks is that any residual detergents could not only induce toxicity, but also interfere with the LAL assay reagents, leading to false negatives. This is due to the masking effect, wherein an LPS molecule becomes surrounded by detergent molecules and thus shielded from interacting with the LAL reagents. However, the authors were able to keep detergent levels below critical levels in their decontaminated stocks, allowing for accurate endotoxin readouts using LAL.8 This study highlights the importance of thorough decontamination of gene therapy products, as well as the necessity of stringent buffer-exchange washing in order to remove residual detergent. As the popularity of gene therapy increases, it will remain crucial for scientists to be aware of the potential dangers of endotoxin contamination and the need to avoid false negatives caused by detergent carryover.8 Summer 2021 Volume 13 Issue 2

Drug Discovery, Development & Delivery

As with therapeutics based on gene therapy, the possible contamination of cell therapy products is also something to be considered. Cellular therapy products include cellular immunotherapies, cancer vaccines, and other types of both autologous and allogeneic cells for certain therapeutic indications, including hematopoietic stem cells and adult and embryonic stem cells. Although gene therapy involves the transfer of genetic material into the appropriate cells by way of a carrier or vector, cell therapy is the transfer of cells having a relevant and necessary function into a patient.4,6 When culturing any kind of cells in a laboratory environment, avoiding contamination is always a chief concern.

Biological contaminants are often the focus of such efforts, and they also can be the most straightforward to detect and avoid.

For instance, most bacterial or fungal contamination can be visually detected in the cell culture media and prevented using antibiotic treatments. Other biological contaminants, such as mycoplasma or other cell lines, are more difficult to detect, but can still be monitored via commercially available testing kits. www.ipimediaworld.com

In contrast to biological contamination, chemical contamination receives relatively little attention and is more difficult to detect and avoid. Among the most insidious chemical contaminants are endotoxins. Potential sources of endotoxin contamination include water, cell culture media, sera, glassware, and plasticware.

As mentioned with the gene therapy products, endotoxins found in cell therapy are highly resistant to both autoclaving and irradiation, meaning they can be present even in the absence of viable bacteria.

Their high hydrophobicity also gives them a strong affinity for plasticware and unlike live bacteria, endotoxins cannot be observed visually in cell culture media. Furthermore, endotoxins cannot be depleted with antibiotics, instead requiring specialised endotoxin removal solutions.

By taking steps to avoid endotoxininduced cell culture problems, researchers can be more confident in experimental results. Various methods have been suggested to aid in keeping cell cultures and their resulting therapies free of endotoxin contamination. Among those are: utilisation of high-purity water and low-endotoxin FBS, as well as incorporating the use of plasticware that is certified to

be endotoxin-free.7 However, in addition to the use of purified raw materials and reagents, establishing procedures for strong aseptic technique and sterilisation will be vital in reducing the chances of endotoxin contamination.

Aseptic technique is one of the core skills for any biology researcher.

Preventing contamination of cell cultures is necessary to avoid experimental artifacts and potential cell death. Additionally, contamination in an animal research context could lead to infections or death.

Most biological contaminants can be avoided using standard sterilisation reagents, such as bleach or ethanol.

However, endotoxin is highly stable and can persist even in the absence of viable bacteria. Thus, it is crucial for QC technicians to maintain rigorous standard operating procedures for aseptic technique.

One example of an aseptic technique relevant to endotoxin is the practice of changing one’s gloves regularly. An inexperienced cell culture technician may assume that frequently spraying their gloves with ethanol is sufficient to maintain sterility. However, ethanol can INTERNATIONAL PHARMACEUTICAL INDUSTRY 41

Drug Discovery, Development & Delivery

leave endotoxin contamination behind, so it is important to set standards for how frequently users should change their gloves.

endotoxin contamination can arise after opening reagents, or be transferred from glassware/plasticware, it is also important to perform regular endotoxin testing.

Endotoxin contamination can greatly disrupt an in vitro experiment, particularly those involving immune cells. Macrophages show increased IL-6 secretion in response to endotoxins, while T cells show increased proliferation and lymphokine production.

For both gene therapy and cell therapy products, the Limulus amebocyte lysate (LAL) assay is a method that offers a costeffective and highly sensitive option to quantify endotoxin levels. The assay relies on proteins extracted from the blood of horseshoe crabs and in the presence of endotoxin, these proteins undergo a clotting reaction which can be quantified to give a highly accurate readout of endotoxin levels. This assay continues to play a crucial part in maintaining the safety of our gene and cell therapy treatments, particularly when used during large-scale productions or crucial in vitro experiments.

Non-immune cells can also be subject to dysregulation by endotoxins. Though endotoxins are classically viewed to act through the CD14 receptor, cells lacking this receptor can still show strong responses to endotoxin contamination. For instance, one study reported that cardiac myocytes experience contractile dysfunction upon exposure to endotoxins. Other studies have reported altered protein production in CHO cells and altered clonal efficiency in ureteral epithelial cells.

Additionally, the sensitivity of different cell lines to endotoxin contamination is highly variable. Some cell lines show dysregulation at less than 1 ng/mL of endotoxin, whereas others require much higher concentrations of up to 5000 ng/ mL. It has also been theorised that cell lines grown for many years in culture (such as HeLa and CHO cells) may have been naturally selected for endotoxin resistance over time. Based on this, it is difficult to determine a universal safe threshold for endotoxin contamination.

When working with cells in culture, it is crucial to purchase low-endotoxin products when available. However, since 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

REFERENCES 1.

2.

3.

4.

5.

‘How Does Gene Therapy Work?’ (2020 June).

Genehome. Available at URL: https://www. thegenehome.com/how-does-gene-therapywork/vectors?gclid=Cj0KCQjwkZiFBhD9ARIsA GxFX8C53pUEumd-W82HmYSL_5gBGNPtMMD rR_882PILGN_0n9vF8icjPboaAjA-EALw_wcB ‘Plasmid’. (2021 May 6). Wikipedia. Available at https://en.wikipedia.org/wiki/Plasmid ‘Vectors in Gene Therapy’. (2020 December 16). Wikipedia. Available at URL: https:// en.wikipedia.org/wiki/Vectors_in_gene_ therapy ‘Cellular and Gene Therapy Products’. (2021 March 2). U.S. Food and Drug Administration.

Available at URL: https://www.fda.gov/ vaccines-blood-biologics/cellular-genetherapy-products#:~:text=Cellular%20 therapy%20products%20include%20 cellular,adult%20and%20embryonic%20 stem%20cells Lundstrom, K. (2019). “Gene Therapy Today and Tomorrow”. National Center

6.

7.

8.

for Biotechnology Information, ‘Diseases’.

Published online 2019 April 28. Available at URL: https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC6631424/ David, A., Professor. “How Cell Therapy differs from Gene Therapy”. Future Learn.

Available at URL: https://www.futurelearn. com/info/courses/making-babies/0/ steps/23934#:~:text=Whereas%20gene%20 therapy%20involves%20the,appropriate%20 cells%20of%20the%20body.

Easthope, E. (2020). “Five Easy Ways to Keep Your Cell Cultures Endotoxin-Free”.

Biocompare, published online 2020 April 20.

Available at URL: https://www.biocompare. com/Bench-Tips/563017-Five-Easy-Ways-toKeep-Your-Cell-Cultures-Endotoxin-Free/ ‘Removal of Endotoxin from rAAV Samples Using a Simple Detergent-Based Protocol’.

(2019 December 13). Molecular TherapyMethods & Clinical Development, published online 2019 September 6. Available at URL: https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC6804492/

Lisa Komski Lisa Komski is the Sales General Manager for the LAL Division of FUJIFILM Wako Chemicals U.S.A. Corporation.

With a nearly 30-year career of working in the Chemicals and Life Science industries, she has established herself as a strong business development professional skilled in U.S. Food and Drug Administration (FDA) requirements and cGMP. Lisa holds degrees in Biology and Medical Technology.

Email: lisa.komski@fujifilm.com Summer 2021 Volume 13 Issue 2

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 43 OMPS/ipi/ad/ob/0621/7

Drug Discovery, Development & Delivery

Choosing the ‘Right’ Device to Deliver Your New Therapy: Four Simple Steps When you develop a new therapy, the device you develop or select to deliver it will be key to the overall success of your product. You may have spent considerable time and investment developing your drug; however, if your device doesn’t perform technically, or the patient struggles to use it, then the chances of that drug successfully delivering the therapy to the patient are severely compromised.

So, how do you select the ‘right’ device to deliver your therapy? Typically, you will have one of two options: either develop your own from scratch, or license an existing or developing one from someone else.

There may be good reasons to embark on your own device development, such as the ability to tailor the device to your specific needs. Despite this, pharmaceutical companies often choose the latter option.

Getting a new device approved takes time.

In the United States, it can take an average of seven years, in fact. Finding something that is already available, either on or near to market, that can be licensed can be a

much more appealing option, offering a less time-consuming, less risky and often more cost-effective way of procuring a device than a ground-up development.

With so many devices available on the market, however, where do you start? This is where it helps to have an “ADEA” of how to identify promising devices for your therapy, following four initial steps: align, define, explore and assess.

Step One: ALIGN Your Stakeholders When setting out to license a new technology, it is important that your stakeholders are united behind common goals and a shared vision.

Doing this early on will make sure you stay on task and help to avoid any disagreements in the later stages of your project.

An effective way to align your stakeholders is to hold a strategic workshop with key individuals from across your business and other relevant parties. Try to get a breadth of representatives in this meeting to ensure everyone involved in the project has their say, including regulatory, clinical, formulation, devices and commercial.

It’s important to set clear outcomes for your workshop, such as agreeing what your goals and objectives will be for your project,

therapy and device, as well as collectively identifying what you want to achieve. This is also a great opportunity to share knowledge between your different stakeholders and identify any gaps that need to be filled.

While these workshops are typically performed in person, the recent pandemic, alongside advances in collaborative software, has enabled successful, efficient and effective methods for engaging multiple stakeholders in disparate locations. It is now easier than ever to get many participants involved who may otherwise have not been able to attend, such as colleagues and contacts from different offices and locations.

Step Two: DEFINE Your Requirements Once you’ve reached a consensus among your stakeholders, it’s time to bring this group together once again to define your device requirements. The challenge here is making sure you find a balance between the commercial, technical and user requirements for your device, identifying which are essential and which are simply “nice to haves”.

As the user should be at the centre of any device selection or development, at this

Figure 1 44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2021 Volume 13 Issue 2

Drug Discovery, Development & Delivery stage it also pays to have established a clear understanding of the needs, behaviours and challenges of your target users. This can further help you to define your key requirements. Are there any particular user behaviours your device will need to address or change? Do your end users have any physical or cognitive challenges to take into consideration?

Putting together a simple spreadsheet with a scoring system for each requirement can be a helpful tool to carry out some prioritisation too. As seen in figure 1, each participant puts a score against each requirement, which is then totalled to provide a red, amber, green rating.

To make sure everyone is aligned on what makes a requirement “essential”, it can also be helpful at this stage to assign a weighting value to indicate the importance of each requirement. Say your device needs to deliver a payload of ‘x’ in a time of ‘y’. You might give this requirement a weighting value of ‘5’ as this is very important to the performance of the device, whereas the final cost of goods for the device might only get a total value of ‘3’ as it is less important.

As can be seen in Figure 2, you can then use the same system to define your scoring criteria and ranking scores for each requirement. For example, a device that can deliver your payload in the correct time without needing modifications might get a ranking score of ‘5’, while one that needs significant adjustment and modification to achieve this gets ‘1’. Using a set scoring system ensures that all the potential technologies are assessed on the same basis.

Step Three: EXPLORE Your Options Now that you have defined your requirements, it is time to start searching for potential device candidates. As you explore the device technology landscape, keep in mind your prioritised requirements and try to find devices that would potentially meet them. Your search doesn’t need to be limited to devices on the market either – it can also include technologies that are still in development and nearing market.

There are a variety of sources you can use to explore the device technology landscape, including conferences, publications and supplier websites. If you’re unsure where to start, you can also speak to a device development expert to help.

Similarly to the requirements stage, creating a database to list the devices you identify can help ensure you capture the right information for each one. Think about the positives, negatives, key features, key performance attributes and potential risks www.ipimediaworld.com

Figure 2

for each device, and write this up into a short summary for an easy comparison. See Figure 3.

Step Four: ASSESS Your Options Having established a list of candidate devices, it is time to assess them against the requirements and scoring criteria you set out in step two. By multiplying the weighting value you assigned against the ranking scores for each device, you can total up the scores and begin to see how they compare against each other. It can also help to map these results visually, by plotting the scores for any market and user facing criteria (attractiveness) vs. the scores for the technical and commercial criteria (fit) – as shown in Figure 4.

As you score each device, it will likely become apparent that there is no option that meets all your requirements perfectly.

Some may score better from a user’s perspective, others from a technical or commercial perspective. It’s important here to consider any trade-offs or modifications you might need to make to improve the

device in areas where it scores weaker, to help inform your final decision.

While you may need to commit some time and investment into modifying or developing your chosen device in order to bring it in line with your requirements, this can still be much more cost-effective and convenient than a ground-up development. The closer to your requirements and the more developed the devices in your shortlist are, the less commercial risk you might face. By taking on an effective device that has been tested and verified to deliver therapies, you will have a much easier route towards launching your therapy to your users with ease.

The Next Steps Following these steps will help ensure your team are united and invested in the device(s) you choose to move forwards with. By exploring your options from a commercial, technical and user perspective, you will be able to filter a potentially large number of options down to a shortlist that best fits your needs.

Figure 3 INTERNATIONAL PHARMACEUTICAL INDUSTRY 45

Drug Discovery, Development & Delivery have with the system can further help to identify any opportunities for improvement and differentiation.

Figure 4

Of course, the journey doesn’t end here, however. Once you have selected a shortlist of devices, you will still need to carry out a detailed programme of technical and commercial assessment to further refine the list.

For example, depending on the development status of the devices under consideration, and if there any design modifications required, a further programme of development and testing will be needed.

Development and Testing From a technical perspective, the key performance criteria of each device will need testing with your drug formulation to ensure compatibility, including consideration of any changes to the primary pack and any stability testing that may be needed.

Modifications to device components and functionality might also be required to improve delivery performance.

Modifications Likewise, modifications to the device form, packaging, instructional material and overall look and feel could also be beneficial. This can help you ensure the device is designed to meet the needs of your target user group, while also addressing some of the other big drivers we see in our industry at the moment, such as improving adherence or sustainability.

Market Research Whether any modifications are required or not, you may wish to undertake market 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

research to assess your users’ likely acceptance and/or preference for the devices you have selected. Having established a clear understanding of the needs, behaviours and challenges of your target users prior to defining your key requirements is particularly helpful here; however, this presents another opportunity to assess your device selection against these requirements.

Usability testing Usability is another key area to consider.

Different user groups may have different cognitive or physical challenges as a result of their condition or age, such as dexterity, hearing or eyesight problems, or just learned behaviours from using other devices to manage their condition. An assessment of device usability with your target end users will be beneficial at this stage to highlight any areas of concern.

At first this initial engagement with users may be used, alongside the other technical and commercial assessments, to further refine and filter your shortlist of devices. But as you progress further along the process and start to make modifications or improvements, end users should be consulted at several points in the development to inform your design and ensure their needs continue to be addressed.

This can also be extended to assessing the device packaging and any printed or digital information or accompanying app/software, with your target users. Reviewing all the interactions and touchpoints a user may

Due Diligence Separate from the device technology itself, a programme of technical and commercial due diligence will also need to be initiated to help you determine the suitability of the supplier. For example, the capabilities of the device supplier should be assessed to determine a good fit with you, the investor. This might involve assessing their development and manufacturing capabilities and facilities, the abilities of their staff and leadership team, and their openness to sharing documentation and processes. You may also wish to conduct a review of their quality systems and relevant accreditations.

From the commercial side, a programme of commercial due diligence should be undertaken to assess the supplier’s commercial activity, viability and potential, along with their commercial position, revenue, and competitive dynamics. It should not be underestimated the time it might take to agree a deal!

Conclusions Device selection can be a lengthy process and the early stages can be the most confusing and critical. Putting the user at the centre of the process and exploring and assessing the full range of options that meet your specific needs will ensure you set off on the right path. By working through the above steps with a multi-disciplinary team, you will gather the evidence you need to make an informed decision on how to progress and feel confident that the choice you make will be the right one for you.

Charlotte Harris Charlotte is Head of Front End Innovation at Team Consulting. An experienced strategist, facilitator and project manager, her role focuses on the early stages of medical device development, from opportunity exploration and strategic support to early ideation. Charlotte has a BEng in Integrated Engineering and a MSc in Medical Engineering and Physics.

She has worked in the medical devices industry for over 20 years.

Email: charlotte.harris@team-consulting.com

Summer 2021 Volume 13 Issue 2

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Clinical and Medical Research

Medical Monitor’s Conundrum: Making Sense of Site/ Central Discordance in Radiology Assessment Concerns over disagreements between the interpretation of medical images performed by investigators and those performed by blinded independent reviewers (BICR) accompany most trials that involve imaging biomarkers.

The following is intended to be a brief introduction into this topic and provides some guidance on how to manage such disagreements.

What is Site/Central Discordance?

Intra- and inter-reader variability is well known in radiology and continues to exist even with standardised response assessment criteria such as RECIST 1.1, both at the level of the site and central review. In fact, depending on study design and assessment criteria, the variability between readers can range between 30% and 70%. Site/central discordance refers to the discrepancy in the treatment response that is made at the clinic by the treating physician versus the evaluation that's done

by BICR at an imaging core lab. Since such discordance is unavoidable, it is critical to proactively have a plan in place to address when it happens.

In 2011, the Oncology Drug Advisory Committee (ODAC) from the FDA provided briefings on an analysis of five oncological trials across different indications (breast cancer, renal cell cancer, and sarcoma).

The assessment of progression-free survival (PFS) was compared between the investigator and the BICR. The analysis looked at the differences in the type of response and the timepoint of progression in these trials. Discordance was noted in all five trials, both for type of response and timing of the PFS event.

The discrepancy was similar in both arms (experimental and control). Interestingly, the discordance varied not only among the different indications but also within a single indication of breast cancer.

Dr. Peter Eggleton of Merck recently stated at the Calyx Engage industry forum, “I don't see site/central discordance as a problem.

I see site/central discordance as a natural consequence of having different processes 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

in place. And if I accept that there is a level of site/central discordance above which you are very uncomfortable, there is also one below which I am very uncomfortable. I was once handed a study with a site/central concordance of 96%. I instituted a deep dive into this because I didn't believe that it was possible for two different processes to come up with such a similar answer. We suspected that information was leaking across from the site to the BICR. Concordance can be too low as well as too high. There is not a competition to get 100% concordance.”

Why does it Occur?

Numerous factors contributing to the discordance can broadly be classified into three groups: • • •

Factors related to the protocol Image-read workflow Variability in radiology review

Protocol Factors — Inherent Factors Related to the Protocol which could Potentially Bias the Investigator toward Treatment Decisions.

•

•

•

Trial design: In an open-label trial, there is a potential for bias as the investigator is aware of the patient’s treatment arm as compared to a doubleblind, randomised, controlled trial.

Line of therapy: If the investigational drug is a first line of therapy, the investigators are highly likely to move to an alternative therapy (as against another protocol with patients with no potential alternative therapy) based on very early evidence of clinical progression, even with equivocal imaging findings, since they are accountable for the treatment and wellbeing of the patient. However, the BICR will document findings as equivocal in alignment with the IRC (Imaging Review Charter) guidance.

Study indication: Certain malignancies are known to have incredibly challenging imaging manifestations and associated inherent variability. For instance, ovarian cancer manifests with tiny peritoneal metastases which can be difficult to quantify, leading to high variability.

•

Assessment criteria: Long-standing, well-established standardised criteria, like RECIST 1.1, will have fewer gaps in interpretation and, hence, disagreement compared to newer, more complex criteria. For example, the Lugano criteria used for lymphoma involve a highly complex multi-modality assessment that is integrated with controlled clinical data, thus potentially more disagreement.

Image-read Workflow – Some Points Highlighting the Differences in Approach to Image Interpretation and Response Assessment between Clinic and BICR. •

Consistency of readers: Image reviews at sites are often done at academic centres, where a scan can be read by multiple subspecialised radiologists, including trainees. For example, if a head, neck, chest, abdomen, and pelvis scan is done for a subject, the head and neck may be interpreted by a neuroradiologist, while chest, abdomen, and pelvis may be read by a body imaging expert. Furthermore, the imaging of a given patient may be read by different radiologists across timepoints, based on clinical rotations at the site. A structured, standardised reporting template customised for the trial may also be lacking. At some sites, the radiologist captures the measurements of the tumour in a clinical report, and these are later transcribed by trial coordinators into the electronic data capture system that is customised for the trial. This process depends on the trial coordinator’s training and understanding of the assessment criteria and may have the potential for transcription errors as well.

In contrast, the BICR is performed by a group of radiologists who are specifically trained on trial-specific rules. The assessment for a subject is done by a single reader (or two readers with an adjudication) not only for the entire imaging anatomy, but also across all the timepoints on a highly customised case report form Summer 2021 Volume 13 Issue 2

Clinical and Medical Research (CRF) specifically created for the study.

These CRFs often have the algorithmic logic built-in to support responses based on the imaging assessments, charter rules and measurements. This standardised process limits the scope of errors, reduces variability, and helps maintain consistency across the trial.

•

Availability of clinical information: At the site, the radiologist has access to all clinical data (such as physical examination, ECOG score, tumour markers, etc.) and historical imaging while reviewing the current scan. Correlation of clinical data and comparison with historical imaging findings are sometimes crucial and can change the interpretation of an ambiguous or atypical scan.

Furthermore, there is also an opportunity for interaction with the treating oncologist in tumour boards, where a multidisciplinary approach is taken to better define the next steps of therapy. This allows for a comprehensive evaluation of the patient using all available information.

However, by design, the BICR has either no or very limited access to clinical data. This can be a direct cause of disagreement between site and central radiologist. Dr. Cheryl Sadow of Peritus Imaging, who has acted as an independent reviewer on over 200 trials, stated that, “The challenge central readers face in not having access to clinical information is the need to infer what has transpired during the course of the study. Without knowledge of symptoms or biopsy information to suggest otherwise, in general, the central reader will be conservative in assuming new disease is related to the known malignancy. For example in Figure 1, in the CT images presented for a subject enrolled in a prostate cancer trial, a newly enlarged paraesophageal node (red arrow) would generally be assessed as new disease, despite the atypical location for prostate metastasis. The site reader has access to the development of new clinical symptoms and might suggest a biopsy of this node based on the atypical location, which was subsequently confirmed as a second primary esophageal malignancy.”

•

Training and quality checks: Lastly, although site radiologists are excellent

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Figure 1: Follow up CT chest in a patient enrolled in advanced prostate cancer trial with evidence of new mediastinal node? Metastasis? Secondary Malignancy. Biopsy needed for confirmation.

clinicians, they are not all trained on the intricacies and nuances of various standardised clinical trial assessment criteria. Whereas central readers not only have excellent qualifications as radiologists but are also extensively trained in an ongoing manner throughout the course of the trial on specific criteria for the study. In addition, there is an ongoing quality check of reads that are performed for central reads to ensure the alignment with the charter and protocol guidelines. Training sessions and an ongoing quality check can be a challenge to implement consistently across all sites and hence contribute to the discordance in assessment.

It is important to note that differences in the approach of image analysis are due to the differences in the roles and responsibility of a reader at site vs. a core lab. The site reviewers are integral to patient care, including the assessment of complications that can be related to, or unrelated to, therapy. In contrast, central review is intended purely for the assessment of treatment response that is unrelated to the clinical care of patients.

Variability in Radiology Review — Image Interpretation can be Variable among Radiologists.

The elements of this innate variability associated with radiology in the clinical trial setting include differences in lesion selection, inconsistencies in measurements, differences in determining progression based on non-targets, and new lesion selection. In 2010 there was a study analysing the discrepancy rate in interpretation of abdominal and pelvic CTs

among experienced radiologists. A total of 90 CTs done for various indications were reviewed and later blinded and rereviewed by three experienced radiologists.

The study concluded that there can be as much as 26% to 32% interobserver and intraobserver discrepancies among the radiologists.1 What Can We Do About It? The management of discordance needs to be addressed in the startup phase of the trial, and adequate measures need to be taken to mitigate discordance and maintain it within a range consistent with study design and assessment criteria. Some of these steps are summarised below: 1)

Ensure consistent and high-quality image acquisition:

•

A thorough review of the study protocol by a team of experts at the core lab, including radiologists, ensuring a comprehensive inclusion of all the modalities.

Collaboration between the sponsor and the core lab to provide investigators with protocol-specific imaging guidelines for standardisation.

Implementing robust quality control mechanisms to query for image quality.

•

• 2)

Tackle complicated assessment criteria by:

•

Identifying potential gaps and consulting key opinion leaders to clarify the approach in dealing with such uncertainties.

Accurately documenting the assessment guidelines both for the central and site radiologists, with training of the trial coordinators on the criteria.

•

INTERNATIONAL PHARMACEUTICAL INDUSTRY 49

Clinical and Medical Research

Practical Example — Potential Differences in NSCLC Read Outcomes “Axial CT chest images of a subject enrolled in non-small cell lung cancer trial, baseline images (top row) and follow-up images (bottom row). (A) Baseline CT image in lung window shows a left upper lobe lung mass (red arrow) selected as target disease; two mediastinal nodes (yellow arrows) seen on soft tissue window (B, C) were selected as non-target disease by the site reviewer due to lack of intravenous contrast. On the follow-up, (D) CT image in lung windows shows the target lung mass increased significantly resulting in progressive disease by target disease, even though the nontarget mediastinal nodes had decreased in size as seen on the soft tissue window (E, F). For the central review, due to strict guidelines and ongoing reminders for measuring as many lesions as possible, the central reviewer measured lung mass and mediastinal nodes as target disease at baseline, to include maximum target lesions possible. Hence despite the increase in size of lung disease, because the mediastinal nodes had decreased in size significantly, overall assessment was partial response on follow-up.” - Dr. Nisha Sainani

the reality of site/central discordance or overreacting to control it will never work; instead, awareness and understanding of the risks and how to mitigate them can best set your study for success.

David Leung of Bristol-Myers Squibb recently stated, “Some tend to think of discordance as an intrinsically bad thing: an error, a sign of human imperfection. But imagine a miracle drug that cures all, resulting in more than a 95% shrinkage of all tumours. Conversely, imagine another drug that is terrible where all tumours clearly progress. In both cases you will find no discordance between any readers, site or central. In real life, however, we have drugs that are somewhere in between.

There will be subtleties that are difficult to interpret and will result in differences in interpretation among readers. So, I firmly believe that as long as we understand the reason for discrepancy, we will find that in most cases they are not caused by error or human imperfection, but by challenges of judgement and limitations of criteria.”

REFERENCES 1.

Conclusion Variability within radiology review is well understood. Site/central discordance is inevitable, and its existence needn’t negatively impact trial outcomes. A discordance within acceptable range (based on the indication and assessment criteria) is expected and, in fact, indicates that the

site/central reading systems are working independently without any bias. However, proactive steps need to be taken to manage discordance within an acceptable range. It is crucial to evaluate the discordance early on and implement mitigation steps at the initiation, as well as in an ongoing fashion during the course of the study. Ignoring

Abujudeh et al; Abdominal and pelvic computed tomography (CT) interpretation: discrepancy rates among experienced radiologists. Eur Radiol. 2010 Aug;20(8):1952-7.

Dr. Surabhi Bajpai Calyx's Dr Surabhi Bajpai is a boardcertified radiologist with over 12 years of radiology experience. Before Calyx, she spent four years as a research fellow in Abdominal Imaging, Massachusetts General Hospital, Boston which is affiliated with Harvard University.

Dr. Manish Sharma Calyx’s Dr. Manish Sharma is a boardcertified radiologist with over 17 years of experience in medical imaging and clinical trials currently focused on evolving reader training, variability, and monitoring using data-driven analytics.

50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 51

Technology

Pharmaceutical Trends: Water Activity Measurement

Introduction Water activity (aw) has been broadly used in the pharmaceutical industry since the publication in 2006 of USP <1112>, an informational chapter on the application of water activity in pharma. While <1112> provided guidance for the utilisation of water activity, it was not an official method.

Now USP has developed USP <922> Water Activity as an official method which will hopefully further facilitate its implementation as an integral part of a pharmaceutical quality programme. Potential applications for water activity in pharmaceuticals include stability control, microbial risk prevention, optimised formulation, reduced caking and clumping, and moisture migration control.

The resulting key benefits of these applications are higher quality production output, greater consumer satisfaction and confidence, and less product waste and recalls. Clearly, water activity is a powerful and often essential quality parameter for pharmaceutical products.

What is Water Activity?

Water activity is defined as the energy status of water in a system and is rooted in the fundamental laws of thermodynamics through the Gibbs free energy equation1. It represents the relative chemical potential energy of water as dictated by the surface, colligative, and capillary interactions in a matrix. Practically, it is measured as the partial vapour pressure of water (P) in a headspace that is at equilibrium with the sample, divided by the saturated vapour pressure (P0) of water at the same temperature (T). Water activity is equal to the equilibrium relative humidity (ERH) divided by 100:

This water activity index covers a range from 0 for bone-dry conditions up to 1.00 for pure water. Water activity is often incorrectly referred to as “free water”, 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

which is misleading because “free” is not scientifically defined and is interpreted differently depending on the context. As a result, the concept of free water can cause confusion between the physical binding of water, a quantitative measurement, and the chemical binding of water to lower energy, a qualitative measurement. Rather than a water activity of 0.50, indicating 50% free water, it more correctly indicates that the water in the product has 50% of the energy that pure water would have in the same situation. The lower the water activity, the less the water in the system behaves like pure water.

Water activity is an intensive property that describes the energy of the water in a system, whereas moisture content is an extensive property that determines the amount of moisture in a product. Although related, water activity and moisture content are not the same. Moisture content is typically determined through loss-on-drying or chemical titration and though useful as a measurement of purity and a standard of identity, moisture content does not correlate as well as water activity with microbial growth, chemical stability, or physical stability. Water activity and moisture content are related through the moisture sorption isotherm.

USP <922> Water Activity Method Recommendations for the determination of water activity are outlined in USP <922> Water Activity. This method became official in May 2021 and provides guidance for water activity measurement. It includes a brief theoretical background explanation and discusses some factors that influence water activity, including solute concentration and temperature.

Sensor types and calibration: USP <922> also provides a short review of the various sensor types available for measuring water activity and highlights the strengths of each.

It provides guidance on the qualification of instruments with water activity instruments classified as Group B instruments. It highlights that water activity meters should be calibrated using standard solutions and this should be done at a minimum yearly, or whenever a calibration check fails.

Calibration verification checks should be conducted daily based on the instructions from the instrument manufacturer and using a minimum of two standards that book-end the typical water activity range. The number of replicates used for a calibration check should match the number of replicates used for sample testing.

Sampling: For sampling, guidance is given to limit exposure of the sample to ambient conditions by using sealed containers with limited headspace. The transfer of samples from extreme temperatures is discouraged due to the potential for condensation to form inside the containers. Water activity measurements should be conducted according to the manufacturer’s instructions and reported along with the temperature.

Applications: In terms of suggested uses for water activity, USP <922> extends beyond the usage suggestions of USP <1112> to include: •

Selecting ingredient isolation and product manufacturing process conditions in terms of maintaining aw below the critical threshold to obtain thermodynamic control of the desired solid form (e.g., hydrate versus anhydrate).

•

Selecting excipients for which aw may impact their material flow, compression characteristics, hardness, and performance characteristics (e.g., disintegration and dissolution) of dosage forms.

•

Optimising fluidised bed drying processes.

•

Reducing the degradation of active ingredients within product formulations (e.g., those susceptible to chemical hydrolysis).

•

Establishing the level of protection to product formulations to moisture by primary packaging materials during their shelf-life.

•

Optimising the shelf-life stability of probiotics.

Summer 2021 Volume 13 Issue 2

Technology

Figure 1. Moisture sorption isotherm showing the deliquescence of a crystalline material.

• •

Providing a complementary method for monitoring changes in water content.

Controlling and monitoring physical, chemical, and microbial product stability.

•

Optimising formulations to improve the antimicrobial effectiveness of preservative systems.

•

Reducing the susceptibility of formulations to microbial contamination.

•

Providing a tool to justify the reduction of microbial testing of nonsterile drug and dietary supplements formulations (see Application of Water Activity Determination to Nonsterile Pharmaceutical Products 1112).

Let’s take a look at each of these applications in turn.

Critical Water Activity for Crystalline Excipients Excipients, among many functions, act as bulking agents and protect active pharmaceutical ingredients (APIs) in pharmaceutical solid dosage products.

Typically, the matrix of these excipients is either crystalline or amorphous. For crystalline excipients, the addition or loss of waters of hydration or deliquescence can result in undesirable changes in product quality, such as modification of dissolution properties or reduction in the efficacy of the API. These change processes are thermodynamically controlled and, therefore, are related to water activity. The moisture sorption isotherm, which describes the relationship of moisture content to water activity, will clearly show the deliquescence of the crystalline material by a sharp 90 degree turn in the isotherm (Figure 1)2.

The water activity where these changes occur www.ipimediaworld.com

Figure 2. Moisture sorption isotherm indicating the critical water activity for a glass transition. Below the critical water activity, the product remains stable. Above the critical water activity, the product becomes unstable and shelf-life is reduced.

is called “critical water activity”. The key to avoiding problems with a crystalline excipient is to specify that the water activity be in a safe range based on the critical water activities identified through the moisture sorption isotherm. Any incoming excipient supplies should then be monitored for water activity to ensure that this specification is being met.

Critical Water Activity for Amorphous Excipients Amorphous excipients are typically lowmoisture and are in a meta-stable glassy state. Their ability to provide protection to the API depends on them remaining in the glassy state throughout the life of the product. A transition of the excipient matrix from the glassy state to the rubbery state, called a “glass transition”, will result in structural collapse, increased mobility, changes in dissolution, and increased susceptibility to caking and crystallisation3.

Consequently, the product will not flow, compress, or tablet properly, and dissolution may occur prematurely. A glass transition can be induced through either a change in temperature or a change in water activity. The water activity where

a glass transition occurs for a product is called the “critical water activity” and can be identified as a sharp inflection in the moisture sorption isotherm (Figure 2)4. To maintain the functionality of amorphous excipients, it is important to determine its critical water activity and take measures to ensure that the water activity of the product remains below that critical water activity throughout the life of the product.

Water Activity and Microbial Safety Microorganisms require access to water of a sufficient energy to allow for movement of water into the cell. This water is critical for maintaining turgor pressure and normal metabolic activity. The energy of the water surrounding the microorganism is described by the water activity and for water to move into the microbe, the interior water activity of the organism must be lower than the water activity of its surroundings. In other words, water activity is not the water available to microorganisms to grow; it is the energy of the water and that determines if water can move into or out of the cell.

When a microorganism encounters an environment with lower water activity than

Figure 3. Mode of action for water activity control of microbial growth INTERNATIONAL PHARMACEUTICAL INDUSTRY 53

Technology

Table 1. Minimum water activity levels required for the growth of various microorganisms

its internal water activity, it experiences osmotic stress and water leaves the cell, thereby lowering the turgor pressure and causing metabolic activity to cease (Figure 3).

In response, the organism will try to control its internal water activity through the concentration of solutes. This ability to lower the internal water activity is unique to each organism, which is why different microorganisms have different water activity minimum growth limits (Table 1)5.

Notice that moisture content has not been mentioned as having an impact on microbial growth because it is not the amount of water that determines if a microorganism can access it, but the water activity (energy) compared to the internal water activity of the organism. Consequently, any efforts to provide control limits for the risk of microbial contamination, and an accompanying reduction in microbial limits testing, must be based on water activity measurements and not moisture content.

Water Activity and Degradation of Active Ingredients The water activity of solid dosage pharmaceuticals will typically be less than 0.70 aw, indicating that microbial growth is not likely to occur. However, products in this range do not have an unlimited shelflife. For these products in the 0.40–0.70 aw range, chemical degradation of the API is a strong candidate for the mode of failure because reaction rates are at a maximum. In general, as water activity increases, so do reaction rates6. The most common reaction that can result in the degradation of APIs is hydrolysis although lipid oxidation (rancidity) and enzymatic reactions may also play a role in the loss of active ingredients. The most effective way to prevent these reactions from resulting in significant loss of the API is to process them to a low water activity where reactions will be at a minimum, and then choose the appropriate excipient that will do the best job of maintaining that water activity.

Tracking Moisture Migration with Water Activity As shown by the moisture sorption isotherm, an increase in water activity is accompanied by a subsequent increase in moisture; however, the relationship is non-linear and unique to each product.

An increase in the slope of the isotherm indicates an increase in hygroscopicity, which will limit the change in the water activity as moisture is absorbed. This is often a desirable characteristic in excipients because it allows the product to absorb moisture while still maintaining the water activity of the API at levels that limit the rate of degradative reactions as shown in the previous section.

Another way that the water activity of an API can increase to unsafe levels is through moisture migration in multiple component pharmaceuticals, such as capsules. If the components are at different water activities, then water will move between the components regardless of their moisture content. Water moves from high water activity (energy) to low water activity7.

Moisture will continue to move between the components until an equilibrium water activity is achieved, which is dictated by the moisture sorption isotherms of each component and is not the midpoint between the initial water activities (Figure 4). If the water activity of the API increases, it could possibly be at high enough levels to speed up degradation. To avoid this problem, the components must be designed to have the same water activity.

Conclusion Water activity is sometimes an overlooked and underestimated parameter in pharma quality and formulation. However, it offers critical information for optimising product stability. Issues with deliquescence, caking and clumping, dissolution, microbial susceptibility, API degradation etc. can be resolved by identifying the ideal water activity range for the product and implementing water activity measurement as a routine parameter for batch release.

With the water activity at this ideal range, most pharmaceutical products will also qualify for reduced microbial limits testing, resulting in time savings and reducing production costs.

Figure 4. Moisture sorption isotherms for a product with two components at different initial water activities. The black dots indicate the initial water activity while the arrows indicate the direction of water movement for each component and the accompanying change in moisture content. The dotted vertical line indicates the water activity where the components will come into equilibrium and moisture movement will stop. The points where the isotherm curves cross the dotted vertical line indicate the moisture content of each component at the final water activity.

54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

REFERENCES 1.

Fontana, A.J. and Carter, B.P. 2020.

Measurement of Water Activity, Moisture Sorption Isotherm, and Moisture Content Summer 2021 Volume 13 Issue 2

Technology

2.

3.

4.

5.

6.

7.

of Foods. In Water Activity in Foods: Fundamentals and Applications, 2nd Edition.

Wiley-Blackwell.

Lipasek, R.A., Ortiz, J.C., Taylor, L.S. and Mauer, L.J. 2012. Effects of anticaking agents and storage conditions on the moisture sorption, caking, and flowability of deliquescent ingredients. Food Research International, 45(1), 369–380.

Roos, Y.H. 2020. Water Activity and Glass Transition. In Water Activity in Foods: Fundamentals and Applications, 2nd Edition.

Wiley-Blackwell.

Carter, B.P. and Schmidt, S.J. 2012.

Developments in glass transition determination in foods using moisture sorption isotherms. Food Chemistry 132:16931698.

Beuchat, L.R. 1983. Influence of water activity on growth, metabolic activities, and survival of yeasts and molds. J. Food Prot. 46:135.

Bell, L.N. 2020. Moisture Effects on Food’s Chemical Stability. In Water Activity in Foods: Fundamentals and Applications, 2nd Edition.

Wiley-Blackwell.

Bell, L.N. and Labuza, T.P. 2000. Moisture sorption: practical aspects of isotherm measurement and use (Vol. Second). St. Paul, MN: American Association of Cereal Chemists.

Brady Carter Dr. Brady Carter is a Senior Research Scientist with Carter Scientific Solutions.

He specialises in water activity and moisture sorption applications. Dr. Carter earned his PhD and MS Degree in Food Engineering and Crop Science from Washington State University and a BA Degree in Botany from Weber State University. He has 20 years of experience in research and development and prior to starting his own company, he held positions at Decagon Devices and Washington State University. Dr. Carter currently provides contract scientific support to Novasina AG and Netuec Group. He has been the instructor for water activity seminars in over 23 different countries and has provided on-site water activity training for companies around the world. He has authored over 20 white papers on water activity, moisture sorption isotherms, and complete moisture analysis. He has participated in hundreds of extension presentations and has given talks at numerous scientific conferences. He developed the shelf-life simplified paradigm and hygrothermal time shelf-life model. www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 55

Manufacturing

Dwell Time and its Influence on Tablet Production

Manufacturers of pharmaceutical tablets are continuously under pressure to make production more efficient. It needs to be quicker, more cost-effective and able to keep in line with the competition from fellow oral solid dose producers and developing markets. Let’s not forget, on top of all these challenges quality has to be a top priority.

So what is the answer? What production process can meet all of these requirements?

There is no all-encompassing solution to efficient tablet production. It involves many elements and considerations from the design of the tablet, through to what tablet tooling material and coating is used.

However, a very important consideration when looking for solutions to optimise manufacturing processes is the dwell time.

Dwell time is defined as the amount of time that the surface of the tablet punch head stays in contact with the compression roller in a standard tabletting press. This can only be counted as dwell time when the compression force applied is above 90% of its peak value.

Compaction, or dwell, plays a significant part in the quality of the final tablet. In order to produce tablets from granule or powder, it is necessary to use the correct compression force. Too much, or too little of either, can result in tabletting problems like sticking.

particles returning to their original shape immediately when the applied stress is alleviated. Those ingredients displaying plastic properties are permanently deformed when stress is applied above their elastic limit. Any stress will permanently change the shape of the particle.

The force employed and the length of time in compression can affect the way the formulation reacts, where the behaviour of a particle under compression can either stay deformed or return to its original shape.

In cases of formulations with more timedependent consolidation behaviour, a long dwell time is important to create strong bonds between the particles.

‘Punch displacement velocity (i.e., strain rate) and dwell time are two factors that can significantly affect the compression behaviour of powders. As a rule of thumb, slower compression and decompression speeds and longer dwell times will improve the mechanical properties of a tablet. When certain elastic particles are subjected to a compression force for a longer period, further plastic behaviour is demonstrated; less “spring back” happens, which results in a more stable compacted tablet.’1 Finding a Solution to Friability Friability, or the tendency to crack, chip,

crumble or break during compression can be hugely challenging and negatively impact production. The problem is in part due to the formulation. It is important to get the compression force right – too high and it can adversely affect the tablet, but if the formulation is not cohesive and does not bind together sufficiently, then friability will occur.

Many tablet formulations are dwellsensitive and require more time under compression to guarantee that they come out of the press without any faults. Some granules are difficult to compress effectively and require extended time under peak compression to ensure they receive the required hardness to shape into the fully formed tablet.

Let the Air Out At pre-compression, a long dwell time at low to medium compression force is essential to expel air from the powder bed and for uniform distribution of granules in the die bore prior to final compaction under the main compression. Air must be expelled in order for the particles to stick together and form the tablet.

Air in the formulation can cause severe problems during manufacture. If the air is insufficiently squeezed out and/or density

Understanding a Formula’s Features Many issues can be traced to the characteristics of certain ingredients in a formulation that display different particle deformation. When compression force is applied to the formulation, the particles will react in different ways depending on whether they have plastic or elastic properties. These deformation characteristics can lead to tabletting issues such as picking and capping.

Particles that exhibit elastic deformation will change shape during applied stress.

This effect, however, is reversible, with the 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2021 Volume 13 Issue 2

Manufacturing variations occur in the tablet volume, the tablet tensile strength is negatively affected, and the risk of tablet capping (when the top of the tablet separates horizontally when ejected from the press) or delamination (when the tablet splits apart) increases. This problem used to be predominantly solved through a combination of applying tapers to the die and sometimes slowing the press down to expel air. However, with today’s requirement for faster tablet production, this approach is no longer a viable option and new, effective methods of increased dwell time to reduce air entrapment are required.

Working with Varying Moisture Content All ingredients that are used in tablet manufacturing – whether active pharmaceutical ingredients or excipients – contain differing moisture content. There is a vast array of formulations, and each has varying characteristics – therefore, moisture control during the process becomes very complex.

Moisture often helps with the binding of the powder, or the compaction effect.

However, if there is too much moisture, then the adhesive forces created between the granule and the punch tip face may be too great, and can potentially cause sticking due to capillary action.

Moisture can enter the process through either ‘wet’ granulate itself, or as a result of excess humidity in the compression chamber, formulation preparation and storage areas. It is therefore desirable that these temperature and humidity levels are controlled – but this is not always possible.

In order to counter issues with moisture causing sticking, utilising the optimum dwell time can have a positive effect on the final tablet produced. Once calculated, the optimum dwell time can allow for the formulation’s moisture content, without detrimentally impacting the quality of the tablet.

Alternative Methods to Increase Dwell Time The fundamental importance of extended dwell time can be demonstrated by the frequent application of other techniques to increase the time that the punch is in contact with the compression roller. Some of the most frequent methods include: • •

The reduction of the tablet press speed in case of capping or insufficient hardness.

Installation of larger compression rollers to increase the total

www.ipimediaworld.com

• •

compression time.

Using punches with a greater head surface to increase the size of the dwell flat.

The purchase of a modern tablet press with dwell enhancing features.

These alternatives are not always viable with the strict time and monetary constraints put on tablet manufacturers.

Making small changes to the size of the compression roll does not extend dwell time, so another method is required.

New capital equipment may also appear to be the answer. Yes, it can improve productivity but it clearly involves significant capital expenditure. The most feasible answer is through the use of specific tooling designed to increase the dwell without slowing down the press.

Elliptical head form tooling is the solution to compression timing. This innovative tooling

has many benefits which positively affect the tablet manufacturing process.

Not only does the tooling increase dwell time on existing presses without the need for expensive modifications, but it solves dwell time problems without upsizing punches. Faster press operation can also be achieved, leading to increased output and improved productivity. The enhanced tablet compaction also results in a better quality tablet.

Elliptical head form punches can run on standard cams, giving users higher press speeds with challenging products and formulations. It also enhances tablet compaction/cohesion and can increase dwell time by up to 50% over a standard punch head, allowing more dwell than a D-type punch on a B-type tool. This increase helps to solve compression problems without upsizing punches or investing in a new press.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 57

Manufacturing The following case study illustrates the benefits of using elliptical eXtended dwell flat tooling in a production environment when tested by a leading pharmaceutical manufacturer.

Case Study The challenge A speciality pharmaceutical company agreed to assess the elliptical head form tooling. The goal was to create an operating environment where tablet quality was increased and waste reduction was improved on the production of a cold and flu tablet. The formulation would regularly stick to upper and lower punch faces. To minimise the problem, several methods were used to increase the compaction force, such as running the press to rejects to clear the sticking and manually scrape the tooling or remove the tooling for a polish, which resulted in downtime during manufacture.

Equipment A high-speed compressing machine with industry standard B-type tooling was used in the trial during the manufacture of a tablet measuring 10.5 mm round and weighing 3.46–3.66 g. A full set of punches including elliptical head form tooling was provided for the trial.

Results The maximum press output of 150,000 tablets per hour (tph) was regularly reduced to prevent sticking as the formulation was found to have low hardness and friability issues. Elliptical head form tooling stopped the problem of sticking, while increasing output from 150,000 to 225,000 tph. The use of this innovative tooling improved compaction force dwell time by 44% and an output of 225,000 tph was achieved, an improvement of 50%.

Overall it has been demonstrated through rigorous trials that the use of elliptical head form tooling helps to prevent sticking, friability, capping, and tablet hardness.

It also enhances tablet compaction and cohesion and can increase dwell time on a standard punch type. This increase helps to solve compression problems without upsizing punches or investing in expensive modifications or new presses.

Get Your Timings Right Dwell time is hugely significant when mass producing quality solid dose forms.

Understanding dwell sensitivity and how your formulations will react to compaction can literally make or break a tablet.

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Summer 2021 Volume 13 Issue 2

Manufacturing

Every formulation is different and requires its own carefully calculated compression time. If this is not factored into the production, the results can be detrimental to the bottom line, with product quality, time to market and cost implications all affected. The application of modern techniques like elliptical head form tooling plays an important role in successful tablet manufacture.

REFERENCE 1.

Pharmaceutical Dosage Forms - Tablets, Third Edition - Edited by Larry L. Augsburger, Stephen W. Hoag (publication date and publisher?)

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

Email: alex.bunting@iholland.co.uk

www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 59

Manufacturing

Extrusion-Moulding-Coating Process Advantages for Continuous Manufacturing of Oral Solid Dosage Forms Introduction Traditionally, the pharmaceutical industry has employed batch processes to manufacture solid oral dosage forms.

In batch manufacturing, the typical lead time of a solid oral dosage form can be up to one year1, which can result in drug shortages in case of a significant change in demand. In addition to major reductions in the production time and footprint, continuous manufacturing decreases the manufacturing costs significantly2, as well as the number of the unit operations involved. In batch processing, failing a quality control test may result in a large batch of material to be wasted. Continuous manufacturing on the other hand can be coupled with inline analytics to monitor the process material constantly and reject a much smaller quantity, in case of an anomaly. With the encouragement of regulatory bodies3,4, the pharmaceutical industry is shifting towards continuous manufacturing. Already approved drug products manufactured using continuous processes include Orkambi (US/EU) and Symdeko/Symkevi (US/EU)

by Vertex, Prezista (US/EU) by Johnson & Johnson, Verzenio/Verzenios (US/EU)

by Eli Lilly, and Daurismo (US) by Pfizer5.

This paper describes the principles and operation of the Extrusion-MouldingCoating (EMC) unit operation at Continuus Pharmaceuticals for continuous manufacturing of solid oral dosage forms, starting from the active pharmaceutical ingredient (API) and excipients. The EMC unit has a mean residence time of a few minutes and is fully contained and automated. The capabilities and advantages of the EMC unit are discussed, in addition to its integration to upstream unit operations. The EMC unit has been extensively studied both as a standalone unit operation and as part of an integrated continuous manufacturing pilot plant5,6 and proved its robustness and reproducibility during integrated runs over multiple days.

Extrusion and Injection Moulding Technologies A versatile method for continuous manu60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

facturing of solid oral dosage forms from the API and excipients is integrated hot melt extrusion and injection moulding.

Hot melt extrusion (HME) has been used in many industries including plastics and food industries, and more recently the pharmaceutical industry as well, due to its efficiency in increasing bioavailability of poorly soluble drugs7, in addition to facilitating taste masking8. The process starts with feeding of powder API and excipient(s) into the extruder hopper in the desired ratio via gravimetric feeder(s).

Depending on the formulation, the API can be pre-blended with the excipients or fed separately. While the mixture progresses through the extruder screw(s) and is being mixed, the temperature is elevated to melt the polymer(s) or the mixture, and obtain a homogeneous melt, facilitated by application of shear. The mixture is then passed through a die under high pressure and the extrudate is collected for further processing. There are extensive numbers of publications on HME9, facilitating the ease of selecting the suitable polymers for the desired solid oral dosage form properties. Different polymer properties can be utilised depending on the melting point of the API, whether it is crystalline or amorphous in the dosage form, and the desired drug release profile. The extruder barrel can be separated into different zones to customise the temperature gradient.

Furthermore, the extruder can have a single screw or twin screws, and while the

diameter of the screw can vary from 18 to 30 mm in the pilot scale, it can exceed 50-60 mm in the manufacturing scale10. The screw configuration can also be customised to modify the mixing and shear the mixture experiences. Vents can be implemented to the extruder to release trapped moisture inside the mixture.

Injection moulding (IM), which has also been used in the plastics industry, consists of filling the melt into predesigned mould cavities while applying a certain amount of pressure to produce the desired solid form. The moulds can be customised to accommodate different tablet sizes and shapes, which affect the tablet properties. Combining the benefits of HME and IM processes was initially studied by the Novartis-MIT Center for Continuous Manufacturing11 and further investigated by other research groups12,13.

More recently, a fully integrated HME and IM process equipment has been developed

by Continuus Pharmaceuticals and IMA. This unit, Extrusion-Moulding-Coating (EMC), includes the extrusion, the moulding and the coating processes and it is a fully customised and patented machine which allows the continuous manufacturing of solid oral doses directly from the powder API and excipient(s).

As visible from Figure 1, the powders are directly fed into the twin screw extruder which allows the melting and mixing of the formulation and the homogeneous material flows to the injection unit. Here, the material

Figure 1. Extrusion-Moulding-Coating (EMC) schematic view.

Summer 2021 Volume 13 Issue 2

Omya Consumer Goods omya.com

Omyanutra® 300 A highly compactable porous mineral ingredient tailormade for fast dispersible tablets · high absorption capacity · enhanced compactability · improved mechanical stability · fast disintegration

info.pharma@omya.com

www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 61

Manufacturing is injected into the mould simultaneously with the injection of the coating materials.

The final shaping occurs thanks to cooling and hardening of the material in the mould cavities, and lastly the drug product is automatically ejected and collected for packaging.

Batch vs. Continuous Manufacturing of Solid Oral Dosage Forms via the ExtrusionMoulding-Coating (EMC) Unit Currently, the majority of solid dosage forms are produced by a series of batch processes consisting of blending, wet granulation, drying, sizing, secondary blending, and tabletting (Figure 2).

All these steps and processes have an associated cost, occupy space and require energy and personnel. In addition, they add time for process and scale up development, as well as for the quality control testing of the outputted intermediate material.

Granulation is employed to avoid challenges associated with powder handling, such as: poor flowability, segregation and low bulk density, static electricity; and powder compaction properties. For instance, during wet granulation, a solvent is added to the powder blend to facilitate binding of powder particles into granules. Subsequently this product undergoes a drying step. As the typical granulation process might produce a broader particle size distribution than required, a corrective sizing step such as milling is included after the drying process.

This milling step is highly energy-consuming.

The particles that did not pass the size criteria may be discarded or recycled and fed into the granulator, reducing the overall efficiency of the operation.

This entire series of batch processes can be replaced by the integrated hot melt extrusion and injection moulding system (the EMC unit) at Continuus Pharmaceuticals (Figure 3)5,6.

The EMC process is fully automated; the API and excipients are fed into the extruder by gravimetric feeders. The drug load of the final dosage form can be controlled by adjusting the feed rates of the API and excipient streams accordingly. The gravimetric feeders can be automatically fed by a pneumatic conveying system as integration with the upstream unit operations. This allows for a fully contained setup that prevents operators’ exposure to potentially hazardous APIs. The twin screw extruder mixes and melts the formulation with the application of shear at high 62 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 2. General schematic tableting process used to produce most solid dosage forms vs. integrated continuous ExtrusionMoulding-Coating (EMC) unit.

Figure 3. Extrusion-Moulding-Coating unit (EMC) which is a fully integrated extrusion and injection moulding/coating equipment.

temperatures, and outputs a homogeneous melt into the transfer manifold, which connects the extruder to the injection unit.

The mixture is then injected into the cavities of the tablet mould, where it cools down and solidifies. These tablets are then ejected from the mould and collected for further packaging. This entire process, from the extruder to the final moulded drug product, has a mean residence time of approximately five minutes. Furthermore, the process does not require the usage of solvents, hence no further drying is necessary. This eliminates the need to test for residual solvent content as well. The process also reduces the number of personnel needed for operation significantly, as it is fully automated. In addition, since it has a high powder containment, it does not expose the operator(s) to hazards that come with having loose powder as part of the process. As it can be remotely controlled, safety concerns

related to mechanical movements are also eliminated. Process analytical technologies (PATs) can be used inline to continuously monitor the process performance, without the need for sampling, reducing offline analytical work required. The process is highly versatile as it can be used for solid dosage forms with crystalline or amorphous APIs, low and high dosage strengths, as well as immediate-, modified- and controlledrelease drug delivery systems, thanks to the availability of polymers with a wide variety of melting temperatures and solubility profiles.

The EMC Unit Applications The EMC unit operation has been studied extensively both as a standalone unit operation and integrated with upstream unit operations as part of an end-to-end integrated continuous manufacturing (ICM) pilot plant (Figure 4)5,6. The end-to-end ICM Summer 2021 Volume 13 Issue 2

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Manufacturing pilot plant case study aimed to produce a commercially available generic drug, which is currently manufactured by batch processing, from its commercially available raw materials. The ICM plant continuously ran for five days and produced API which was constantly conveyed to the EMC over three days. In this study, a specific ratio of API and polymer blend was used and it was shown that the EMC produced in-specification tablets14. Prior to the final continuous run, the first part of the work has been a thorough pre-formulation and formulation study carried out simultaneously with evaluation of process feasibility and development. After some testing for process cycle development and automation of the process steps, continuous manufacturing runs were performed. The process cycle included selection and optimisation of all process parameters like the twin screw speed, material’s back pressure on the system, shot size for the injections, injection pressure profile, process individual zone temperatures, etc.

The aim of this work was to prove that the EMC is able to continuously produce inspec tablets over multiple days and the drug product quality attributes were reproducible throughout the run.

The critical quality attributes (CQAs) for these tablets included tablets’ physical attributes, API crystal form, API assay and uniformity of dosage units, individual and total impurities, and dissolution time.

Content uniformity is essential to provide the same dosage strength in each dosage form. API crystal form is another key factor affecting performance of the dosage form since different crystal forms may have significantly different attributes such as solubility, dissolution rate and stability.

During these experiments, inline PATs were implemented: a nIR probe was used to monitor the assay/content uniformity of the API in the melt and a Raman probe was used to monitor the API’s solid state. A combination of mass balance and HPLC was used as the corresponding offline analyses

to nIR and a combination of XRPD and DSC for Raman spectroscopy. A correlation between offline primary analytical techniques and inline PATs was assessed. The nIR API content predictions were shown to match the analysis results given by HPLC, and the API solid state predictions were compliant with the XRPD and DSC results. The critical process parameters were monitored, studied and controlled. Moreover, an additional work aimed at developing a model-based predictive in vitro dissolution testing was performed to demonstrate the equivalence of the predictive model to the routine offline in vitro dissolution testing according to USP. This study proves unit robustness and process performance reproducibility and shows that the EMC unit can continuously manufacture tablets that are within specification over multiple days of run time.

Conclusions The amount of time, energy, footprint and cost, and numbers of equipment and

Figure 4. End-to-end integrated continuous manufacturing (ICM) pilot plant.

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Summer 2021 Volume 13 Issue 2

Manufacturing

Moulded tablets obtained with the Extrusion-Moulding-Coating unit.

personnel involved in pharmaceutical manufacturing can be reduced drastically by switching from batch to continuous processing. The EMC unit can continuously produce solid oral dosage forms from the API and excipient powders within minutes, replacing multiple unit operations including granulation, drying, and milling, and without the use of solvents. It is a robust process that consistently produces dosage forms within specification; it is a fully contained and automated system, improving operator safety and product quality. Critical quality attributes such as API crystallinity and content uniformity are monitored inline to ensure product quality. While extrusion improves bioavailability of poorly soluble drugs, as well as their taste masking, injection moulding provides the flexibility to form tablets of different size and shapes, making the EMC unit an attractive alternative to batch manufacturing of solid oral dosage forms.

4.

5.

6.

7.

8.

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Adamo, A. et al. On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system. Science 352, 61–67 (2016).

Schaber, S. D. et al. Economic Analysis of Integrated Continuous and Batch Pharmaceutical Manufacturing: A Case Study.

Ind. Eng. Chem. Res. 50, 10083–10092 (2011).

Allison, G. et al. Regulatory and Quality

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11.

12.

Considerations for Continuous Manufacturing.

May 20–21, 2014 Continuous Manufacturing Symposium. J. Pharm. Sci. 104, 803–812 (2015).

Nasr, M. M. et al. Regulatory Perspectives on Continuous Pharmaceutical Manufacturing: Moving from Theory to Practice: September 26-27, 2016, International Symposium on the Continuous Manufacturing of Pharmaceuticals.

J. Pharm. Sci. 106, 3199–3206 (2017).

Hu, C. et al. An automated modular assembly line for drugs in a miniaturized plant. Chem.

Commun. 56(7), 1026–1029 (2020).

Testa, C. J. et al. Design and Commercialization of an End-to-End Continuous Pharmaceutical Production Process: A Pilot Plant Case Study.

Org. Process Res. Dev. 24, 2874–2889 (2020).

Repka, M. A. et al. Applications of hot-melt extrusion for drug delivery. Expert Opin. Drug Deliv. 5, 1357–1376 (2008).

Maniruzzaman, M. et al. Taste masking of paracetamol by hot-melt extrusion: an in vitro and in vivo evaluation. Eur. J. Pharm.

Biopharm. 80, 433–442 (2012).

Crowley, M. M. et al. Pharmaceutical Applications of Hot-Melt Extrusion: Part I. Drug Dev. Ind. Pharm. 33, 909–926 (2007).

Patil, H., Tiwari, R. V. & Repka, M. A. HotMelt Extrusion: from Theory to Application in Pharmaceutical Formulation. AAPS PharmSciTech 17, 20–42 (2016).

Mascia, S. et al. End-to-End Continuous Manufacturing of Pharmaceuticals: Integrated Synthesis, Purification, and Final Dosage Formation. Angew. Chem. Int. Ed. 52, 12359– 12363 (2013).

Melocchi, A. et al. Evaluation of HotMelt Extrusion and Injection Molding for Continuous Manufacturing of ImmediateRelease Tablets. J. Pharm. Sci. 104, 1971–1980

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(2015).

Puri, V. et al. Development of MaltodextrinBased Immediate-Release Tablets Using an Integrated Twin-Screw Hot-Melt Extrusion and Injection-Molding Continuous Manufacturing Process. J. Pharm. Sci. 106, 3328–3336 (2017).

Feasibility studies of Continuous Manufacturing of Injection Molding Tablets via Extrusion-Molding-Coating (EMC). https://ima.it/pharma/feasibility-studiesof-continuous-manufacturing-of-injectionmolding-tablets/, h t t p s : //w w w. p h a r m te c h .co m /v i e w / continuous-manufacturing-of-injectionmolding-tablets.

Federica Casati Federica Casati, PhD in Pharmaceutical Sciences, joined IMA in 2017 and relocated to IMA’s partner Continuus Pharmaceuticals in Boston (MA, USA).

Her main responsibilities are preformulation/formulation studies and process development for the manufacturing of solid dosage forms.

Recently she moved back to IMA for combining pharmaceutical process understanding with IMA’s mechanical design strength.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 65

Packaging

How the Rise of Biologics is Spurring a Packaging Revolution Marcelo Cruz at Tjoapack explores the rise of biopharma treatments and explains why, to keep up, pharmaceutical packaging needs to change.

With global sales of biopharma treatments hitting an all-time high of $300 billion in 20201, it is clear that the biologics space is playing an increasingly important role as a driver of growth in the wider pharmaceutical industry. In fact, biologics are expected to account for almost a third of the total value of the global pharmaceutical market by the end of 20232.

The reason why biologics is growing so quickly is simple. The ageing population in North America and Europe, combined with poor diet and environmental pollution in many emerging economies, is leading to an uptick in diagnoses of serious chronic diseases, from auto-immune conditions, to cancer, to diabetes.

More and more, these illnesses are being treated via new-generation biopharmaceuticals, such as monoclonal antibodies. As the global population increases further in the coming years, we can expect demand for these new treatments to continue to grow.

Biologics Bringing Change of Direction for Drug Delivery The boom in biologics is causing considerable flux in the popularity of a number of common drug delivery methods, and is behind a recent increase in the use of parenteral delivery in particular.

For many biopharma treatments, the only currently effective delivery mechanism is injection. As such, the success of the former necessarily drives the success of the latter.

As a result, the global injectables sector is expected to reach a value of $624.5 billion worldwide by the end of 2021 – doubling in size since the middle of last decade3.

However, while parenterals necessarily go hand-in-hand with biopharma, they do have one significant downside – they are 66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

not as easy for patients to self-administer as other dosage forms.

Poor useability can have a negative impact on patient adherence, making them reluctant to take their treatment and the right dose and frequency. Drug delivery that requires a professional to administer can also have implications for patient compliance, due to the inconvenience of having to visit the doctor every time a dose is required.

By making injectable drugs easier to use and self-administer, drug developers can maximise the effectiveness of the treatment by supporting patient compliance. They can also relieve pressure on healthcare systems by minimising the need for chronic patients to be seen by doctors.

The Potential of Pre-filled Syringes Taking this into account, it is imperative for the developers of injectable biopharma treatments to consider ways of making their treatments as patient-centric as possible. A host of companies have invested considerable time and funding in developing new delivery systems designed to support easier self-administered injections at home, and even on the go.

One vital development with the potential to solve this issue is the pre-filled syringe.

Coming ready-filled with exactly the right amount of treatment for a single dose, these make it easier for patients to administer their medication themselves without having to measure out their required dose. This saves patients time and safeguards against the consequences of over- or under-dosing.

Given this advantage, pre-filled syringes can help drug companies improve patientcentricity to stay ahead of the competition.

Nevertheless, the adoption of pre-filled injectables does pose challenges when it comes to production and packaging that need to be tackled in order to maintain optimum manufacturing efficiency.

Tackling Pre-filled Packaging Challenges There are a number of production and packaging requirements for pre-filled syringes that manufacturers need to consider. Pre-filled syringes in particular

require a clean sterile manufacturing environment in order to protect the health and wellbeing of the patients using them, with specialist equipment and standard operating procedures.

Pre-filled biologic treatments often have additional aseptic processing requirements that must be met. This is because the products involved are generally more complex than those in other dosage media.

As such, they often require unique handling to cater for temperature parameters, exposure to oxygen and so on, to ensure both the safety and efficacy of the product.

In addition, pre-filled syringes often have a higher number of components that need to be included in final kits. A staked needle, a loose needle, or even a safety device may be included in the kit, depending on the nature of the treatment within the syringe. Devices may feature a finger flange, or simply have a backstop. The only components that consistently feature are the plunger rod and label.

On top of this, manufacturers may need to include other inserts, such as alcohol pads for sterilising the skin prior to administration, or information leaflets in the secondary packaging to provide patients with guidance on using the syringe.

The Potential of Outsourcing Taking these packaging challenges into account, it is no surprise that many manufacturers are reconsidering their operations to meet future demand for pre-filled injectables. Many don’t have the capabilities or the flexibility in-house to adapt their production lines to address these issues – increasingly, they are exploring outsourcing as an option.

In the past, packaging was considered a low-priority part of the pharmaceutical production process. As a result, companies have often outsourced it to contract development and manufacturing organisations (CDMOs) as part of a broader development and manufacturing service.

However, it is increasingly the case that CDMOs lack the specialised processing Summer 2021 Volume 13 Issue 2

Packaging deliver cold-chain packaging and storage support, to help companies maximise their products’ shelf-life and protect the health of patients.

Specialist Partnerships Crucial to Biologics Success If the biopharma space is to meet future demand for treatments for cancer and other chronic diseases, drug companies need support not just developing their innovations, but delivering the finished products to patients safely and efficiently.

Packaging has a key part to play in achieving this goal. By working with CPOs that specialise in their chosen delivery mechanism, drug developers can benefit from expert knowledge about handling their therapy.

They can also enjoy innovative supply chain management support, enhancing efficiency and maintaining regulatory compliance.

With such support, they can be confident their drugs will deliver for patients, transforming their health and their lives for the better.

REFERENCES 1.

2.

capabilities or the line capacity to meet the complex packaging needs of products such as pre-filled injectable treatments.

More and more, we are seeing companies partner with expert contract packaging organisations (CPOs) to fill this knowledge gap, meeting drug companies’ specialist packaging needs while reducing cost and enhancing production efficiency.

CPOs are particularly well placed to support the industry in meeting future biologic packaging needs. They have comprehensive expert knowledge of the regulatory environment and the unique processing needs of injectables. In addition, they can offer the flexibility and the capacity to meet every customer’s needs. As a result, they can provide drug companies with a customised packaging service that can benefit their businesses over the long term.

Whatever the specific packaging requirements of a treatment, CPOs provide a service that not only optimises efficiency and output, but quality too. This means that they are becoming more than a supplier www.ipimediaworld.com

of simple transactional services, they are increasingly becoming integral strategic partners that can help pharma companies deliver even better products for patients.

Beyond Packaging In addition to providing support in scaling up the packaging process for pre-filled syringe products, CPOs can deliver other key benefits that can add further value for drug companies.

For instance, biologic therapeutics have special handling requirements that require stringent chain-of-custody integrity throughout the transport process to where the patient takes possession of the packaged product. CPOs have unique abilities in this area, providing manufacturers with tailored support to account for differing market requirements.

CPOs can provide assistance in a wide variety of transport areas, including vial labelling, re-labelling or over-labelling, serialisation for single or multipacks, or even inventory control. In addition, they can

3.

https://www.manufacturingchemist.com/ news/article_page/Trends_and_opportunities_ in_biopharmaceutical_product_development_ and_manufacturing/170557 https://www.statista.com/statistics/1085563/ revenue-chemical-drugs-and-biologics-globalpharmaceuticals/ https://www.marketsandmarkets.com/MarketReports/injectable-drug-delivery-market-150. html

Marcelo Cruz Marcelo Cruz is Director Business Development and Marketing at Tjoapack. With over a decade of experience in the pharmaceutical industry, and over 15 years of driving global strategic marketing and sales, Marcelo is responsible for the overall Business Development strategy and organic growth activities at Tjoapack. In his role he also leads the development and implementation of inbound and outbound marketing strategies to accelerate lead generation and drive the wider commercial strategy for the business.

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Packaging

Serialisation: Headache or Opportunity?

The scourge of counterfeit drugs continues to threaten global health programmes. When it comes to dealing with the impact of counterfeit trade, there is an increasingly heavy burden placed upon healthcare systems, healthcare professionals, national medicine regulatory authorities, law enforcement agencies and criminal justice systems. To counter this growing threat, government bodies are enacting more robust and stricter regulations to control the genesis and proliferation of fake medicines.

Track-and-trace is an important aspect of serialisation and has long been recognised for its ability to protect against counterfeiters, as well as facilitating more effective recalls.

Despite the critical nature of governmentenforced initiatives to ensure the safety of consumers, as well as overall trust in the industry, many regulations are presenting real challenges to pharmaceutical manufacturers.

In this article we will examine three key questions: • • •

Why is serialisation perceived as a headache by pharmaceutical companies?

How can we understand and address the challenges that arise from serialisation?

What are the opportunities for companies which effectively utilise this technology and what can be achieved by embracing serialisation?

What is Serialisation?

Serialisation entails the encoding of each pharmaceutical product coming off a packaging line, with a unique identification code which can be traced and pinpointed at each stage in the supply chain. The unique identification code can be stored in an online database along with other valuable information about the product, such as manufacturer and batch details. This process enables complete monitoring and 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

tracing of each product – from the packaging line right through to the patient.

Serialisation regulations vary between regions and countries, as well as being at different phases of implementation across the globe. To meet the demands of the country-specific deadlines, most global pharmaceutical companies should be trackand-trace and serialisation ready.

Why is Serialisation Needed?

The main challenge we face in combatting counterfeit medicine is that counterfeiters are getting smarter. In today’s world, access to technology has become incredibly easy, so criminals and counterfeiters are able to keep up with ongoing changes and technological developments in the industry.

Increasing numbers of internet pharmacies are also helping the fake medicines industry reach directly to the customer. Also, a lack of consumer awareness about counterfeit medicines is helping counterfeiters to expand their business.

Innovative and effective solutions have become essential to secure the supply chain and ensure safe products for consumers.

Product authentication and implementing track-and-trace technology are two key aspects of ensuring supply chain integrity in the current climate.

A recent report by the UN Office on Drugs and Crime says “counterfeit goods and fraudulent medicines pose a serious risk to public health and safety”.1 We can also note the economic cost of counterfeit medicines for industry, government and society as a whole. Each year in the European Union alone it causes: • • • •

Loss of 4.4% of legitimate sales Loss of €10.2 billion in revenue for the sector Destruction of 90,900 direct and indirect jobs Loss of €1.7 billion in government revenue (taxes and social contributions) 2

Establishing a robust, global system has far-reaching benefits for all stakeholders, from the pharmaceutical manufacturer to the end consumer. Track-and-trace will

help overall control of the supply chain, coupled with providing brand protection for pharmaceutical companies. The technology improves trust in the product, due to supply chain visibility and data security between different stakeholders.

During the last 10 years, the track-andtrace industry has undergone vast change.

Customers have moved from a reluctance to meet the regulation mandates, to utilising track-and-trace data for supply chain and production planning. Today, implementation is recognised as not just printing on cartons; businesses are now beginning to embrace the data management and security benefits from track-and-trace. The industry is moving from solely focusing on compliance, to creating real value for businesses and to consumer safety.

Why is Serialisation Considered to be a Headache?

Although serialisation offers fair transparency and is a necessary requirement by regulatory bodies, it still presents a major challenge for the pharmaceutical industry.

Firstly, it is a long-term, substantial investment for individual companies.

Secondly, it involves increased risk and complexity of current operations. Various bodies of evidence from early adopters of serialisation have demonstrated that productivity in terms of overall equipment effectiveness (OEE) has the potential to decrease. Serialisation demands tremendous changes to the entire IT structure, packaging and warehouse equipment and – most importantly – the data exchange system at each level of the value supply chain. For example, pharmaceutical companies in the EU have expressed concerns about the cost implications associated with the upgrading of pharmaceutical packaging lines to apply serialisation and tamper-verification features for the EUFMD. Additionally, the changing regulatory frameworks, lack of uniform standards, and complex distribution networks make it difficult for pharmaceutical companies to cope with the overall implementation deadlines. Because of these challenges, pharmaceutical companies can be reluctant Summer 2021 Volume 13 Issue 2

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

www.nemera.net information@nemera.net Phone: +33 (0)4 74 94 06 54

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 69

Packaging to make changes to their processes or to invest in track-and-trace technology through their own initiative. Instead, they often only make changes to implement serialisation into their manufacturing, production and logistics as an obligation when governmental regulations are enforced.

Understanding and Addressing the Challenges As mentioned earlier, the implementation of serialisation will entail changing various business functions within the organisation, creating the need for collaboration among different departments. The production line, packaging, IT and engineering business units must work together to complete the line remodelling. It is also important to align the upstream and downstream trading partners to enable traceability of the products in the supply chain.

The addition of specific software and application components to the existing IT architecture of an organisation is one of the most critical aspects of implementing a serialisation and traceability system.

Serialisation data is required to be fully integrated with centralised systems (at a corporate level), to allocate and manage serial numbers within the packaging processes. These systems also allow seamless data communication and storage to avoid any data duplication.

For ERP architecture level, organisations will require specialised software to retrieve and store all the necessary data in set databases. A dedicated on-site serialisation server will assess the complete production line from a track and trace perspective.

The objective is to achieve accurate serial number commissioning on the production line, which does involve a significant investment of time and money.

Ensuring that serialisation and traceability are built into the supply chain is of the utmost importance. Once the products are serialised, the next step is to prepare and check diverse compliance data that can track the drug products as they are shipped, received, or analysed by operating facilities.

It is recommended that organisations seek enterprise-wide solutions that will eventually support serialisation datasharing throughout the internal supply chain, including trading partners. This involves integrating serialisation data with the enterprise resource planning (ERP) 70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

system and adding context or business data.

It is this integration that enables product visibility from the point of manufacturer, to the patient.

There is no escaping the cost implications of serialisation for the pharmaceutical industry. Although there are low-cost serialisation solutions in the marketplace, these are not going to provide the required capability and benefits in the long-term.

This would therefore represent a shortsighted investment. The critical parameter to evaluate serialisation is not cost, but value.

Value, in turn, is defined as the combination of cost and benefit. It is the latter parameter that sometimes gets neglected. Ultimately, it is the value-proposition that should be the driver of the complete implementation strategy for any organisation.

What can be Achieved using Serialisation?

Often, we are too caught up in the challenges of implementing change, instead of reviewing the value proposition(s).

Innovation is essential for any industry, and in the case of serialisation within our sector, we cannot now go backwards, so it is critical we accept it and move forwards.

It is important to recognise and prepare for the challenges that come as a part of change. However, rather than viewing serialisation as a headache, it may be more beneficial to focus on the opportunities that will arise through integrating and investing in the various technologies that support serialisation. These include the following: •

•

• • •

• •

Efficiency gains – Substantial efficiency gains can be expected in reducing manual processes for cross-party data validation and reconciliation and reducing repetition.

Brand enhancement – Improved trust in product provenance, and secure consumer confidence for quality, societal, and environmental impacts.

Revenue growth – Market penetration and new product/markets development.

Risk reduction – Reduced risk of counterfeit products and mitigated risk from lower-quality components.

Cost savings – Improved financing and credit rates due to greater transparency and certainty of movements of products and savings through streamlined operations.

Innovation drive – Leveraging innovation can increase efficiency and change outdated ways of working.

Product recall – Track-and-trace supports

easy product recall with supply chain control.

What are the Future and Associated Opportunities?

Businesses are under more pressure than ever to protect their products from counterfeiting. If a customer purchases a fake version of an authentic brand, or hears through the media that a particular product has been victim to counterfeiting, they can quickly become disillusioned with that brand. For any business trying to build a reputation in this era of online marketplaces, trust is arguably the single most important asset they can have. Without it, businesses could be leaving themselves exposed to unnecessary losses.

The track-and-trace industry is going through changes as a result of the Fourth Industrial Revolution. We foresee technologies like blockchain, IoT and machine learning playing key roles in securing the pharmaceutical supply chain from counterfeited goods.

In 10 years from now, track-and-trace will have become an integrated and essential part of any pharmaceutical business. It will soon be a must-have technology in complete production. Manufacturers will be interested in, and able to, monitor and track products at each point in the supply chain, 24/7. We can foresee track-andtrace expanding its reach downstream and upstream, accommodating tracking of the complete pharmaceutical process, from API/ molecular level, to actual consumption of product and consumer feedback.

In the future, our industry will not consider track-and-trace implementation as an obligation, but it will be appreciated as a key tool for the business to improve processes and quality guarantees for the consumer. The data captured throughout the pharmaceutical manufacturing process and the supply chain will be used for predictive quality improvement using traceability.

Improving Efficiencies and Creating Competitive Edge Serialisation presents many challenges for pharmaceutical businesses. Whilst reluctance to embrace serialisation is perhaps understandable, in the end it is neither productive nor beneficial. Given the inevitable acceleration of global regulatory requirements, as well as the myriad benefits serialisation can bring for Summer 2021 Volume 13 Issue 2

Packaging

businesses, embracing change now will help organisations stay ahead.

efficiency and consumer trust. All of which creates true competitive advantage.

Track-and-trace has long been recognised for its ability to protect against counterfeiters and facilitate more effective recalls.

Today’s manufacturers are using it as a strategy to better observe and manage the entire ecosystem of their production facilities, and make smarter manufacturing a reality.

REFERENCES

•

1.

•

Track-and-trace is not just about creating a defence against counterfeiters and improving recalls. It is also about taking the opportunity to improve operations, quality,

2.

https://www.unodc.org/documents/treaties/ publications/19-00741_Guide_Falsified_ Medical_Products_ebook.pdf https://euipo.europa.eu/tunnel-web/ secure/webdav/guest/document_library/ observatory/resources/research-and-studies/ ip_infringement/study9/pharmaceutical_ sector_en.pdf

•

holistic-approach-common-solution/ https://www.sciencedirect.com/science/ article/pii/S2405896319314314 https://www.accenture.com/_acnmedia/ PDF-93/Accenture-Tracing-Supply-ChainBlockchain-Study-PoV.pdf https://blog.matthews.com.au/how-trackand-trace-can-help-you-become-amanufacturer-of-the-future/#:~:text= Track%2Dand%2Dtrace%20helps%20increase, efficient%20for%20each%20production%20 centre

OTHER SOURCES •

https://www.expresspharma.in/managementpharma/challenges-of-global-track-and-trace-

Gaurav Mohite Mr. Gaurav Mohite, Product Manager at ACG Worldwide, has over 10 years of expertise in holistic Track and Trace solution for Pharmaceutical industry.

He was part of complete Track & Trace implementation team across all the ACG implementation globally. He completed his master’s for Jamnalal Bajaj Institute of Management Studies (JBIMS) in marketing and bachelorette degree in Engineering. At the early stage of his professional career, he worked on vision inspection systems and Track & Trace applications as a developer and business analyst throughout the pharmaceutical industry. He is currently working as product manager and working for product marketing, strategy planning and technologic innovations.

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 71

Packaging

Fake Medications? Suggestions and Approaches to Help Ensure that Patients and their Family Members are Not Left Worrying Cancer diagnosis. A male patient is in his 80s and his general physical health is no longer amenable to chemotherapy. The team of specialists decides on a treatment regimen consisting of daily pills combined with infusions every 14 days. The package of 30 pills requires a prescription and the cost is in the four-digit range.

The entire family is happy that there is still a small chance that the cancer can be contained. It goes without saying that at the beginning of the therapy, side-effects cannot be ruled out. Still, after 10 days of treatment, the patient is having early, yet very drastic symptoms not listed on the package insert. Suspicion sets in. Are the pills inside the box truly the original tablets?

A search online shows the medication is available at a variety of prices.

The Pharmacist Placed the Order for the Medication Online. Was there a Gap in the Supply Chain?

We assume that everything was proper and legitimate in this case and that the content of the packaging was actually an original product. Yet how could we have been able to prevent these doubts that spread throughout the family?

that prescription drugs can be traced back to their origin: a unique code for each package, allowing for tracking, and tamperproof sealing for the package are intended to guarantee this.

notice that a specific code is even being verified.

Can the Code be Falsified? Weaknesses in the Implementation of EU Directive 62/2011 In the specific example of very expensive cancer therapy, let's first take a closer look at the unique code: For a medication with pricing in the four-digit range, it would definitely pay off for fraudsters to reprint a few codes that are already on the market.

If the faked packs are scanned at the pharmacy first, before the original product, the duplication of the code may in fact only be noticed when the counterfeit product is already in use. This may happen only rarely, yet patients are never involved in any way in the scanning and posting processes that take place at the pharmacy or hospital. The patient is considered to be too immature.

The Patient should Take Full Advantage of the Digital Benefits of the Unique Identifier The principle of multiple use of a UID (Unique Identifier) is not yet being used in the EU. Both general and patient-specific information can be linked to the security code via the Codikett platform or other trusted services, for example, by making dual use of the code, so to speak. This would increase the patient’s trust in the drug and calm his relatives, while integrating the patient’s data into the verification process at the same time. This in particular would be critical in order for him to be prepared for the fact that in all likelihood the trade of medications online will become more and more liberalised, e.g. as a first step for non-prescription medicines. The patient should definitely learn to pay close attention to the codes!

While unique codes could actually provide invaluable additional benefit to the patient, such as reading out the package insert, general information on how best to deal with the illness, etc., in the current set-up of the system, the patient or the customer at the pharmacy does not even

How Safe is Medication Packaging and its Sealing?

This is where the greatest risk lies for a medication in the four-digit cost range.

All along the supply chain, it is rather easy for fraudsters to exchange the genuine content for a placebo and seal the package

Until recently, only those medications purchased online were considered dangerous – 90% of all products purchased from internet pharmacies have been shown to be fake. Organisations such as ASOP – Alliance for Safe Online Pharmacies – are supporting the official efforts in Europe and the US aiming to improve the situation, in particular by educating users about the dangers of this illegal yet convenient and anonymous way of buying medications online.

However, the more parcel shipping is becoming an everyday part of the supply chain, the greater the vulnerability of stationary pharmacies to potential fraud.

With its Directive 62/2011, the EU has introduced stringent measures to ensure 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Codikett as well as other security web services can connect more information to the obligatory unique identifier, thus involving patients in the EU path for patient safety.

Summer 2021 Volume 13 Issue 2

Packaging without it being noticed, and then divert the genuine medication obtained this way, e.g. in another part of the world.

Sealing labels should attract users’ attention, e.g. by displaying a distinct opening indication upon removing, called “VOID”-effect. These effects with clear messages are difficult to counterfeit.

The safety aspect of sealing was effectively argued away in the course of the implementation of EU Directive 62/2011.

While ISO 21976:2018 (Packaging — Tamper verification features for medicinal product packaging) well stipulates that the securing of packaging should be planned and implemented on a risk basis, direct sealing of boxes is often used to secure even very expensive medications or those at risk of being counterfeited. However, this does not provide for any visible evidence of tampering when the package is cut open and re-sealed.

So not a bit of "tamper verification" as it is referred to in the guideline. Yet, also for sealing labels, it seems that quite often not much effort is being put forward to protect them against reproduction by counterfeiters and fraudsters. Here as well, ultimately the patient is rarely involved.

In talks with quite a few patients, we find that most are not even aware of the fact that seals or direct sealing of boxes are being used – at best, they only observe it subliminally.

The free market is taking a different approach here: the new Amazon guideline for providers of hygiene articles prescribes clearly visible, easily noticeable and conspicuous seals for cosmetics and medical products. Hopefully, this will bring about a different thought process for the implementation of FMD as well.

Dr. Marietta Ulrich-Horn Dr. Marietta Ulrich-Horn holds a PhD in philosophy from the University of Vienna, and an MBA from the Vienna University for Economics and Business and the Carlson School of Management, Minnesota. She is co-founder and CEO of SECURIKETT®, a company offering a wide range of product protection solutions: complex security labels for physical product protection, and the digital cloud solution CODIKETT® for track & trace in global applications. The motto is: authenticate, identify and locate the original.

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 73

Packaging

EU Falsified Medicines Directive (FMD) – A Technical & Implementation Success From 19th February 2019, pharmaceutical manufacturers were legally bound to implement processes for the creation and management of an audit trail covering every single packet of prescription medicine produced for import or trade into the European Union (EU).

The EU legislator’s serialisation challenge had implications across the physical aspects of pharmaceutical production lines and the data management processes that drove them. This article explores what the implications for pharmaceutical producers were, the benefits that have resulted from an increased focus on production line efficiency, and what might be next for EU FMD. The EU’s Falsified Medicines Directive was a strategic move by European legislators to safeguard the public against potentially substandard prescription medicines and eliminate counterfeit goods from the legitimate supply chain. The directive requires that authentic producers of prescription medicines include specific, machine-readable data on their product packaging for verification throughout the entire supply chain – down to the point of sale at an individual pharmacy level.

Industry Response Six months before the Food and Drug Administration’s stringent Drug Supply Chain Security Act (DSCSA) came into force, GS1 collaboratively investigated US production lines and found just one in 16 pharmaceutical packages was displaying a readable barcode complete with all four DSCSA data elements1. Anecdotal evidence would suggest a very similar picture presented itself across the EU in the six months prior to the launch of the EU FMD. Indeed, while the majority of pharmaceutical companies and contract manufacturing centres were compliant at the point of go-live, for as long as six months after February 2019 Domino had requests to aid with the FMD compliance requirements.

The reality today – nearly two years on – 74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

EU Falsified Medicines Directive: A Recap of the Requirements Since early 2019, manufacturers of pharmaceutical goods have been required to add additional security labelling to certain products sold in the European Union.

Under the terms of the EU Falsified Medicines Directive (EU FMD), prescription pharmaceutical products are now required to have a verifiable 2D data matrix code and tamperevident labelling included as part of their product packaging. In addition, a human-readable unique serial number is required to meet the directive’s requirements, as well as a product code, batch number, and expiry date for the contents.

Data matrix scanners are a much less forgiving verifier of data than the human eye and operate on strict binary principles, which means that even the slightest cell corruption will result in the rejection of the code.

Upon scanning, the 2D data matrix code provides access to data that has been transmitted to the European Medicines Verification System (EMVS) portal and will reside in corresponding national databases. is that EU FMD is no longer a big issue for pharmaceutical manufacturers in Europe.

Given the choice of market displacement by competitive products that were compliant or equipping production lines with new serialisation technology, the industry as a whole conformed and is now fully aligned with the legislation. And from a technical perspective, particularly given the huge volume of pharmacies across Europe connected to the system, the directive has been a resounding success. Indeed, other geographies are now actively exploring regulatory change similar to EU FMD, such as south-east Asia and Brazil, for example.

So, what next for EU FMD?

The medicine’s name, common name, pharmaceutical form, strength, pack size and pack type, as well as a serial number and a national reimbursement number for certain markets, is instantly accessible via the 2D code. Additionally, a record is created each time a product is scanned, allowing the product in question to be tracked through the National Medicines Verification System (NMVS) at every stage of the supply chain.

Any issues or inconsistencies with products that arise will be flagged in the systems, and the medicine in question instantly rejected by the respective party. This information is then passed on to the Medicines and Healthcare Products Regulatory Agency, which may wish to investigate the product in question, as well as the company that manufactured it.

Two years on from the introduction of the EU FMD and the legislation has not only increased the security of legitimate medicines, but it has also helped manufacturers to improve production line efficiency and is providing access to data on supply chains and the point of sale of medicines that could be used to enhance operational and commercial performance.

Monitor Print Quality and Longevity While the legislation is only two years old, one challenge we have yet to see play out is in the longevity of code print quality. With most medicines having a shelf-life of four to five years, the EU FMD’s stringent specifications for code quality, contrast to substrate, and lightfastness capability may yet see medicines being rejected at the point of sale if the print grades used on a production line have not been suitably verified.

Under the ISO 15415 standard, there are eight parameters that measure overall code quality. Only codes that meet the specifications of grades A to C will be acceptable to DG Sanco – the European Commission Directorate-general for Health Summer 2021 Volume 13 Issue 2

Packaging

and Consumer Protection. All else will be rejected.

For those manufacturers who find themselves facing product rejection due to poor print quality, printing pin-sharp data at high speed can be achieved in multiple ways. The thermal inkjet (TIJ) method, known for high-quality alphanumeric text, barcodes, and 2D data matrix codes, produces extremely durable print that is favoured within the pharmaceutical sector.

Its superfast drying capacity and excellent adhesion to a variety of porous and nonporous packaging surfaces will prove vital to post-coding tamper-evident labels on pharmaceutical packaging.

over-the-counter (OTC) market could be next. Russia’s serialisation requirements2, which came into effect in July 2020, cover all prescription and over-thecounter medicines manufactured within or imported into Russia and set a clear precedent.

While unlikely to be implemented in the immediate future, it is highly conceivable

that the EU legislation will be extended to OTC medicines within the next five years.

As pharmaceutical manufacturers have experienced, equipping production lines with new control systems, high-speed printers, and cameras requires significant project management and – depending on company size – can take six to nine months.

Laser printers are also capable of delivering high-quality codes, at high speeds, onto multiple substrates. The technology produces durable, indelible serial numbers and matrix graphics onto different packaging types, ensuring a final code that will stand the test of time, remaining readable for the entire shelf-life of a pharmaceutical product.

Consider the OTC Market With the success of EU FMD with regard to prescription medicine, it is likely that the www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 75

Packaging opportunities for serialisation in the future.

And of course, let’s not forget the impact that Brexit may yet have. With the UK SecurMed system now effectively disconnected from the EU FMD hub, the next few months may see new UK-specific serialisation requirements emerge that manufacturers are well-advised to keep a watchful eye on.

Domino Printing Sciences (Domino) has provided coding and marking solutions to the pharmaceutical industry for over 20 years. Our sales and support teams assist pharmaceutical companies from the consultation and purchase phase through to setup and ongoing servicing. With the help of its partners, Domino has the experience and technology to ensure small to mediumsized manufacturers meet compliancy within six months and ensure products can be sold legally and safely within Europe, the UK, and beyond. Domino’s print quality grades are independently verified.

REFERENCES Once installed, it will then take time for overall equipment effectiveness (OEE) to return to pre-installation rates. This is because of the serialisation equipment’s interaction with other departments, such as IT, logistics, order processing, and quality control. Testing will need to be performed to make sure that all sections of the business are working in tandem and the new or upgraded serialisation equipment is fully integrated.

However, despite the significant initial disruption, a positive by-product of serialisation has been that OEE has increased. Reports from some pharmaceutical manufacturers have suggested that new technologies which were initially installed to provide serialisation, including control systems and verification solutions, have increased overall productivity by 10–15%.

Explore Data Opportunities The benefits of pharmaceutical serialisation in terms of boosting patient safety, and the security of legitimate medicines, have been well documented. What should also be considered is the wealth of data that serialisation presents for manufacturers and how this can be used to build efficiencies in the wider pharmaceutical supply chain.

76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The EU FMD has presented pharmaceutical manufacturers with a raft of data on their downstream supply chains that, hitherto, they have not had access to – from general market access data on where specific drugs are performing well to sales data down to an individual pharmacy level.

Such data presents an opportunity for sales teams to engage with pharmacy chains to improve sales performance and could – direct-to-consumer legislation permitting – enable forward-thinking manufacturers to consider a whole new level of consumerfocused marketing or engagement. This capacity to springboard a company into the big data revolution is the kind of insight that excites the C-suite and marketing department of any business.

Conclusion Aside from the benefits of retaining European customers, implementing serialisation with the right focus on long-term data quality will have reduced waste, provided better control of products, and is now set to give manufacturers’ supply chains an efficiency boost – which ultimately serves to optimise pharmaceutical production processes in the long term. What the market must now consider is where EU FMD will go next, and in particular, manufacturers of OTC products would do well to start exploring

1.

2.

Assessing Current Implementation of DSCSA Serialization Requirements https://www. gs1us.org/DesktopModules/Bring2mind/ DMX/Download.aspx?Command=Core_Do wnload&EntryId=1210&language=enUS&PortalId=0&TabId=134, visited on 7th April 2021.

‘Painful’ 2020 Russian regulations will make EU rules ‘look like a walk in the park’ https://www. pharmaceutical-technology.com/comment/ russia-serialisation-requirements/, visited on 7th April 2021.

Bart Vansteenkiste Domino’s Global Life Sciences Sector Manager Bart Vansteenkiste has a 20-year history with the company, focusing on EU FMD legislation since 2011. He works with Domino’s European OEM partners and trade associations, including the European Federation of Pharmaceutical Industries and Associations and Medicines for Europe.

A Dutch, English, French, and Spanish speaker, Bart presents at conferences worldwide.

Email: bart.vansteenkiste@domino-uk.com

Summer 2021 Volume 13 Issue 2

// Flexibility is the key to successful pharma production – our CombiSys is perfectly in line with your needs. ///

www.ipimediaworld.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 77

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78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Summer 2021 Volume 13 Issue 2

Packaging

Thinking Inside the Box

Can New Temperature Control Packaging Initiatives Meet Cold Chain Sustainability Goals Without Compromising Performance?

The idea of sustainability as we know it today began to step out of the shadows around 30 years ago.1 Back then, healthcare executives and practitioners couldn’t know whether this would prove to be a will-o’-the-wisp or a guiding light on a critical journey. Yet much of what was mooted in the 1980s is illuminating pharma and medtech strategy now. It’s easy to see why when you consider — according to Health Care Without Harm’s JeanYves Stenuick — that ‘healthcare’s climate footprint totals 4.4% of global net emissions’.2 The production of pharmaceuticals and equipment may inherently devour natural resources, but decarbonisation missions are not something that can be tackled alone.

In their quest to reach ‘carbon net zero’, executives are having to look beyond core business and enforce sustainability objectives on partners, suppliers and vendors. One area in particular makes a considerable greenhouse gas contribution: the supply chain.

The Sustainability Landscape The sources of the industry’s emissions are incredibly varied. One gets a sense of this in Deloitte’s predictive paper on healthcare and life science, where in a 2025 landscape, ‘organisations have adopted mitigation strategies to reduce their carbon footprint and are implementing carbon-neutral solutions, such as using renewable clean energy and sustainably-sourced materials, across their clinical development and supply chain functions. Likewise, healthcare organisations prioritise suppliers that have zero-carbon landfill policies and recycle water and waste. They are also reducing demand through preventive care, choosing supplies and equipment with lower carbon footprints, and reducing travel through increased telemedicine availability.’3 Despite this diversity, Jean-Yves Stenuick notes that a whopping ’71% of healthcare emissions are linked with the supply chain, including the production, transport, disposal 79 INTERNATIONAL PHARMACEUTICAL INDUSTRY

of pharmaceuticals, other chemicals and medical devices.’4 This prioritises logistics — and more specifically, temperature control packaging (TCP) — as one area that can reduce its environmental impact. Some companies have adjusted parts of their modus operandi to align with these greener initiatives. And the pioneers have rallied to expand their portfolios by incorporating easily-recyclable TCP systems. Innovation has been put into overdrive of late, galvanised by heightened market activity. But to what extent have these new initiatives been embraced by the life science sector? And are they here to stay?

Scaling the Priority Ladder In a recent Temperature Control Sustainability Report, industry leaders regarded the implementation of sustainability in TCP as a key aspect of their future plans.

In fact, almost 90% of the managers polled stressed its importance, while 70% already have it on their radar.5 The driving forces?

Corporate strategy and customer demand.

The preference for being able to move temperature-sensitive pharmaceuticals around the globe in easily-recyclable shipping systems supported by sustainable processes has shifted from being a nice-tohave to an imperative.

Paper, cardboard, plant-based fibres and compostable substances are widely regarded as the materials that will propel the movement forward. They enable the reduction of plastics which in turn reduces the impact of CO2. The awareness, the intent and policy are falling into place. But when it comes to key buying criteria for TCP systems, there are other factors that must be taken into account, some of which are regarded as non-negotiable.

Global availability and total shipping costs are inevitably in the mix. Minimising ‘dead space’ in transportation and storage holds by utilising appropriate packaging sizes is a useful differentiator. But these are all superseded by the need for qualified temperature control. They have to be.

Product efficacy and patient safety are never up for debate. Furthermore, the period

for which products remain safe is part of the overall safety package, with the timetemperature conundrum working together to guarantee the integrity of temperaturesensitive pharmaceuticals.

The big shift has been where the environment is concerned. It has hauled itself off the priority basement to become a serious consideration where purchase decisions are concerned, to the point where the ‘re-use, recycle, renew’ message featured as a number one priority with over 68% of respondents in the Temperature Control Sustainability Report.6 The Foundation for a New Era The progression from single use, to reusable, to totally recyclable TCP systems is clearly gathering momentum. Traditionally, ‘ship and forget’ solutions could either be repurposed or upcycled into products such as mattresses, cushioning, boards or mouldings.

This was a precursor to a reusable era where advanced, robust, high-performance shippers have ensured product integrity by combining vacuum insulation panels with phase change materials to sustain shipments within their required temperature range throughout transportation. But even these higher-performing systems come with a caveat: multiple uses are required to achieve sustainable cost-effectiveness. This necessitates the use of returns programmes which also means there is some impact on carbon footprint.

Inevitably, life science companies with committed sustainability initiatives have called for environmentally-sound TCP alternatives that can easily be recycled locally and globally (it’s worth noting that many products labelled as recyclable are not easily recyclable, which means they’re unlikely to ever be recycled at all). The brains departments in the TCP organisations have been busy. Not only have new sustainability product developments had to ensure value at the end of life by encompassing carbon and plastic neutrality, but they’ve also had to encapsulate functionality while measuring up against regulatory and cultural criteria.

Attempts to level the cost of innovation Summer 2021 Volume 13 Issue 2

Packaging have only magnified the challenges facing developers.

All of this has had to happen without any compromise on the one thing healthcare companies can’t budge on: performance.

Satisfying Performance and the Planet Although there’s still some latitude for reusable or renewable high-performance TCP systems to work alongside recyclable solutions, TCP companies have been compelled to find new ways of making their product lines effective, sustainable and economically viable. Calls for a rudimentary parcel shipper fashioned in this mould have been growing louder, primarily to protect shipments of routinely-dispensed prescription products and over-the-counter medicines at 2°C to 25°C. In their search for a remedy to satisfy all criteria, the TCP industry’s research and development teams have done their thinking inside the box

80 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and found new innovation in an old friend: paper. And for good reason. Currently, the infrastructure is in place for recycling paper, much more so than plastic.

Recovery rates for packaging and foodservice plastics [in the US] are about 28%. In Europe, the plastic-packaging recycling rate reported is somewhat higher at approximately 40%, compared to approximately 80% for paperboard.7 That said, a switch to paper can increase weight. But the carbon footprint trade-off means there would still be a reduction in CO2E/kg of anything between 10% and 30%. So can a paper-based TCP system do the job, and literally tick all the boxes?

When continuously tested on packaging prototypes in environmental chambers, certain configurations of layered, corrugated cardboard have been found to offer superb insulation, as well as considerable impact

resistance. The thermal capabilities have then been bolstered by temperatureregulated, water-gel cool packs to provide prolonged temperature protection. This has culminated in a handful of market leaders being able to manufacture reliable, biobased, plastic-free TCP systems for use in the wide-stability temperature bracket.

Effective for anything up to 72 hours, the latest iterations are easily recyclable and leverage kerbside-collectable mentality but for industrial purposes. Importantly, the compliance demands for pharmaceuticals, clinical trials and diagnostics are able to be met by the pioneers; they offer a superior level of packaging qualification.

Going the Extra Mile The science behind this new wave of systems may meet regulatory compliance and performance benchmarks, but as we move forward, healthcare organisations will need

Summer 2021 Volume 13 Issue 2

Packaging more from their partners if they are to reach their decarbonisation goals. Encouragingly, 24% of senior management are already required to work with sustainably-minded TCP vendors, and that figure is set to surge over the next few years.8 In the not-toodistant future, standard benchmarks will almost certainly have to be met right across the board, perhaps even through eco audits.

As it stands, vendors which are transparent about their sustainability efforts are being prioritised. Some TCP companies are now adhering to ISO 14000 international standards and integrating elements of the environmental management system into their core business processes. They may even, for example, have a recycling service available where used systems are collected for you and recycled into new industrial products.

Others are going further. In a bid to protect the raw material that enables the manufacture of eco-based systems, they are working with forestry commissions and replanting trees as they’re used. But is there a cost to embracing this approach?

The answer is yes — and no.

The Cost of Eco-conformity As with most innovations, the corporate wallet takes an initial hit. But businesses often look first to costs on paper, whereas there are savings to be made off paper. This is a case where what’s taken away with one hand is given back with the other.

Best estimates indicate an uplift in costs on actual paper-recyclable solutions of somewhere between 10% and 15%. Then the counter punches weigh in. Tax on single-use plastic products increases year-on-year; a switch to paper removes it. Then as part of the green dot verification process, plastic users also have a corporate responsibility to make contributions to the plastic industry in their fight against waste; a switch to paper removes that too. And although paper-based products may require an outlay for recycling services, landfill costs also disappear (100% kerbside-recyclable means materials can be collected by local municipalities). Even a change of transportation method from air to ocean freight can reduce costs and carbon footprint.

Perhaps surprisingly, all of this may not matter. Feedback in the Temperature Control Sustainability Report also indicated that almost two-thirds of senior executives are prepared to back up their green ambitions www.ipimediaworld.com

with financial outlay, and more than onethird would put at least an additional 10% on top of their current budgets to make it happen.9 A Future All Wrapped Up If the past is anything to go by, TCP innovation of the paper-based variety may only be in its infancy. This is an industry where new developments go from 0 to 60 in about six seconds — or, quite literally, just six months if you look at the speed with which temperature-controlled shippers for COVID vaccines were developed. Given the design, production, testing and qualification involved, that’s pretty fast.

Now that the green seeds have been sown, 100% recyclable solutions could extend beyond protecting pharma products at 2°C to 25°C into other temperature brackets. More thermal products could also follow suit. The next logical step would be for easily-recyclable thermal packaging and temperature protection — such as covers — to hit the market. We shall see.

Either way, the general forecast consensus clearly points to passive single-use systems gradually giving way to reusable and recyclable systems over the next few years.

What’s certain is this: TCP solutions that are sustainable but only at great expense are unlikely to get traction. It is the balance of performance, affordability and sustainability that will trigger adoption and ensure pound-for-pound value at the end of life. On the surface, a shift to easilyrecyclable, paper-based systems may only appear to be one small step towards the greater goal of reaching carbon net zero, but it could well transpire that it’s a giant one.

REFERENCES 1.

2.

3.

4.

5.

Rack J, A brief history of sustainability, The world energy foundation, August 2014, visit: https://theworldenergyfoundation.org/abrief-history-of-sustainability/ Nawrat A, Are healthcare’s sustainability goals bold enough?, Pharmaceutical Technology, December 2020, visit: https://www. pharmaceutical-technology.com/features/ are-healthcares-sustainability-goals-boldenough/ Taylor K, Barber M, The future unmasked: predicting the future of healthcare and life sciences in 2025, p3, 2020, visit: https:// www2.deloitte.com/content/dam/Deloitte/ pt/Documents/life-sciences-health-care/ predictions-2025/LSHC-Prediction-09-2025.pdf Nawrat A, Are healthcare’s sustainability goals bold enough?

Softbox Systems, Temperature Control

6.

7.

8.

9.

Sustainability Report, 2021, visit: https:// www.softboxsystems.com/white-papers/ temperature-control-packaging-sustainabilityreport/ Softbox Systems, Temperature Control Sustainability Report.

Berg P, Feber D, Granskog A, Nordigården D and Ponkshe S, The drive toward sustainability in packaging—beyond the quick wins, January 2020, visit: https://www.mckinsey.com/ industries/paper-forest-products-andpackaging/our-insights/the-drive-towardsustainability-in-packaging-beyond-thequick-wins# Softbox Systems, Temperature Control Sustainability Report.

Softbox Systems, Temperature Control Sustainability Report.

Matt Tomkinson Matt Tomkinson is Technical Solutions Specialist at Softbox®, a leading, passive temperature control packaging solutions provider for the pharmaceutical, life science and cold chain logistics industries. He supports the global commercial team with two decades of in-depth cold chain knowledge, market insights, and strategy. As a trusted adviser on best-in-class temperature control logistics solutions, he finds innovative ways to help customers achieve their objectives.

Paddy O’Hara With a product design background and extensive familiarity with the diverse materials and processes involved in product development, Paddy O’Hara was able to make a smooth transition from managing packaging solutions for prominent retail brands to temperature protective packaging for Softbox® SilverSkin®. He is part of the senior management team and oversees process end-to-end, ensuring elite standards in design, development, qualification and validation. His expertise in materials and market trends enables him to deliver outof-the-box solutions and provide highly specialised technical and qualification support on customer-specific projects.

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Logistics & Supply Chain Management

Tackling Supplier Management Challenges to Build a More Agile and Resilient Supply Chain The ongoing supply chain disruptions caused by COVID-19 have made one thing clear: Pharmaceutical companies need a new and innovative way to work with suppliers and supply chain networks, so they can more quickly adjust to changing conditions, avoid or mitigate disruptions, and ensure that the right medicines are delivered to patients on time, in full (OTIF).

Digitalising the supplier management function will require the use of multienterprise work management to eliminate data silos and enable various stakeholders to work together and share data within the same, secured application.

Recent data from analyst firm IDC's recent pharma industry survey found that prior to COVID-19, 74% of suppliers were achieving 98% or better OTIF delivery rates.

After the pandemic hit, OTIF rates for those same suppliers plummeted by 28%.

As companies seek ways to work with their suppliers in this “new normal”, multienterprise work management has emerged, allowing the ability for supplier relationship management teams to orchestrate shared work across different functions both inside and outside the organisation to achieve actionable visibility, greater agility, and better end-to-end supply chain resilience.

Multi-enterprise work management supports the primary role of supplier relationship management, which is building better relationships through shared goals and collaboration.

With a multi-enterprise work management system on a digital network platform, supplier relationship management teams can overcome obstacles such as: • • • •

Poor supply chain visibility.

A lack of supply chain agility.

Sub-optimal OTIF delivery performance.

The need for better supply chain resilience.

Yet pharma companies and supplier relationship management teams still face 82 INTERNATIONAL PHARMACEUTICAL INDUSTRY

myriad challenges, including the increasingly complex outsourced supply chain; the virtual workforce, which may be here to stay; and the ongoing drive toward digital transformation.

Working Across a Network of Suppliers is Challenging The global market for outsourced services in pharma and biotechnology reached an estimated $54.8 billion in 2020, and it’s projected to reach $90.9 billion by 2027, according to a recent report from market research firm Global Industry Analysts, Inc. As the use of outsourced services grows, the supplier relationship management team’s role becomes more challenging because they have to work across a network of contract manufacturers, packagers, consultants, and other business partners located all over the world.

At the same time, COVID-19 is fundamentally changing the way we interact with our colleagues, customers, and business partners. With many life sciences companies planning to embrace work-fromhome policies even after the pandemic has ended, the need to support extended virtual internal and external teams is greater than ever.

like improved intercompany processes and greater supply chain visibility, agility, and resilience, enabling better execution of changes and response to disruptions.

Digitalising the supplier management function will require multi-enterprise work management to eliminate data silos and enable various stakeholders to work together and share data within the same, secured application.

Tighter Collaboration Leads to Better, Faster Supply Chain Network Decisions Supplier relationship management teams work closely with contract manufacturers and other supply network partners to collaboratively make decisions.

Here’s an example that happens frequently in the industry: •

A contract manufacturer begins a production run for a pharmaceutical company but only has enough ingredients to produce half of the order. In the absence of a collaborative decision-making process, that CMO may assume the right thing to do is produce and deliver half the order.

•

But what if the next product scheduled to be manufactured for that pharma company could be produced and delivered on time, in full? The pharma company might prefer to put the current production run on hold and move on to the next one, opting to ship a complete order, as opposed to fulfilling an order over time in dribs and drabs.

•

Pharma Companies are Increasingly Interested in Digitalising their Supply Chains Companies across all industries have been working to become more digital for years, and the COVID-19 pandemic has added new urgency that is fuelling this trend.

The pharma company’s supplier relationship management team may also need to rapidly source from a secondary supplier, check finished goods inventory, update quality assurance to make the change, and work with upstream and downstream partners to adjust production and delivery plans.

Pharmaceutical companies have lagged other industries in digitalisation of their supplier management function despite the potential benefits that digitalisation offers,

With a multi-enterprise work management application on a digital network platform, that CMO could simply create an issue that says, “We have only half of the

To be successful in an increasingly complex supplier network, companies need new types of solutions to work more effectively with teams inside and outside of the organisation. A highly outsourced supply chain drives a need for digital network solutions that reduce or eliminate inefficient manual processes that are difficult to track and measure – phone calls, emails, text messages – and improve visibility for all supply chain stakeholders.

Summer 2021 Volume 13 Issue 2

Logistics & Supply Chain Management API for the 20mg and 50mg capsule orders.

How would you like to prioritise the use of this API?” From there the team could provide visibility to necessary parties and orchestrate a timely response.

Currently, this type of supplier issue would typically be addressed through a flurry of phone calls, emails, and timeconsuming, disconnected processes. With a multi-enterprise work management application, all the information needed to make the best decision is available in a single, shared environment to internal and supplier team members.

The Supply Chain is Not Broken — But there is a Better Way As the COVID-19 pandemic emerged and began causing supply chain disruptions in 2020, there was no shortage of news articles and blogs stating that the pharma supply chain is “broken”. But it’s not. While the pharma supply chain certainly has serious obstacles to overcome from an agility perspective, pharma companies and their partners continue to produce high-quality products that improve the lives of patients.

www.ipimediaworld.com

Working through and managing supply chain disruptions, incidents, and changes requires a great deal of flexibility and ingenuity, and supplier relationship management teams continually rise to the challenge. But by necessity, they are forced to rely on manual processes that inherently hinder supply chain agility.

A multi-enterprise work management solution empowers teams to launch coordinated responses to even the most complex incidents, ensuring that each stakeholder understands their role in getting the issues resolved. By collaborating on a multi-enterprise work management system on a digital network platform, companies can: • • • •

Overcome the top supplier relationship management challenges.

Digitally transform supplier management processes.

Improve supplier relationships.

Drive supply chain agility and resilience.

Multi-enterprise work management is a critical enabler of greater supply chain resilience. But achieving a truly resilient supply chain will also require a commitment

to digitalisation and a rethink of the way supplier issues have typically been resolved.

John Bermudez As GM of TraceLink, John Bermudez will be responsible for leading the overall strategy, business planning, and operational execution for TraceLink’s Digital Network Platform business.Bringing over 30 years of experience in management, marketing, product management, engineering, software development, research and SaaS transformation, Bermudez is an established leader in supply chain management, most recently leading Infor’s supply chain management digital transformation and acquisition strategy.

During his career, Bermudez was Vice President at Oracle and AMR Research/ Gartner, where he co-authored a book on the impact of e-commerce on supply chain management.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 83

Logistics & Supply Chain Management

COVID Vaccination Serialisation – The Journey So Far

Alf Goebel, CEO, advanco, examines how successful the pharmaceutical serialisation and track-and-trace sector has been in overcoming the multiple logistical challenges posed by the global COVID vaccination roll-out.

The leading provider for Level 3 and Level 4 Item Level Serialisation, advanco was acquired by Parabellum Investments, led by Founder and Chief Executive, Rami Cassis, in 2020.

The global COVID pandemic has been one of the worst disasters we have collectively faced for generations, resulting in hundreds of thousands of deaths, disabilities, and losses of livelihoods.

However, in an exercise which underlines just how effective the pharmaceutical sector can be when it needs to perform under pressure, several manufacturers managed to successfully develop vaccines in less than 12 months – an extraordinary achievement, given it has historically taken around a decade, or longer, to develop new vaccines.

With regulators also acting with urgency to provide full sign-off for them to be used on the public, the pressure is now on to manufacture more doses of COVID-19 vaccines than any other vaccine in history to inoculate enough people to achieve global vaccine immunity, with the ultimate aim of putting an end to COVID once and for all.

Together with this mammoth, global, manufacturing pressure goes the need to provide cast-iron serialisation, or track-andtrace, services for this medicine.

The need for complete reliance that the vaccine is the real deal is essential.

We have already seen instances of forged vaccines. Only at the start of February this year were 3000 fake vials of COVID vaccine seized in China, an operation resulting in the arrest of 80 people. With depressing predictability, I am confident this is just the tip of the iceberg, with further fake vaccines being produced across the world at this very moment in time.

The pharmaceutical serialisation sector has therefore had to step up more than ever 84 INTERNATIONAL PHARMACEUTICAL INDUSTRY

before. Not only does the global vaccine roll-out need track-and-trace technology, delivered accurately and swiftly, this huge task has had to be done in addition to the sector’s “day-job” of serialising the routine, everyday medicines and medical equipment needed across the world to battle the globe’s collective ailments and diseases.

How successful has this mammoth COVID vaccination serialisation operation been so far? And what, if anything, needs improving to ensure the programme remains a success in the weeks and months ahead?

Addressing the Challenges of COVID Serialisation Before we assess how successful, or otherwise, global vaccine serialisation efforts have been so far, we firstly need to set the scene.

To ensure the vaccinations – some of which need to be prepared, stored, and shipped in temperatures as low as minus 80 degrees Celsius – can be handled in the specific manner called for, the pharmaceutical sector has had to quickly learn, adapt, and implement some major changes to its processes. It is likely these changes will need to continue to evolve to cope with the expected long-term fallout of the pandemic, with no guaranteed end-date in sight, new strains being discovered with alarming regularity and the lifespan of the vaccines still not known for sure – meaning the jabs may have to be given repeatedly across the world.

One of the major issues that the pandemic has highlighted is the practical difficulties of implementing serialisation processes being faced by manufacturers who rely on their own in-house systems.

Prior to the pandemic, such producers were well-versed in producing their own drugs and medication. While some of these products might have called for specific conditions, the chances are that nothing too extreme was required. However, when it comes to some of the COVID vaccine types, the entire cold chain process, covering everything from production and packaging requires the product to be produced, stored,

and distributed at anywhere between minus 20 and minus 80 degrees Celsius.

Some of the manufacturers quickly realised that these conditions came with a whole set of new problems they had not dealt with before, especially relating to serialisation. The technology needed to cope with these extreme temperatures just did not exist – whether this was implementing the serialisation codes or being able to physically scan and read them. These were major issues which needed to be solved with speed.

Bear in mind this was all being figured out while the eyes of the world were watching, with manufacturers facing intense pressure to produce the vaccine and ship it out to all four corners of the world a lot more quickly.

Additionally, the volume of vaccines needed has placed pressure on global supply chains for materials such as glass vials, syringes, and stabilising agents.

The solution to these challenges has been found to be based around technology that can track the progress of serialised items as they proceed through all stages of their lifecycle. This allows all essential information to be captured during packaging and warehouse operations, controlling the full process-flow, tracking and logging events and exceptions to a central repository, allowing manufacturers to report and optimise all processes.

Fighting the Counterfeiters The intense, global demand for a COVID vaccine has led to the dangers of counterfeiters manufacturing their own deadly solution – one which could cost lives.

When you look at the wider counterfeiting operation in the pharmaceutical sector, it is predicted that 10% of pharma products worldwide are counterfeit, with the global counterfeit drug market exceeding an eyewatering $75bn. Research further estimates that the death toll caused as a result could increase to 10 million people by 2050.

Pharmaceutical counterfeiting has been a deadly problem since the advent of the pharmaceutical sector itself. However, the pandemic has shone a new spotlight onto Summer 2021 Volume 13 Issue 2

Logistics & Supply Chain Management the essential services of the serialisation strand of the overall pharmaceutical sector.

Once again, the importance of traceability and track-and-trace services have been emphasised – underlining still further the need for such services to be watertight, even in the difficult conditions of working in temperatures of up to minus 80 degrees Celsius.

several vials, rather than on each individual vial. This data is being stored in the serialisation data repository (EPCIS repository) and stands ready to be shared with any healthcare system.

However, this is likely to change. The dangers of only serialising per-carton comes from the many people who will be vaccinated from each. If they then disperse and go all over the world, tracking will become an issue. Once the roll-out has reached a satisfactory level and the global pharmaceutical sector has time to reflect on the intricate details and processes that have had to be instigated over the past year or so, we will likely be looking at a new per-vial serialisation process.

What Has Worked Well so far with Vaccine Serialisation?

Considering the globe had never even heard of COVID-19 until 18 months ago, the pharmaceutical sector has had to act incredibly swiftly. The ability, therefore, to research, develop, produce, and manufacture a vaccine, together with receiving all regulatory approval, underlines just how well the sector has managed to utilise existing infrastructure, solutions and processes.

When you consider the biggest ever rollout has relied on these systems, it should certainly be considered as a success.

Likewise, the trust in established vendor quality and excellence has been outstanding.

Without this trust and the ability to work together, we certainly would not be as far ahead with the roll-out as we are now.

Another success must be a general move towards local production.

While there is a still an overwhelming reliance on geographies such as China for the supply of much of the globe’s medication, the COVID pandemic has seen this pattern starting to shift. We are seeing a move towards local production and sourcing through the repatriation of supply chains into Europe and the USA. This repatriation is a big deal for the future of the pharmaceutical sector. It signals confidence in the capabilities of Europe, resulting in ongoing investment into the continent. This will result in job creation and a renewed interest in the brand name of Europe as a global centre to produce essential pharmaceuticals.

While you would naturally expect trackand-trace providers in the pharmaceutical sector to be driven by the latest technology, the advent of the pandemic has ensured the industry has collectively re-evaluated the technology it needs.

The technology driving the actual serialisation processes is, as would be www.ipimediaworld.com

In Conclusion What has been achieved since the start of the pandemic is admirable. expected, the latest-generation and latest specifications. However, in line with almost every other business sector across the globe, pharmaceutical serialisation companies are continuing to invest in technology to ensure they continue to adapt to the strict conditions needed for the global roll-out.

The serialisation sector specifically, and the pharmaceutical sector generally, has shown it is able to rise to challenges on a global scale and use its experience, technological prowess, and all-round excellence to offer solutions that will tackle major issues head-on.

What Could Have Been Improved?

Foresight around just how complex the supply-chain needs to be to cope with the vaccine deployment, and the ability to work within the specific demands needed, could have been better. Yes, the pharmaceutical sector has been working – successfully, by and large – under great pressure. However, I would argue the sheer complexity of the supply-chain needed caught many of us by surprise.

There have been various major challenges that have needed to be addressed, and there are some aspects that could have been done better. Certainly, there are processes that will need to be tightened up or improved in the coming months.

Moving forwards throughout the remainder of this year, the pharmaceutical sector should concentrate on fine-tuning and solving the challenges that this complex supply-chain needs to function.

This is especially true when you consider the need to roll out the second vaccination jab that many treatments need – and, of course, there is the potential that ongoing booster-jabs will need to be administered at regular intervals (although the jury remains out at the time of writing on this potential development).

Additionally, the actual serialisation process will need to be addressed.

Most serialisation is currently being carried out on each carton, each containing

However, when you consider the incredible achievements that have been made in these unprecedented times, the journey so far has shown a pharmaceutical sector that we should all be proud of.

Alf Goebel Alf Goebel is a C-level software sales and marketing executive, with strong operational experience specializing in high growth business in Europe and the US. Alf has extensive experience with Global Partnerships SAP and has held senior executive positions at a number of leading technology companies, including Snow Software and MSC Software.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 85

Application Note

Trust but Verify: Importance of Packaging Compendial Testing to Secure the Parenteral Drug Supply Chain Marc Mittermuller, Flor Toledo Rodriguez, Dan Haines Trust. We normally think of trust in the context of our personal relationships with other people, but how often do we consider trust with respect to the products we use? Most of the products used on a daily basis we implicitly trust to work as advertised because (a) we assume the company providing the product has done sufficient functionality, safety testing and quality control, (b) that there exists somewhere a governmental/ regulatory rule requiring testing of said product for human safety by some approved standard before the product can be sold to the consumer, (c) we usually have experience with the products and expect that any defect will be easily visible by eye, and (d) the potential long-term health impact from a defective product is normally low.

But what about those products such as medicines/drugs which we use that bypass our bodies’ protective defence mechanisms (skin barrier, stomach acid, mucus membranes, etc.)? For these products (i.e. parenterals) we go one step further with trust but verify, due to the potentially severe impact to patient safety from counterfeit, mislabelled, mis-packaged, defective or non-compliant products.

Supply Chain and Regional Pharmacopeia for Compendial Testing While a discussion for verifying the safety of the entire supply chain for a finished drug product is beyond the scope of this article, just assessing the safety (i.e. authenticity and required performance attributes) of the parenteral primary packaging supply chain is a sufficiently demanding task. There are currently an estimated 7.8 billion humans on earth.1 The worldwide production of borosilicate glass containers (the dominant material used for parenteral products for over 100 years) is approximately 50 billion per year;2 with significantly increased demand for confrontation of the current global pandemic challenge. This also requires the same amount of closure systems (elastomeric stoppers for vials, plungers/ seals/tip caps for syringes or cartridges, 86 INTERNATIONAL PHARMACEUTICAL INDUSTRY

not an easy task to procure additional components quickly as the number of major glass tubing manufacturers and elastomer raw material manufacturers is small.

Depending on what performance attribute is being assessed, the glass converting process has a much larger impact (i.e. on the hydrolytic resistance of the inner surface) than the processing steps of the primary material by the glass tubing manufacturer.

There are tens of different glass compositions and tens of different elastomers available on the international market. Depending on where the finished drug product is sold, different pharmacopeias (i.e. United States Pharmaceopeia – USP, European Pharmacopeia – Ph.Eur., Japanese Pharmacopeia – JP, People’s Republic of China Pharmacopeia – ChP) and/or international/ national standards (i.e. ICH, ISO, ASTM, DIN, YBB) regulate the testing and release of primary packaging materials. Despite intensive harmonisation efforts between the regulatory/standard bodies, both small and significant testing method differences and requirements remain. This often means for a worldwide drug product release that two or three very similar tests measuring the same performance attribute must be conducted to satisfy the regionally different regulatory requirements.

The process of trust but verify for compendial testing is multi-faceted, with redundant testing built into the system to help minimise mistakes. From a 30,000 foot perspective, this is an iterative process stretching across decades with two possible starting points. The normal procedure is that a raw material or component within the existing design space (i.e. approved materials) is introduced to the market and tested according to existing regulatory/ standards, the standards being adjusted over time if required due to increasing product requirements and specifications.

As advances are made in materials science, when a new material/component that meets an industry need outside the existing design space is introduced to the market, it requires testing according to existing regulatory/ standards as well as additional tests from the manufacturer or end use customer.

The additional testing is required because new materials can cause or contribute to

new container/drug product interactions to occur that are not found in existing materials, resulting in extensive review and oftentimes update/change/addition to the standards. No matter the starting point, the subsequent use of the raw material or component requires the following testing pathway: (a) testing by supplier to generate a certificate of analysis related to manufacture of material to customer specification and applicable regulatory standards, (b) downstream retesting of the material on a lot-to-lot basis or on a time period basis by the pharmaceutical company/contract filler or by outsourcing to a contract testing laboratory. Downstream testing (i.e. by the pharmaceutical company or their contract filler) of the components is required due to regulatory guidance3 assigning the final responsibility for finished product safety to the pharmaceutical company.

Quality Requirements for Contract Laboratory One underappreciated, but very important contributor to successful testing, is the qualification and experience level of the testing laboratories. Glass is manufactured normally under ISO quality management systems such as ISO 9001:2015 and ISO 15378:20174,5 and tested by the manufacturer under GMP or GLP quality management systems (good manufacturing practice; good laboratory practice). Testing by pharmaceutical/contract fillers is normally conducted under these quality management systems. However, while contract laboratories may operate under GMP/GLP systems, it is increasingly common for contract laboratories to be accredited under a standard quality management system such as ISO 17025:2017.6 While GMP/GLP/ISO 17025 share many of the same principles, the certification process is significantly different because ISO 17025 requires external, independent, non-customer based assessment via onsite auditing to receive accreditation. ISO 17025 accreditation in addition requires verification that the testing procedures have been validated and traceable back to standards. Of course, customers also audit the testing laboratory, usually based on a combination of ISO 17025 standard and relevant aspects of company-specific Summer 2021 Volume 13 Issue 2

Application Note GMP/GLP. There is tremendous variability in the quality of compendial testing that can be directly traced by auditors on the qualification and training of the employees, method validation, equipment selection, qualification of instruments, etc. of the testing laboratory.

Example of Compendial Testing Required for Glass Vials for a Worldwide Product Launch Let’s use for an example of the trust but verify process a pharmaceutical company ready to launch a new drug product worldwide in an ISO 10R tubular glass vial7 and go through the testing required of the glass container component. We will focus only on the testing required to fulfil compendial regulations for commercial production. A supply agreement has been negotiated with glass vial suppliers on the technical basis of a glass vial specification document to provide a suitable container meeting essential parameters/tolerances.

This is part of the risk mitigation process to ensure supply of containers, which also could include supply from multiple production sites, supply from multiple suppliers, warehouse/delivery management, etc. The glass vial suppliers first have to obtain the appropriate glass tubing which comes with a certificate of analysis giving the results of testing for hydrolytic resistance (e.g. ISO 7198, ISO 7209), light protection (e.g. USP <660> 10, Ph.Eur. 3.2.1.11), and heavy metals (article 11 of 94/62/EC12). The glass tubing supplier ensures tubing passing these tests by regular (daily, weekly, monthly) testing of running tubing production by additional testing of chemical composition, transmission, coefficient of thermal expansion (CTE), density, viscosity, glass stress sealant, transformation temperature (Tg), working point, and other parameters. Glass tubing suppliers also conduct dimensional and cosmetic inspections.13 The combined testing assures the glass container manufacturer that the glass tubing (i.e. raw material) is of sufficient quality to meet the required pharmacopeia specifications for containers.

By agreeing to produce a 10R tubular vial according to ISO 8362-1,7 the vial manufacturer commits to producing the container within the dimensional specifications (Figure 1, from7) for the selected container and fulfilling the requirement for European blowback/ American blowback / no blowback (Figure 2) along with testing for hydrolytic resistance of the inner surface according to <USP> 660; Ph.Eur. 3.2.1 or ISO 4802-1,14 residual stress, and cosmetic limits according to ISO 8362-1.7 www.ipimediaworld.com

This is the bare minimum requirement. If a higher glass cosmetic quality level is part of the glass supply agreement, then additional testing by various tools/systems of each vial will be conducted with agreed-upon acceptable quality limits (AQL) such as for SCHOTT TopLine vials.15 The classification and identification of non-conformities is conducted either according to industry standards such as the defect evaluation list16, PDA TR43,17 or company-specific defect catalogues such as the SCHOTT Vial Defect Manual.18 The supply agreement will also define the secondary packaging material of the glass container (shrink-wrap, polyethylene tray, tub and nest), number of vials per container, number of units per level of pallet, and number of levels per pallet, configuration of units on each level, pallet protective packaging, and method of transportation. For each lot of vials produced a certificate of conformity or certificate of analysis will be issued to the pharmaceutical client/contract filler showing compliance according to the major pharmacopeia regulations (USP <660>, Ph.Eur. 3.2.1., JP 7.0119) and international standards (ISO).

Once the vials are shipped out by the manufacturer, the trust but verify process Key Attributes

10R

Brimful Capacity (mL)

13.5 ± 1

D1 Body Width (mm)

24 ± 0.2

D4 Inner Neck Diameter (mm)

12.6

H1 Overall Height (mm)

45 ± 0.5

R1 Shoulder Wall Thickness (mm)

4±2

S1 Body Wall Thickness (mm)

1 ± 0.4

Figure 1: Selected key dimensional attributes of 10R vial from ISO 83627

starts in earnest. Depending on the pharmaceutical company/contract filler and experience with the glass vial manufacturer, vials may be accepted directly into the vial filling process (“accepted by certificate”) or undergo incoming inspection. Typical incoming inspection involves a sampling plan based on lot size and AQL-level based on ISO 285920 for checking the dimensional and cosmetic attributes of the vials, done directly by the glass manufacturer (i.e. tail gate samples) and accepted on certificate or by the pharmaceutical company in-house staff or outsourced by the pharmaceutical company to third-party laboratories. Per regulatory agency guidance such as the US FDA3 a regular testing interval check of manufacturer’s data has to be conducted.

Pharmaceutical companies require this checking for each lot of components for critical attributes like dimension and visual non-conformities where sampling frequency, amount of samples, and skip lot procedure is defined,20 but for less critical attributes on a reduced frequency basis.

This step is the heart of the trust but verify process, in essence a double-checking / double verification of the materials before release and use in the packaging of the intended drug formulation to ensure that the correct packaging is used.

The pharmacopeia mandated tests for glass containers for parenteral products are given e.g. in USP <660>, Ph.Eur. 3.2.1., and JP 7.01. For example, USP <660> requires determination of the hydrolytic resistance by glass surface and glass grains extraction and subsequent titration tests to assign the glass to one of three types: Type I, II, III (Figure 3). As an alternative to the glass grains testing, surface etching testing can be used to confirm Type I (borosilicate

Figure 2: Exemplary SCHOTT 10R European blowback tubular injection vial drawing INTERNATIONAL PHARMACEUTICAL INDUSTRY 87

Application Note

Figure 3: Glass hydrolytic resistance testing methods to distinguish between Type I, II, III glasses and to check quality of the raw glass and finished glass containers

glass) vs Type II (treated soda lime glass) to assign if the hydrolytic resistance performance measured by the glass surface test is accomplished by the inherent glass chemistry (i.e. borosilicate) or by treatment (i.e. ammonium sulfate inner surface treatment of soda lime glass). Determination of the amount of arsenic is required by testing according to e.g. USP <211>21 or Ph.Eur. 3.2.1. If the glass containers are coloured (i.e. amber glass) to provide light protection of the drug product then the containers must be assessed spectrophotometrically via UV-VIS spectroscopy to meet transmission limits based on the size of the container.

Ph.Eur. 3.2.1. allows for an alternative method for surface hydrolytic resistance testing via flame spectrometry, which is comparable to ISO 4802-2 testing.22 JP 7.01 adds additional testing requirements for visual conformity and soluble iron. Careful reading of these pharmacopeia tests reveals small differences in the methods.

Taking the example of hydrolytic resistance testing, method variations include type of acid used for hydrolytic resistance testing (hydrochloric vs. sulfuric), acid concentration (0.02 M vs 0.01 M), pH indicator (methyl red vs bromocresol green), heating temperature (121°C vs 100°C), heating time (30 minutes vs 120 minutes), etc. For some tests, totally different analytical techniques for detection are described. Regarding arsenic release testing, Ph.Eur. 3.2.1. needs an instrumentbased detection method (hydride generation atomic absorption spectrometry) whereas USP <211> uses colorimetry.

Example of Compendial Testing Required for Rubber and Polymer Components The pharmacopeia mandated tests for 88 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Table 1: SCHOTT pharma services compendial and standard testing methods Sample Type

Container (glass)

Test method

ISO 4802-1 / ISO 4802-2

Titration / FAAS

Ph.Eur. 3.2.1. / USP <660>

Titration

Glass surface etching

Ph.Eur. 3.2.1. / USP <660>

Titration

Glass grain / glass powder

DIN EN ISO 719 / ISO 720 Ph.Eur. 3.2.1. / USP <660>

Titration

Arsenic

Ph.Eur. 3.2.1. / USP <660>/<211>

FAAS / Colorimetric

Light transmission

Ph.Eur. / USP / JP

UV-VIS

Visual conformity

JP 7.01, test 1

Visual Inspection

Soluble alkali

JP 7.01, test 3 method 1

Titration

Soluble iron

JP 7.01, test 5

Colorimetric

Heavy metals

EUR-Lex Article 11 94/62/EC

ICP-OES

Inner surface 121 °C Glass grains 121 °C

Rubber component

Technique

Glass surface

Boron oxide

Syringe (glass)

Standard

Hydrolytic resistance of the inner surface

ChP 4009 / YBB 00232003-2015 ChP 4006 / YBB 00242003-2015 ChP 4001 / YBB 00252003-2015

Titration Titration Titration

Glass grains 98 °C

YBB 00362004-2015

Titration

Acid resistance

YBB 00342004-2015

Gravimetry

Alkali restistance

YBB 00352004-2015

Gravimetry

Heavy metals

YBB 00372004-2015

Colorimetric (ICP-MS)

Needle diameter and composition

DIN EN ISO 9626 and ISO 5350

SEM-EDS / VGA

Tungsten

In-house

ICP-MS

Silicone oil

In-house

GF-AAS

Flange strength

In-house

Pressure testing

Needle pull-out force

In-house

Tensile testing

UV

DIN EN ISO 8871-1

UV

Ash

DIN EN ISO 8871-2 / ISO 247

Gravimetry

Density

DIN EN ISO 8871-2 / ISO 2781

Balance

Particle count

DIN EN ISO 8871-3

Microscopy

Solution S tests

Ph.Eur. 3.2.9. / USP <381>

Bromobutyl rubber plungers

YBB00082004-2015

Polyisoprene rubber caps

YBB00102004-2015

Colorimetric / UV-VIS / AAS / Balance / Titration Colorimetric / UV-VIS / AAS / Balance / Titration Colorimetric / UV-VIS / AAS / Balance / Titration

AAS: Atomic Absorption Spectroscopy; FAAS: Flame Atomic Absorption Spectroscopy; GF-AAS: Graphite Furnace Atomic Absorption Spectroscopy; ICP-MS: Inductively Coupled Plasma - Mass Spectrometry; ICP-OES: Inductively Coupled Plasma - Optical Emission Spectroscopy; SEM-EDS: Scanning Electron Microscopy - Energy Dispersive X-ray Spectroscopy; UV: Ultra-Violet; UV-VIS: Ultra-Violet - Visible; VGA: Vapour Gas Analysis

Table 1: SCHOTT pharma services compendial and standard testing methods Summer 2021 Volume 13 Issue 2

Application Note elastomeric closures (i.e. stoppers, tip caps, etc.) of glass containers for parenteral products are given in e.g. USP <381>23 and Ph.Eur. 3.2.9.24 For example USP <381> requires biological reactivity (according to USP <87> or <88>), physicochemical, and functionality testing to confirm suitability for usage and classification of the elastomer as a Type I or Type II closure. USP <381> physicochemical testing requires preparation of extraction solution from the elastomer and testing for appearance (turbidity/opalescence), colour, acidity or alkalinity, absorbance, reducing substances, volatile sulfides, and ammonium.

Ph.Eur 3.2.9. physicochemical testing in addition requires testing for extractable zinc, extractable heavy metals, residue on evaporation. These physicochemical testing requirements are also found in ISO 8871-1.25 USP <381> functional testing assesses penetrability, fragmentation, and self-sealing capability. Type I closures have the highest requirements and are preferred for all injectable applications whereas Type II closures have improved mechanical attributes for specific device functional needs (e.g. multiple piercing) but do not meet the Type I specifications

for appearance, absorbance, and reducing substances.

Other ISO and USP Standards Other international industry standards give guidance for additional testing on filled finished pharmaceutical products. Taking as an example a filled glass syringe, ISO 110408:201626 details the testing via the following performance characteristics: Break loose and gliding forces, burst pressure resistance, flange strength resistance, closure system removal force/torque, connectivity/leakage testing, residual volume, needle penetration force, and needle pull-out force. These tests are designed to ensure that the delivery device for the injection functions performs as intended and is within established specification ranges for patient safety and patient comfort attributes of the injection device.

Besides glass, plastic packaging systems are more and more used as primary packaging materials for pharmaceutical use; e.g. for prefillable syringes, cartridges, vials, among others. These plastic packaging systems demand a high stability of the

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materials used during the manufacturing process and while stored with drug formulation or cosmetic preparation for which these are intended. The requirement and specification of testing depends on the type of end material used. In this case, the pharmacopeia mandated testing for plastic materials of construction and plastic packaging systems for pharmaceutical use are given in USP <661>,29 which will be replaced by USP <661.1>27 and USP <661.2>.28 The packaging components or systems need to be constructed from well-characterised materials for its envisaged application.

Examples of these polymeric materials are made out of cyclic olefin copolymer (COC), cyclic olefin polymer (COP), polypropylene (PP), polyvinylchloride (PVC), among others.

Their physicochemical properties and chemical suitability for intended use have been well established by suitable testing and defined acceptance criteria.

Overview of Compendial Tests Supported

by SCHOTT Pharma Services Different test procedures inside the various pharmacopeias as well as the different national and international guidelines

Application Note occupy a significant amount of technical and human resources to fulfil the requirements for drug product distribution. Providing and maintaining these resources and always staying updated with regulations and guidelines is often not economical for the pharmaceutical company. SCHOTT pharma services provides compendial and standard testing under DIN EN ISO/IEC 17025 accreditation for glass containers, elastomeric closures, and needles as per Table 1 below. In-house methods have been validated and standard compendial test methods based on regulatory standards have been verified according to DIN EN ISO 17025 requirements.

Summary Because human health matters, it is very important to secure the supply chain for parenteral drugs by compendial testing of the applied primary packaging components.

A verification of compliance of received components by the drug manufacturer is required in addition to test properties and certificates provided by the component supplier. A broad knowledge base about regionally different pharmacopeia regulatory standards and a very high quality level for the supporting contract laboratory is fundamental to support the pharmaceutical industry for compendial testing of glass, elastomer and polymer packaging components.

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CFR Code of Federal Regulations Title 21 Section 211.84, https://www.accessdata.fda. gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch. cfm?fr=211.84#:~:text=Sec.,by%20the%20 quality%20control%20unit.

ISO9001:2015 Quality Management Systems – Requirements, International Organization for Standardization, https://www.iso.org/ standard/62085.html.

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International Organization for Standardization, https://www.iso.org/standard/62085.html.

ISO17025:2017 Testing and Calibration Laboratories, International Organization for Standardization, https://www.iso.org/ISO-IEC17025-testing-and-calibration-laboratories.html.

ISO8362-1:2018 Injection Containers and Accessories – Part 1: Injection Vials made of Glass Tubing, https://www.iso.org/standard/74398.html.

ISO719:2020 Glass – Hydrolytic Resistance of Glass Grains at 98 °C – Method of Test and Classification, https://www.iso.org/obp/ ui/#iso:std:iso:719:en.

ISO720: Glass – Hydrolytic Resistance of Glass Grains at 121 °C – Method of Test and Classification, https://www.iso.org/standard/77844.html.

U.S. Pharmacopeial Convention (USP) 43 – NF38, USP <660> Containers – Glass.

European Union Pharmacopeia (Ph.Eur.) 10.3 3.2.1., “Glass Containers for Pharmaceutical Use”.

European Parliament and Council Directive 94/62/EC of 20 December 1994 on Packaging and Packaging Waste, https://eur-lex.europa.eu/ legal-content/EN ALL/?uri=CELEX%3A31994L0062.

SCHOTT Tubing Technical Performance Specification 2017.

ISO4802-1:2016 Glassware – Hydrolytic Resistance of the Interior Surfaces of Glass Containers – Part 1: Determination by Titration Method and Classification, https://www.iso.org/ standard/67782.html.

SCHOTT Vials Perfection in Every Detail, 2017, https://www.us.schott.com/d/pharmaceutical_packaging/dbea150d-eba0-4315-9ef19b7bc8a25b3c/1.7/schott-brochure-schott-vialsenglish-us-20092017.pdf.

Defect Evaluation List for Containers Made of Tubular Glass 5th Edition, Editio Cantor Verlag, 2016.

Technical Report No. 43 (Revised 2013) Identification and Classification of Nonconformities in Molded and Tubular Glass Containers for Pharmaceutical Manufacturing: Covering Ampoules, Bottles, Cartridges, Syringes and Vials, Parenteral Drug Association 2013.

Defect Manual SCHOTT Vials, SCHOTT AG, 2015.

Japanese Pharmacopeia 17th Edition, Section 7.01, Test for Glass Containers for Injections, https://www.pmda.go.jp/english/rs-sb-std/ standards-development/jp/0019.html.

ISO2859-1:1999 Sampling Procedures for Inspection by Attributes – Part 1: Sampling Schemes Indexed by Acceptance Quality Limit (AQL) for Lot-by-Lot Inspection, https://www. iso.org/standard/1141.html.

U.S. Pharmacopeial Convention (USP) 43 – NF38, USP <211> Arsenic.

ISO4802-2:2016 Glassware – Hydrolytic Resistance of the Interior Surfaces of Glass Containers – Part 2: Determination by Flame Spectrometry and Classification, https://www.

Laboratory address in Germany:

Laboratory address in USA:

SCHOTT AG SCHOTT pharma services Hattenbergstraße 10 55122 Mainz Germany Phone: +49 (0) 6131 66 7339 pharma.services@schott.com

SCHOTT North America, Inc. Attn. DR. Dan Heines 201 South Blakely Street, #121 Dunmore, PA 18512 USA Phone: +1 570 457-7485 x 653 daniel.haines@us.schott.com

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23.

24.

25.

26.

27.

28.

29.

iso.org/standard/67783.html.

U.S. Pharmacopeial Convention (USP) 43 – NF38, USP <381> Elastomeric Closures for Injections.

European Union Pharmacopeia (Ph.Eur.) 10.3 - 3.2.9., “Rubber Closures for Containers for Aqueous Parenteral Preparations, for Powders and for Freeze-Dried Powders”.

ISO8871-1:2003 Elastomeric Parts for Parenterals and for Devices for Pharma-ceutical Use – Part 1: Extractables in Aqueous Autoclavates, https://www.iso.org/standard/33770.html.

ISO11040-8:2016 Prefilled Syringes Part 8: Requirements and Test Methods for Finished Prefilled Syringes, https://www.iso.org/ standard/66036.html.

U.S. Pharmacopeial Convention USP-NF <661.1> Plastic Materials of Construction.

U.S. Pharmacopeial Convention USP-NF <661.2> Plastic Packaging Systems for Pharmaceutical Use. U.S. Pharmacopeial Convention (USP), USP 43,<661> Plastic Packaging Systems and their Materials of Construction. * All https reference links were confirmed to be valid as of the date of submission.

Laboratories of SCHOTT pharma services are DIN EN ISO/IEC 17025 accredited (DAkkS) and FDA registered.

SCHOTT pharma services can access more than 40 years’ experience in analytical testing of pharmaceutical packaging containers. All quality relevant documents are electronically available, ensuring a smooth audit process.

All 3 authors are working in different roles for SCHOTT pharma services providing compatibility and compendial testing of packaging material for the pharmaceutical industry.

Marc Mittermüller Marc Mittermüller is a chemist with extensive experience in the analyses of inorganic leachables or elemental impurities and coordinates studies as a Study director.

Flor Toledo Rodriguez Flor Toledo Rodriguez holds a PhD in Chemistry and has held several positions in different companies connected to analytical testing. In her current role she is managing the laboratories of SCHOTT pharma services in Germany.

Dan Haines Dan Haines holds a PhD in Inorganic chemistry and has 20 years’ experience in field of drug container interactions. He is responsible for the laboratory activities and customer relations in North America.

Summer 2021 Volume 13 Issue 2

www.peakscientific.com/precisionSL www.ipimediaworld.com

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Lessons Learned from the COVID-19 Vaccine Cold Chain Control Tower Supply chain visibility technology is proving its worth in the distribution of vaccines and has broader applications.

Now that COVID-19 vaccines have received regulatory approvals and vaccine manufacturers are producing a steady and increasing supply, the focus has shifted from manufacturing to distributing doses.

Vaccine manufacturers have been working closely with cold chain distribution experts and technology providers to plan for monitoring and maintaining the cold chain to ensure the integrity of these crucial products.

The vaccines that are currently in distribution must be transported and stored at temperatures ranging from refrigerated (2–8°C) to frozen (-20°C), or in a dry ice environment, with specific requirements, depending on the manufacturer and vaccine composition.

distributing vaccines globally to regions with varying degrees of infrastructure and regulations. Gaining visibility from manufacture through last-mile delivery, and even onsite, has been critical to ensure vaccine integrity and help stakeholders make critical decisions as they are needed.

Vaccine Cold Chain Challenges and Successes Aside from the rapid scientific development needed to develop an effective vaccine, manufacturers were tasked with gaining stakeholder engagement and buy-in on a level never previously seen. The urgency created by the pandemic and the rapid distribution required led to a change in the way systems and processes previously have worked. Ensuring regulatory compliance required team collaboration across large organisations, governments, and other external parties.

Many parties from all parts of the distribution chain — from developers of thermal packaging, IoT data loggers, and supply chain visibility data automation software systems, to dry ice and vial suppliers, airlines, and carriers — stepped up to prioritise vaccine distribution and solve one of the greatest logistical challenges we have seen.

In a normal cold chain, pharmaceutical manufacturers must have rapid, accurate, and comprehensive capabilities in place to understand where products are and the condition they are in at all times. There are several risk factors in the cold and ultracold chain of COVID-19 vaccine distribution, and for most vaccines generally. First, vaccines must be stored at low and ultra-low temperatures, some of which must be kept at lower than the usual cold chain standard of 2–8°C. Any deviations in temperature during transport or storage can make the vaccine ineffective or even unsafe. Additionally, delays and losses of product in the supply chain can lead to critical vaccine shortages in areas that have been severely affected by the pandemic.

Over the last several months, we have seen tremendous efforts across the COVID-19 vaccine distribution channel, with parties coming together to help solve a common goal for humanity. While we learned during the H1N1 outbreak more than one decade ago that digitally connecting and transforming the end-to-end would be paramount for future supply chains, this guiding principle has proven essential during the current pandemic.

There are handoff points along the supply chain, and each one poses risks of temperature deviations, like pallets being split up or other incidents that can compromise the products' quality condition.

Likewise, the receiving facility staff, including hospitals, clinics, and pharmacies, must review and understand all handling and storage instructions as well as the vaccine quality and safety conditions for each vaccine.

With a significant global impact and human health at stake, manufacturers were tasked with rapid vaccine development, and

Some of the COVID-19 vaccines are shipping directly from the manufacturing site to receiving sites using a high-speed

Pfizer and BioNTech's COVID-19 vaccine was authorised with stringent requirements of the currently authorised products, with storage between -80 °C and -60 °C. The vaccine is being shipped in thermal containers designed to hold dry ice for both shipping and temporary storage.

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delivery model. This typically has involved air and road freight directly to receiving sites.

To ensure the successful and rapid delivery of these sensitive products, shipping in high-volume, small parcel increments, realtime, actionable communication among stakeholders was needed. This requires connecting technology systems and activities to align people and processes and ensure vaccine integrity.

Many supply chains have traditionally used passive and limited use IoT data logger technologies that provide descriptive data, showing what happened after the fact. This delay in information is problematic because stakeholders cannot act on the data to prevent waste and loss. Vaccine integrity has never been more crucial as millions of COVID-19 treatments have already shipped, and potentially more than one billion will ship over the next 12–24 months.

Real-time, GSM-enabled IoT data logger technology and cloud-enabled analytics were designed to measure various scenarios that would require escalation in addition to temperature deviations and geolocation, which can detect if shipments are delayed, or products are split up or arrive at a wrong location. This technology is needed to support the rapid deployment of vaccine distribution on a global scale. Additionally, 24/7 monitoring and response services were required to respond to escalations and work with relevant parties to prevent vaccine product loss.

From a technology viewpoint, connecting people, processes, and stakeholders, both internally for manufacturers, and externally among its selected suppliers, carriers, and other stakeholders, has required a comprehensive mapping of new workflows and then building data and automation models to help streamline their efficiencies.

For example, by integrating an enterprise resource planning (ERP) system with a real-time supply chain visibility software platform, carriers' own internal supply chain control tower system, and a quality management system, has connected and streamlined many value chain activities, spanning business, manufacturing, quality, and logistics.

Summer 2021 Volume 13 Issue 2

Development and manufacturing

Thermal Blankets for the temperature protection of pharmaceuticals and healthcare products in airfreight (+15°C +25°C) and (+2°C +30°C)

Worldwide available at freight forwarders Qualifications & Validations - Multilayer thermal blanket for PMC-ULD – Euro and Block pallets - Temax-4000 blanket with integrated 4x multiple reflection technique - Stress tested in summer (+46°C) and winter (-15°C) profiles - Tarmac tested on solar power and greenhouse effects Ecological notes - Recyclable + Low ecological footprint - NON-laminated composition = easy to dismantle - Re-manufacturing of recycled compounds

www.ipimediaworld.com

KRAUTZ - TEMAX Group

Development and manufacturing Belgium - Europe Phone +32-11.26.24.20 Website www.krautz.org Email info@krautz.org

Temax Americas LTD

Hanover park – Illinois – USA

ISO-9001:2015 certified

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The collaboration, alignment, processes, and data sharing across multiple internal and external stakeholders – such as carriers, manufacturers, governments, health systems, and others – integrating multiple control towers and implementing technology and service-enabled responsiveness has occurred over the last several months on a level never witnessed previously.

What the Cold Chain Control Tower Looks Like The cold chain control tower has evolved to support COVID-19 vaccine monitoring and broader cold chain applications. It provides real-time visibility for the end-to-end supply chain, analytics for decision support, responsiveness needed to prevent product waste, and efficiency to achieve economies of scale while supporting patient- and customer-centricity, cost reduction, and sustainability efforts.

Real-time Visibility The cold chain control tower is powered by real-time information enabled by GSMenabled IoT data loggers that continuously send shipment information to a cloud-based software platform, on product location, security, and quality. Notifications and alerts are automatically pushed to parties as they happen to improve transparency and enable proactive action to be taken to prevent 94 INTERNATIONAL PHARMACEUTICAL INDUSTRY

product waste. Through integrations, data is pushed to internal and external parties, improving communication and alignment, in addition to patient- and customer-centricity.

Analytics Historically, supply chains have had only limited access to shipment data, knowing what has happened only at the end of a shipment, if at all. Many manufacturers do not have access to all shipment data, especially where manual upload from data loggers is needed. Real-time visibility and monitoring have made previous, retrospective processes and minimal data logging irrelevant. We can answer, 'What is happening right now?' so parties can act on critical information fast. Moving forward, supply chain stakeholders can leverage gathered business intelligence and data to predictively answer, 'What will happen?'

This data will enable businesses to execute planning in an entirely new way.

For instance, if a product is shipped using a particular lane or packaging type during a specific time of year, prescriptive analytics can help people understand scenarios that are likely to occur. Information like this is crucial to prevent product waste and stock outages, as well as determine the best route or packaging material. These technologies include the integration of multiple systems

and connect the physical and digital supply chains together.

Responsiveness The availability of real-time data poses a challenge in how to effectively respond to information as it happens. Today’s cold chain control tower solutions provide a greater level of responsiveness, working with manufacturers, logistics partners, and sites to proactively respond to escalations and alerts in real time in order to avert product loss. In addition to alerts that are triggered from the data delivered to the cloud software platform from the IoT devices to notify recipients of temperature deviations and other escalations that require review, solution providers are enhancing these notifications workflows with 24/7 monitoring and response services.

These alerts notify carriers and sites directly if an escalation occurs and is not resolved so that product integrity isn't compromised.

This level of responsiveness leads to product waste reduction throughout the supply chain.

Automation In addition to real-time visibility, a key benefit of an integrated cold chain control tower, is the data and workflow automation that becomes possible. This includes automatic shipment creation, where an enterprise resource planning system can automatically trigger a shipment Summer 2021 Volume 13 Issue 2

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identification number and a customer email communication confirming their order and the order status. Automation also includes an exception-based quality release process, which can significantly reduce the number of hours manufacturers spend on retrieving and reviewing shipment data. By connecting IoT technology to cloud-enabled platforms in real-time, companies can define custom escalations and workflows in addition to communications that are triggered from the connected systems to deliver critical information to the right people promptly.

Processes surrounding these new workflows will help companies save costs and conserve resources, while increasing their supply chain agility and responsiveness.

Measuring Success Companies leveraging the data provided by cold chain visibility technology can now quantify their improvements following their target goals and success metrics. For highvolume, small parcel shipments, some of these goals include avoiding temperature deviations as volume complexity increases and achieving end-to-end visibility of products, while achieving economies of scale and total cost reductions.

Beyond the vaccine supply chain, delivery performance metrics can include insights into 96 INTERNATIONAL PHARMACEUTICAL INDUSTRY

deliveries such as countries and destination; product and packaging such as boxes and doses; deviations, such as alarms and alarm ratios, based on defined escalations; average time to delivery, per carrier; and product quality statuses such as average release time and successful delivery rate.

Many companies are shifting to reusable IoT data loggers and packaging to support their corporate sustainability objectives and are placing an added focus on measuring the quantities of boxes and loggers that are used and returned.

Together, these data and metrics, which can be shared with suppliers and carriers, are providing critical insights into supply chain performance and can be used to drive continuous improvements throughout.

Transformation Timeline COVID-19 vaccine distribution efforts have demonstrated the benefits of digital transformation throughout the cold chain.

Global applications of control tower technology are becoming evident, including for direct-to-patient delivery models, clinical trials, and last-mile delivery.

The vaccine distribution efforts have also demonstrated the power of supply chain

collaboration and pushing data to the right people, at the right time. This has enabled process optimisation that has impacted human health.

Pharmaceutical manufacturers and logistics providers can reap the benefits of digital transformation throughout their primary and secondary distribution models.

While each rollout may vary, the initial phase generally includes achieving real-time visibility, intervention capabilities as they are needed, and fewer shipment rejections, while achieving a zero-touch release process, gaining trends analyses for decision support, and cost savings throughout.

The second phase may include achieving process streamlining and optimisation, predictive and prescriptive insights for whatif analyses and decision support, supplier analytics, data benchmarking, and reduced insurance premiums. The final phase may include process automation, network control, inventory reductions, and complete visibility, through the last mile.

Together, these transformations were previously not possible prior to the pandemic. Moving ahead, control tower technology is likely to fundamentally change the way the industry operates.

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Conclusion The COVID-19 vaccine supply chain has demonstrated the value of data, automation, end-to-end visibility, and collaboration in ensuring quality and compliance, efficiency, waste reduction, and sustainability. Under normal circumstances, the new pharmaceutical distribution models currently in place would have taken years to accomplish, rather than only a few months.

As companies consider their supply chains beyond the pandemic, they are increasingly focusing on achieving greater resiliency, agility, and responsiveness. Some companies have already begun making their supply chains more complex by recruiting www.ipimediaworld.com

additional suppliers. Others have started to integrate their supply chains more closely with their suppliers, logistics providers, and customers.

Resilience is required to meet trackand-trace, monitoring, regulatory, and licensing requirements. To achieve the level of sophistication needed, manufacturers are beginning to strategise and implement smarter solutions to deliver full digitisation to every part of their supply chain operations.

One thing we can likely agree on is that the pharmaceutical cold chain as we once knew it will likely never be the same again.

Gisli Herjolfsson Mr. Herjolfsson is Cofounder and CEO of Controlant, a technology company that is pioneering the development of next-generation supply chain visibility solutions for digitally connected pharmaceutical cold chains. He has driven the vision, culture, and growth of the company for the last 14 years.

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The Role of Hostile Vehicle Mitigation in a Protective Security Strategy Hostile Vehicle Mitigation (HVM) has a critical role to play in protecting property and, more importantly, people. Here, Richard Winstanley at Bft Automation explores how pharmaceutical firms can incorporate HVM into their security plans…

Mitigating against the threat of a cyber attack is a major focus of security strategies for today’s pharmaceutical businesses, and rightly so. But the threat of physical attack sadly also remains a concern, especially for organisations working in any particularly sensitive or controversial areas within pharmacology or those who produce products in high demand or short supply.

While terror attacks do not dominate news headlines the way they did in the years leading up to the Coronavirus pandemic, the threat of terrorism in the UK remains serious and, sadly, hostile vehicles have become increasingly relied on by those seeking to launch an attack.

For pharmaceutical firms that have identified the threat of a terror attack or another serious crime, HVM is a key consideration when planning how to defend their property and, crucially, the people who work there.

Assessing the Risk HVM comes into play as part of an integrated protective approach to security and, as such, should fit within the overarching priorities of a wider security strategy.

With this in mind, the process of introducing HVM should begin with a risk assessment of the threat to every individual site operated by a company. For multinational operations, the nature of the risk is likely to differ according to location – for instance, a UK pharmaceutical firm with a manufacturing plant in a politically volatile country will have different needs to an organisation that is primarily based out of just one country.

Regardless of the size of a firm’s operations, some examples of what this risk assessment should include are: 98 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Retractable bollards allow access for emergency vehicles

1.

2.

3.

4.

Identifying all vehicle access points to every site This includes looking at any weak areas that may be particularly vulnerable to a hostile vehicle attack.

An investigation of the local environment The surrounding roads are likely to have an impact on the threat of HVM. For example, consider how traffic currently flows around the location and whether this can be reviewed to keep vehicles further away from the property.

Also, bear in mind that a hostile vehicle incident usually begins on public roads with little or no warning, but vehicles approaching the property will need an area of ‘run up’ in order to build up speed. If this is denied by the very nature of the road layout, the risk to life and of damage caused to property is reduced.

Parking considerations If the introduction of security barriers is likely to impact on access to parking facilities, there are measures that can be taken to address this, such as the use of automated bollards that can be lowered to allow entry.

The immediacy of any threat In circumstances where a company is made aware of a clear and present threat to their premises, it’s possible to hire temporary security products while you search for a permanent solution.

These are just a few examples and a thorough risk assessment should not be limited to the above. Manufacturers and installers of HVM solutions are well

placed to support security teams in the risk assessment process if needed.

Finding the Right Solution There are numerous HVM solutions which range from automatic bollards to static columns and barriers.

If rammed by a truck travelling at speed, conventional barriers may slow the vehicle, but could still be displaced beyond the point of impact and may still strike at anyone in the immediate vicinity. The simplest and most versatile solution is to install anti-terrorism bollards, either fixed or retractable, which offer protection without impeding on the movement of pedestrians and cyclists.

Certified HVM bollards are not only designed and tested to withstand impact from vehicles of various sizes and design but also at different speed ranges, for example 30mph or 50mph.

The Centre for the Protection of National Infrastructure (CPNI) is a useful starting point to find out more about the range of bollard options available. A Governmentbacked resource for physical and personnel protective security, the website includes details on HVM barriers, with an interactive online list of vehicle security barriers that meet all regulations and standards, including crash test certification: www.cpni.gov.uk As well as ensuring that any HVM solution meets all regulations, it’s useful to look at the following factors: Summer 2021 Volume 13 Issue 2

Logistics & Supply Chain Management • • •

Does the solution provide protection from vehicles large and small?

What’s the potential approach speed attainable?

A site risk assessment to assess how the HVM solution would work in practice is advisable.

Fixed vs Automated One of the first decisions to make before the introduction of bollards is whether it’s more appropriate to use a fixed or automated option.

Fixed bollards present a clear, visible deterrent to potential attackers. For example, for thieves looking to steal goods from a pharmaceutical manufacturing plant, simply having an obvious barrier like security bollards can be enough to make them think twice and choose an easier target.

Plus, if there is a known threat to the property, those who work there are likely to feel safer with an obvious deterrent in place.

However, while barriers are designed to keep hostile vehicles out, security teams must also consider the need to allow emergency vehicles in, should the need arise. This is where a solution such as retractable bollards will come into play, with vehicle access control built in for emergency and operational vehicles. This solution offers flexibility to accommodate temporary changes in traffic flow.

Furthermore, automated bollards can be integrated into a building management system, where a security team would be able to control them in the same way they would a CCTV system and an alarm network.

Integrating bollard controls into a building management system would enable a security team to control them remotely and to deploy them rapidly (referred to as EFO – emergency

A security guard is able to use an emergency fast operation setting to activate bollards

fast operation). For example, if a security guard at a pharmaceutical factory were to notice an unexpected vehicle approaching, they could use an emergency fast operation setting to activate bollards in less than three seconds, as opposed to a more typical time of between five and 10 seconds.

Practical Points Installers and manufacturers can advise on practical details that will influence what make of bollard a security team decides to use. A few points to consider are:

A Note on Aesthetics Fixed bollards are naturally an ideal option for protecting a street entrance or in any other environment where a building is accessed on foot or by bike, as there is no need to lower them to allow vehicles to enter.

But for some companies, the idea of visible bollards may be off-putting. It might be that there’s no need for a visible deterrent and the visual impact of bollards might jar with the immediate setting. Or a company is keen for members of staff to feel safe without a reminder of any threat to security.

In such cases, there are anti-terrorism products available that can preserve the appearance of the surrounding environment while providing safety – by appearing as a row of planters, as just one example.

•

•

•

The height and visibility of the bollards, particularly in low light conditions.

The ground conditions at a site, as permanent bollards require foundations into the ground.

The placement and spacing of bollards in relation to pedestrian movement.

As well as the detailed information provided by the CPNI, another useful resource is the Perimeter Security Suppliers Association (PSSA), which has a dedicated hub of information purely on HVM: https:// hvmhub.com/about/ Whether it’s mitigating against an act of terror targeted at the pharmacological sector or any other serious crimes where a hostile vehicle could be used, HVM can play a significant role in protecting property and, most importantly, those who work in or visit any pharmaceutical firm.

Richard Winstanley Richard Winstanley is the UK Sales Manager at Bft Automation, a manufacturer and distributor of entrance automation technology that controls access for people and vehicles in commercial, residential and urban environments.

Email: info@bft.co.uk Bollards stop a lorry approaching at speed www.ipimediaworld.com

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Pharma Airports – A Key to Global Success?

Setting the Scene The past year has proven that the medical world is at the forefront of human innovation. The pharmaceutical industry is our weapon of choice against the COVID-19 pandemic, whilst simultaneously tackling other diseases, treatments and cures, thus extending our life expectancy age.

Whilst the developments and manufacturing of recent biopharmaceuticals are groundbreaking, the logistics behind it are often overlooked and ignored at board level, resulting in an undervaluation of a well-organised supply chain. With an ever-growing global population and rising demand in biopharmaceuticals, the logistics chain is coming under enormous pressure to fulfil. Add temperature requirements and fast delivery to the mix and you have a recipe for disaster.

One area where multiple pharmaceutical logistic stakeholders meet is an airport, where pharmaceuticals are shipped to all four corners of the world. At the airport stage we have multiple handover points between shippers, trucking companies, freight forwarders, ground handlers and airlines. All these handover points are critical stages where temperature excursions, damages, paperwork issues etc. can happen. Not all airports have the right type of infrastructure, transparency and standardised ways of working to handle time- and temperature-sensitive shipments. So it is vital to select the right partners.

The aviation industry is slowly adopting and listening to the pharmaceutical shippers, but it has to do it as a community, and not on an individual basis.

The Brussels Airport Story Over the past ten years, the cargo area of Brussels Airport (BRUcargo) has been investing and innovating into the pharmaceutical airport eco-system, not only because of its ideal central location within Europe and its proximity to major pharmaceutical manufacturers, but because of its clear company strategy on enhancing 100 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the pharmaceutical supply chain at its airport premises.

The first gap that needed to be filled over a decade ago, was the clear understanding of the pharmaceutical manufacturer’s logistics requirements. Apart from networking and building relationships at pharma conferences, the airport kickstarted a forum that invited pharmaceutical manufacturers in one room, the BRUcargo pharma shipper forum, a bi-annual event. In this setup, the airport was able to identify key weaknesses, listen to essential desires and identify where it could add innovation.

A key topic that was evident in the BRUcargo pharma shipper forums was the lack of pharma standardisation in the air cargo industry. In collaboration with IATA and other stakeholders, a taskforce was launched to compile and create an encompassing programme that trains and validates pharmaceutical stakeholders in the air cargo industry, better known as IATA CEIV. BRUcargo currently holds the largest concentration of CEIV certified companies globally and has implemented this programme into its strategy.

Besides working on the CEIV programme, investments have been made in modernising our infrastructure. Currently, over 30,000m2 of pharma-dedicated cold storage facilities are in operation at BRUcargo, with the vast majority being brand new. A pooled fleet of airside pharma transporters has been added to a list of airside investments, along with a clear focus on digital innovation through the BRUcloud. Digital solutions such as the Pharma Acceptance Dashboard allows stakeholders to visualise pharmaceutical shipment performance at the airport and intervene when issues arise, making transparency a key priority.

These recent innovations and investments gave us a pole position during the COVID-19 pandemic, making Brussels Airport the first airport to distribute the COVID-19 vaccines globally, with millions of doses currently flying out on a weekly basis. And it doesn’t stop there: an investment has been made in an enhanced digital solution to fully map and visualise the journey of each pharma shipment at BRUcargo. This will

enable stakeholders to react before issues arise and add full transparency towards the pharmaceutical manufacturer.

Collaboration – Key to Optimising Pharmaceutical Logistics by Air Apart from local airport initiatives into the pharmaceutical supply chain, international collaboration within the air cargo industry is key to further optimise pharmaceutical logistics. One organisation in particular, Pharma.Aero, is pushing to achieve global pharmaceutical excellence in the air cargo industry by launching select projects.

One of these recurring projects, for instance, is the corridor mappings, where a route is mapped between airport A and airport B, thus identifying weaknesses and strengths. This enables all parties involved in the project to improve or strengthen their pharmaceutical supply chain and make that specific lane robust and reliable for the move of sensitive pharmaceutics.

After all, building relationships with customers and airport stakeholders will evidently lead to fruitful partnerships. Just like Jeff Bezos once said, the same applies to the air cargo industry; “we innovate by starting with the customer and working backwards. That becomes the touchstone for how we invent”.

Samuel Speltdoorn Samuel Speltdoorn is a Cargo Business Development Manager at Brussels Airport. His main responsibilities are the future developments of the pharmaceutical segment, one of the key strategic focus areas at Brussels Airport.

Samuel is actively involved in various Pharma.Aero initiatives, such as the airport to airport corridor validations, Project Sunrays and Project CEIV 2.0.

Samuel chairs the BRUcure COVID-19 vaccine taskforce and moderates the Air Cargo Belgium pharma steering group.

Summer 2021 Volume 13 Issue 2

Real-time supply chain visibility is driving the industry forward Cold Chain as a Service® Integrated technology and services for your end-to-end supply chain and vaccine distribution.

Real-time temperature monitoring

Product location traceability

24/7 monitoring and response services

Mission-critical analytics & insights

Validated for all lanes—air, road, sea. Pay as you go.

Controlant is pioneering the development of next-generation visibility solutions for digitally connected global supply chains that keep products safe. Our Cold Chain as a Service® Digital Visibility Platform solution consists of reusable Internet of Things (IoT) data loggers that send mission-critical quality data and insights in real-time to a proprietary, cloud-enabled software platform, and costreducing operational services..

Businesses are leveraging the improved visibility to collaborate with stakeholders, support their corporate sustainability objectives, and achieve supply chain improvements leading to a substantial return on investment.

For more information, visit controlant.com contact@controlant.com www.ipimediaworld.com Follow us on Twitter @controlant

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News Zolgensma Shows Promise in Presymptomatic SMA Patients Novartis’ gene therapy Zolgensma has shown benefit for presymptomatic spinal muscular atrophy (SMA) patients, according to new data presented at the annual European Academy for Neurology (EAN) virtual congress.

The Phase III SPR1NT study was designed to evaluate the safety and efficacy of a one-time intravenous (IV) infusion of Zolgensma (onasemnogene abeparvovec) in presymptomatic children with a genetic diagnosis of SMA, and two or three copies of SMN2.

All patients in the study achieved the primary endpoint of sitting independently for 30 seconds, with 79% of participants achieving this milestone with the World Health Organization (WHO) window of normal development.

In addition, 100% of patients met the secondary endpoint of survival without ventilatory support of any kind at 14 months of age, versus 26% of patients in the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort.

On top of that, 79% of patients could stand independently, 64% could walk independently and 100% of patients were independent of nutritional and respiratory support for the duration of the study.

In the second Phase III STR1VE-EU trial, Zolgensma demonstrated improvements in motor function and most patients achieved motor milestones not observed in the natural history of SMA Type 1.

Source: Inhouse Staff Writer Pfizer’s JAK Inhibitor Xeljanz Shows Benefit in COVID-19 Pneumonia Pfizer’s JAK inhibitor Xeljanz reduced the risk of severe outcomes in hospitalised adult patients with COVID-19 pneumonia who were not on ventilation, according to new study data.

The STOP-COVID trial was conduction by Pfizer and the ARO from the Hospital Israelita Albert Einstein in Sao Paolo, Brazil, which was also the trial coordinating centre.

Patients were randomised to receive either Xeljanz (tofacitinib) 10mg twice daily plus standard of care (SoC) or placebo twice daily plus SoC for up to 14 days or until hospital discharge.

The trial demonstrated a reduced cumulative incidence of death or respiratory failure through day 28 with Xeljanz (18.1%) compared to placebo (29.9%).

In addition, death from any cause occurred in 2.8% of Xeljanz-treated patients compared to 5.5% in the placebo group.

102 INTERNATIONAL PHARMACEUTICAL INDUSTRY

In the study, serious adverse groups occurred in 14.1% of patients in the Xeljanz group and 12% in the placebo group.

Protocol-specified adverse events of special interest included deep vein thrombosis, acute myocardial infarction, ventricular tachycardia, and myocarditis in the Xeljanz group.

Source: Inhouse Staff Writer Government Announces £36m AI Research Funding Boost for NHS The UK government has announced a hefty £36bn funding boost for artificial intelligence (AI) research technologies in a bid to help the ‘NHS transform quality of care’.

The funding will go toward the winners of the second wave of the NHS AI Lab’s AI in Health and Care Award.

The 38 projects with NHSX and Accelerated Access Collaborative (AAC) backing include projects aiming to improve care and the speed of diagnoses for conditions including lung cancer, heart attacks and mental health difficulties.

The AI award package also includes funding to support the research, development and testing of early phase, promising ideas which could be used in the NHS in the future.

Since the first round of the AI in Health and Care Award in September, where £50m was given to 42 AI projects, over 17,000 stroke patients and over 25,000 patients with diabetes have benefitted from the new technologies.

“AI has the potential to completely revolutionise every part of how we approach healthcare, from how we diagnose diseases and the speed at which our doctors and nurses deliver treatments to how we support people’s mental health,” said Health and Social Care Secretary Matt Hancock.

The AI in Health and Care Award is set to distribute £140m over three years – the next round of applications will open in late June.

It is managed by the AAC in partnership with NHSX and the National Institute for Health Research (NIHR).

Source: Inhouse Staff Writer Study Demonstrates Safety and Efficacy of Co-administering COVID-19 and Flu Vaccines A study conducted by Novavax has found that co-administering a COVID-19 vaccine with a flu vaccine is safe and effective, with the efficacy of both jabs appearing to be preserved.

The study, co-authored by Seqirus, was conducted as part of a Phase III clinical trial of Novavax’s COVID-19 vaccine NVX-CoV2373 in the UK.

The co-administration sub-study enrolled a total of 431 volunteers, all of whom had received a flu vaccine provided by Seqirus.

Following this, approximately half of the volunteers also received NVX-CoV2373, while the rest received a placebo jab.

The study results, published on the pre-print server medRxiv, suggest that the efficacy of both the flu vaccine and the COVID-19 vaccine appeared to be preserved, with no additional safety concerns appearing with co-administration.

In a statement, Seqirus said certain limitations of the study include the small patient population, the lack of formal pre-specified non-inferiority statistical assessment of immunogenicity and the lack of randomisation in recruiting the sub-study, immunogenicity and reactogenicity cohorts.

Source: Inhouse Staff Writer Novartis’ Radioligand Therapy Granted US Breakthrough Therapy Designation Swiss pharma company Novartis has scored a Breakthrough Therapy Designation (BTD) from the US Food and Drug Administration for its investigational radioligand therapy Lu-PSMA-617.

The BTD has been granted for Lu-PSMA-617 as a potential treatment for metastatic castration-resistant prostate cancer (mCRPC).

It was granted based on data from the Phase III VISION study, evaluating LuPSMA-617 plus standard of care (SoC), versus SoC alone, in patients with progressive PSMA-positive mCRPC. In this study, Lu-PSMA-617 demonstrated a significant improvement in overall survival (OS) and radiographic progression-free survival (PFS) for men with progressive PSMA-positive mCRPC. In the Lu-PSMA-617 arm, there was an estimated 38% reduction in the risk of death compared to the best SoC only arm.

Patients receiving Lu-PSMA-617 also demonstrated a statistically significant 60% risk reduction for radiographic PFS or death compared to best SoC only arm.

However, there was a higher rate of drugrelated treatment emergent adverse events reported in the Lu-PSMA-617 treatment arm – 85.3% – compared to SoC alone – 28.8%.

Novartis also has two additional studies with Lu-PSMA-617 in earlier lines of treatment for metastatic prostate cancer ongoing.

One of these studies is investigating the potential clinical utility of the radioligand therapy in the mCRPC pre-taxane treatment setting, while the second study is evaluating Lu-PSMA-617 in the metastatic hormonesensitive setting.

Source: Inhouse Staff Writer Summer 2021 Volume 13 Issue 2

News Biogen, Eisai’s Alzheimer’s Drug Aducanumab Makes History with US Approval The US Food and Drug Administration (FDA) has granted Biogen and Eisai’s aducanumab and accelerated approval, making it the first new treatment approved for Alzheimer's disease in over a decade.

The accelerated approval for aducanumab – now known as Aduhelm – is supported by three studies of the drug involving 3,482 patients.

In these studies, patients receiving the treatment had significant dose- and timedependent reduction of amyloid beta plaque, whereas patients in the control arm experienced no reduction.

Although the exact causes of Alzheimer’s are not fully known, it is characterised by changes in the brain, including amyloid plaques and neurofibrillary or tau tangles.

“This historic moment is the culmination of more than a decade of groundbreaking research in the complex field of Alzheimer’s disease. We believe this first-in-class medicine will transform the treatment of people living with Alzheimer’s disease and spark continuous innovation in the years to come,” said Michel Vounatsos, chief executive officer at Biogen.

Source: Inhouse Staff Writer FDA Approves Alkermes’ Lybalvi for Schizophrenia and Bipolar I Disorder Alkermes’ oral atypical antipsychotic drug Lybalvi has received approval from the US Food and Drug Administration for the treatment of schizophrenia and bipolar I disorder.

Lybalvi (olanzapine and samidorphan) has been authorised as maintenance monotherapy of adults with schizophrenia or bipolar I disorder, for the acute treatment of manic or mixed episodes and as monotherapy or an adjunct to lithium or valproate.

In clinical trials, Lybalvi demonstrated antipsychotic efficacy, safety and tolerability, including statistically significantly less weight gain than olanzapine in patients with schizophrenia in the ENLIGHTEN-2 study.

In the ENLIGHTEN-1 study, which evaluated the antipsychotic efficacy, safety and tolerability of Lybalvi compared to placebo, the drug demonstrated statistically significant reductions from baseline in Positive and Negative Syndrome Scale (PANSS) scores compared to placebo.

"Lybalvi represents an important new treatment option for adults with schizophrenia or bipolar I disorder, their clinicians and caregivers, and reflects Alkermes' commitment to developing new therapies that support patient-centred www.ipimediaworld.com

care," said Richard Pops, chairman and chief executive officer at Alkermes.

Source: Inhouse Staff Writer Takeda’s Dengue Vaccine Bags Positive Longterm Efficacy Results Japanese pharma company Takeda has announced that its dengue vaccine candidate TAK-003 demonstrated continued protection through three years after vaccination, regardless of previous exposure to the disease.

The Phase III TIDES trial enrolled over 20,000 healthy children and adolescents aged four to 16 years in dengue-endemic countries in Latin America and Asia.

The safety and efficacy results from the 36-month follow-up exploratory analysis of TIDES found that, through three years after vaccination, TAK-003 demonstrated overall vaccine efficacy of 62% against virologically confirmed dengue (VCD).

The jab also demonstrated 83.6% vaccine efficacy (VE) against hospitalised dengue, with 86% VE in seropositive individuals 77.1% VE in seronegative individuals.

“Our dengue vaccine candidate continued to provide protection against dengue throughout three years, and was especially robust in preventing hospitalisation,” said Derek Wallace, VP, dengue global programme leader at Takeda.

"These results reinforce my confidence that TAK-003 can help address the significant global burden of dengue,” he added.

Source: Inhouse Staff Writer Almac Creating up to 100 New Jobs in Londonderry Northern Ireland pharmaceutical firm Almac is planning to establish a project management and software engineering facility in Londonderry. It could create up to 100 jobs in the city over the next three years.

Alan Armstrong, its chief executive, said the business was continuing to grow.

"We are fortunate to be able to locate our employees anywhere we choose, offering greater flexibility and access to our various range of services," he said.

"Given the skills pipeline coming from Ulster University at Magee and Coleraine, combined with the excellent choice of workspace available in the Derry/ Londonderry area, we have decided to explore this region as our next Almac location."

The firm said that experience of the pharmaceutical industry was not an essential requirement for the roles as onthe-job training would be provided.

Source: Almac Group

Medicine Supply Chains into NI post-Brexit a 'High Risk Area' The chief pharmaceutical officer has warned that without mitigation, the supply of medicines and medical devices into Northern Ireland would be considered a "very high-risk area".

Cathy Harrison was speaking to the NI health committee about the implications of Brexit and the NI Protocol for the pharmaceutical industry.

The industry currently has a 12-month grace period to prepare.

Until this year, there has been no separate supply chain for NI. It was treated as part of the UK supply chain.

Ms Harrison told the committee an "enormous amount of work" was being done in the area. "Without us taking action, and without a very proactive approach being taken, and if we did nothing at all until the end of this year, then there would be a high level of risk and it would be considered a very high-risk area," she said.

Many medical devices, and about £600m of medicines, are brought into Northern Ireland every year, with around 98% coming from Great Britain.

Source: Inhouse Staff Writer UK Government ‘Concerned’ over Elliott Management’s Plans for GSK The UK government has concerns over activist investor Elliott Management’s plans for GlaxoSmithKline (GSK) after the hedge fund acquired a ‘significant’ stake in the British drugmaker last month.

Britain’s Secretary of State for Business, Energy and Industrial Strategy is believed to have asked government officials to back GSK’s chief executive officer Emma Walmsley, in particular her ongoing restructuring of the company.

There is speculation over what exactly Elliott Management’s plans for the company could entail – with potential scenarios being the sale of GSK or its pharmaceuticals or vaccines divisions.

Walmsley has come under increasing pressure to improve GSK’s performance ahead of a planned split of the company’s consumer health and pharma divisions, which is 'well underway'.

Following the planned completion of the separation, due in mid-2022, GSK will remain solely focused on pharmaceuticals and vaccine products.

Source: In-House Staff Writer INTERNATIONAL PHARMACEUTICAL INDUSTRY 103

Advertisers Index

Page 51

Aurena Laboratories

Page 31

Avantor Inc

Page 77 & 78

Bausch + Ströbel

Page 37

Biopharma Group

Page 100

Brussels Airport

Page 5

BSP Pharmaceuticals S.p.A

Page 101 Controlant Page 14 & 15

Foodmek

Page 23

FUJIFILM Wako Chemicals U.S.A. Corporation

Page 7

Kahle Automation

Page 47

Kraiburg TPE

Page 93

Krautz Temax

IBC

LTS Lohmann Therapie-Systeme AG

BC

Natoli Engineering Company

Page 69

Nemera

Page 35

Nipro Europe Group Companies

Page 61

Omya AG

Page 43

Owen Mumford Ltd

Page 91

Peak Scientific Instruments

Page 63

Pharma Publications

Page 3 R.G.C.C Page 86–90

Schott

IFC

SPL Scientific Protein Laboratories

Page 95

Thermo King

Page 11

Topra

Page 29 & 39

Valsteam ADCA

Page 83

Woolcool

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

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Summer 2021 Volume 13 Issue 2

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

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Summer 2021 Volume 13 Issue 2

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